Solid Tumors in RASopathies: Insights from a Large Monocentric Cohort and Systematic Review of the Literature

Solid Tumors in RASopathies: Insights from a Large Monocentric Cohort and Systematic Review of the Literature | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Solid Tumors in RASopathies: Insights from a Large Monocentric Cohort and Systematic Review of the Literature Chiara Leoni, Valentina Trevisan, Germana Viscogliosi, Denise Pires Marafon, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7979959/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background. The RAS-MAPK signaling cascade mediates cellular responses to external stimuli, regulating key processes involved in tumorigenesis, including growth, differentiation, and survival. RASopathies are a group of neurodevelopmental disorders caused by dysregulated RAS-MAPK activity and characterized by overlapping clinical presentations. While individuals with Neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Costello syndrome (CS), and CBL-associated syndrome have an established increased cancer risk, data regarding tumor predisposition in other RASopathies remain anecdotal. Methods. We investigated the prevalence and spectrum of solid tumors in NS and related RASopathies, excluding NF1, through a retrospective analysis of a large monocentric cohort. These findings were complemented with data from an updated systematic review of the literature. Results. This study reports the largest single-center cohort of individuals with RASopathies monitored for solid tumors to date (n = 138; age range, 2–48 years). Solid neoplasms were identified in 10.8% of individuals with NS, 47.8% with CS, and 7.3% with cardiofaciocutaneous syndrome (CFCS). Multiple tumors occurred in 41.6% of CS patients, and one CFCS patient developed relapsing neoplasia. Tumor onset occurred at a younger age compared with the general population, particularly in individuals with CS. Distinct tumor spectra were observed among NS patients carrying PTPN11 and SOS1 pathogenic variants. Moreover, we identified a subset of potentially high-risk variants in RASopathy-causing genes that may confer increased susceptibility to solid tumors. Conclusion. Our findings provide clinically relevant insights into tumor predisposition across RASopathies and underscore the need for tailored surveillance strategies and evidence-based clinical guidelines for each disorder. Biological sciences/Genetics/Cancer genomics Health sciences/Medical research/Genetics research RASopathies cancer predisposition high-risk variants tailored surveillance Costello syndrome Noonan syndrome Cardiofaciocutaneous syndrome Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Hyperactive RAS-MAPK signaling is recognized as one of the most important events contributing to oncogenesis ( 1 ). Its key role in cancer has been established in a broad range of pediatric and adult malignancies, where mutations in proto-oncogenes such as PTPN11, KRAS, NRAS, HRAS , and BRAF , and in the NF1 , LZTR1 and CBL tumor suppressor genes represent the most common events ( 1 ). While these oncogenic mutations have generally a somatic origin, constitutive variants in the same genes are responsible for a group of multisystemic developmental disorders, the RASopathies, that are characterized by variable predisposition to malignancies ( 2 , 3 ). RASopathies exhibit overlapping phenotypes and multi-organ involvement with major shared features including growth failure, distinctive facial gestalt, variable degree of developmental delay/intellectual disability, a wide range of congenital and evolutive cardiac defects, ectodermal manifestations, and muscular-skeletal involvement ( 3 – 5 ). This family of “systemic”, constitutional disorders include Noonan syndrome (NS, MIM #PS163950),, Costello syndrome (CS, MIM #218040), cardiofaciocutaneous syndrome (CFCS, MIM #PS115150), Mazzanti syndrome (MIM #PS607721), Noonan syndrome with multiple lentigines (NSML, MIM #151100), neurofibromatosis type 1 (NF1, MIM #162200), Legius syndrome (LS, MIM #611431), CBL-associated syndrome (CBLS, MIM #613563), and the recently recognized MAPK1 -associated syndrome (MIM #619087) and ERF Noonan-like syndrome ( 3 , 6 ). Given the critical role of RAS signaling in oncogenesis, RASopathies account for the most prevalent cancer predisposition syndromes ( 7 – 9 ). Several studies have documented a significantly increased, though variable, incidence of both myeloproliferative disorders and solid tumors in affected individuals( 10 – 13 ), with an overall 10.5-fold increased cancer risk compared to age-matched populations ( 12 ). Cancer predisposition is well-established in NF1, CS, CBLS, and certain forms of NS linked to specific PTPN11 pathogenic variants (PVs), whereas both hematologic malignancies and solid tumors are less frequently reported in NS caused by pathogenic variants (PVs) in other disease-causing genes, as well as other RASopathies( 8 , 14 – 16 )Solid tumors are observed in NF1, CS, and NS, more rarely. In NF1, most tumors involve the nervous system, including gliomas, benign neurofibromas, and malignant peripheral sheath tumors ( 14 ). In NS, the most frequent solid tumors reported are low- to high-grade gliomas, neuroblastoma (NB), rhabdomyosarcoma (RMS), and giant cell lesions primarily affecting the jaw( 9 , 12 , 15 – 24 ). Whereas in CS, NB, RMS, and transitional cell carcinoma of the bladder ( 25 , 26 ). Reports of solid tumors in CFCS and other RASopathies remain anecdotal ( 23 , 27 – 29 ). Given the heterogeneity in risk of tumor development, providing appropriate care is challenging. Surveillance protocols vary according to countries, professional’s opinions, and type of genetic alteration ( 8 , 9 ). The association of a mildly increased cancer risk with specific genetic variants has raised awareness, suggesting the need for a personalized screening to promptly guide accurate diagnostic and therapeutic approaches ( 9 , 25 , 30 ). We analyzed the prevalence of solid tumors in a large monocentric cohort of individuals with RASopathies and compared these findings with available data from retrospective analyses obtained through a systematic literature review of RASopathy-related cancer-cases. For each syndrome, we evaluated tumor prevalence and types. Moreover, we compared the molecular spectrum of germline variants in RASopathy genes in patients with and without co-occurrence of cancer to identify variants putatively associated with cancer predisposition. METHODS Patients’ cohort Individuals with RASopathies, except NF1, followed at the Center for Rare Diseases and Birth Defects, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, from November 2007 to July 2023, were recruited for this study. Enrollment criteria included a clinical and molecular diagnosis of RASopathy. Written informed consent was obtained from the participating patients, caregivers, or legal guardians. The study protocol was approved by the local Ethics Committee (Protocol Number: 0033977/21, ID 4218). Data collection and investigations conducted Data were both retrospectively and prospectively collected and stored in a dedicated database. All medical records were reviewed, and a questionnaire was administered during the last clinical evaluation to assess: i) personal history of solid tumor; ii) family history of cancer in first- and second-degree relatives in patients who had developed tumors; iii) risk factors associated to solid tumors development. Information on age of tumor onset, type of tumor (macroscopic diagnosis and histological characterization) and treatment was also collected. Each enrolled patient was examined by experienced pediatricians and geneticists and underwent active surveillance according to the available guidelines ( 8 , 31 – 33 ), expert consensus for solid tumor development in RASopathies( 9 , 34 , 35 ) and tailored surveillance protocol according to local institutional expert consensus ( Supplementary Materials Methodology ). ( 26 ) Germline genetic testing Germline genetic assessment was performed on DNA extracted from peripheral blood samples using parallel sequencing using customized gene panels upon clinical suspicion of RASopathy. MLPA was performed to exclude structural variants involving RASopathy tumor suppressor genes. Sequencing data processing, and variant call and annotation were performed using an in-house implemented bioinformatics pipeline. The gene panels were designed and updated during the timeframe of the study according to ClinGen guidelines and literature ( see Supplementary Materials Methodology ). Systematic literature review Bibliographic search was performed following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and checklist for reporting this review. In detail, a comprehensive literature review was done separately for NS, CFCS, and CS. The literature search was performed between May 2023 and December 2023 on PubMed using specific queries (see Supplementary Materials Methodology ). We evaluated articles obtained from the latest systematic reviews on cancer in RASopathies to identify any potentially overlooked papers during the PubMed search. Abstracts were read to evaluate the relevance to the research topic. For publications, the following year limits were applied: CS (1977–2023), NS (2001–2023), NSML (2002–2023), and CFCS (2006–2023). Results considered eligible for evaluation were finally exported into two datasets (Microsoft Excel files) to identify duplicates and unique records ( Supplementary Fig. 1 ). Data extraction and synthesis of the systematic literature review Data extraction and analysis were performed by four researchers assigned to the two different main topics (NS and CFC/CS). Working in pairs (CR and SM, VT and GV, respectively), four reviewers independently completed the assessment for each topic and two senior reviewers reconciled disagreements (CL and SM). The following information was extracted from the included articles: first author, publication year, publication source, study type, number of patients with NS, CS or CFCS, number of patients with cancer, type of cancer, and cancer histology (when available). Moreover, when provided, the following additional patient data were gathered: gender, vital status, age at diagnosis and eventually death, diagnostic method, genetic testing, and identified variants, when available. Variant assessment Variants reported in the relevant literature to be causative of NS, CFCS and CS were collected. Variants in the included articles were classified using the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) Standards and Guidelines for the Interpretation of Sequence Variants and the ClinGen RASopathy Expert Panel Consensus Methods for Variant Interpretation ( 36 ). In addition, the germline and somatic mutational spectra for PTPN11, SOS1 , and HRAS genes were extracted from the literature and from the public COSMIC database ( https://cancer.sanger.ac.uk/cosmic ). For prevalence calculations, familial cases were counted as a single patient. Statistical analyses Qualitative variables were presented as absolute frequencies and percentages, and proportions were compared using either the Chi-square or Fisher’s exact test, as appropriate. Quantitative variables were described as medians with interquartile ranges (first and third quartiles). All statistical tests were two-sided, with a p-value < 0.05 considered statistically significant. The analyses were conducted using Stata software (StataCorp. 2023. Stata Statistical Software: Release 18. College Station, TX: StataCorp LP). RESULTS Molecular spectrum and occurrence of solid tumors in a large monocentric cohort of individuals with RASopathies A cohort comprising 138 individuals with RASopathies (Fondazione Policlinico Gemelli cohort, FPG cohort, hereafter) was included in the study. Details on the gene involved, age at diagnosis, method used for tumor diagnosis, histology, treatment, and outcome are reported in Table 1 , while demographic data about FPG cohort are detailed in Table 2 . In the NS cohort, which also includes NS-like phenotypes associated with pathogenic variants in SHOC2 and ERF , ~ 10.8% of patients (8/74) were diagnosed with a solid tumor (Table 1 – 2 and Fig. 1 A-C ) . As expected, PTPN11 was the most frequently implicated gene. Notably, in one family (NS#1 and NS#4), the mother and her daughter, who shared the p.Glu139Asp amino acid substitution, developed solid tumors. In detail, the daughter had a retropharyngeal ganglioneuroblastoma and a low-grade pilocytic astrocytoma, while a melanoma in situ was diagnosed in the mother. In this cohort, a statistically significant association between p.Glu139Asp and solid tumors ( p < 0.02;) was observed. CNS tumor progression was observed in two separate patients affected with a low grade pilocytic astrocytoma and an unclassified astrocytic tumor, respectively (Table 1 ). In one case the relapse occurred following chemotherapy treatment, and in the other one during active surveillance (NS#1 and NS#2). See Table 1 for all tumors detected in the NS cohort. Approximately 47.8% (11/23) of the CS patients in the FPG cohort developed a benign or malignant neoplasia. Notably, five subjects showed the occurrence of multiple primary tumors in different districts (CS#1, CS#2, CS#4, CS#5, CS#6) (Fig. 2 A-B, Table 1 – 2 and Supplementary Table 2 ). Bladder tumors [7 urothelial carcinoma (G1-2) and 7 papillary urothelial neoplasia of low malignant potential-PUNLMP] were the most frequent neoplasia observed in the CS cohort. Spontaneous regression of adrenal neuroblastoma was recorded for CS#2. CS#5 presented with multiple neoplasms involving the bladder (PUNLMP), and breast (relapse of intraductal breast neoplasia detected after 11 years from surgical intervention). All patients were alive at last follow-up, except for CS#5 who passed unexpectedly due to sudden cardiac death at the age of 28 years. Finally, solid tumors were reported in ~ 7.3% of CFCS cases in the FPG cohort (3/41 (Table 1 – 2 ). Two patients carried a pathogenic variant in BRAF and developed relapsing neoplastic lesions. The first subject, a male who harbored the p.Thr470Pro amino acid substitution, developed giant cell lesions of the jaw at 8 years of age, which recurred at 14 years of age. The second patient, a female carrier of the p.Lys499Asn change, developed a pylocytic astrocytoma at 13 years of age, which recurred twice, at 15 and 18 years of age. The third individual, carrier of the p.Tyr130Cys variant in the MAP2K1 gene, developed multiple peripheral nerve sheath tumors at 17 years of age ( Table 1 – 2 , Suppl. Table 3) . Literature review and comparison with data from our monocentric cohort A systematic literature review was performed on patients with NS, CS, NSML, CBLS, LS, and CFCS with co-occurrence of solid tumors. Noonan syndrome The cohort including NS and clinically related phenotypes comprised 3,002 published cases with a confirmed molecular diagnosis. Among them, 79 developed a solid neoplasia (~ 2.6%) ( PTPN11 , n = 45; SOS1 , n = 21; RIT1 , n = 3; KRAS , n = 2; NRAS , n = 2; CBL , n = 1; LZTR1 , n = 1; MRAS , n = 1; RAF1 , n = 1; RRAS2 , n = 1; SHOC2 , n = 1) ( Supplementary Table 4) . In most cases, the prevalence of specific PVs does not differ substantially between the two NS populations (with vs . without tumors). For example, SHP2 substitutions at codon 308 (p.Asn308Asp or p.Asn308Ser), representing the most common defects in the entire NS population, occurred in ~ 28.9% of PTPN11 -positive NS patients who developed cancer and in ~ 29.4% of subjects with no cancer history (Fig. 3 A-B). In contrast, a subset of PVs appeared to confer an increased risk of cancer development, such as SHP2 p.Asp106Ala and p.Ser502Thr ( p < 0.02 and p < 0.05, respectively; SOS1 p.Glu846Lys ( p < 0.05), and NRAS p.Gly12Arg ( p < 0.002) ( Supplementary Table 5 ). The association of these changes with increased cancer susceptibility was confirmed combining prevalence in literature data and in data from our monocentric cohort (Fig. 1 A-C). Moreover, a few additional SHP2 residues showed a trend to be associated with cancer in NS patients (Gly 60 , Ile 282 , Phe 285 ; p = 0.11, p = 0.10, and p = 0.12, respectively). Of note, these candidate tumor susceptibility changes did not overlap with those occurring as constitutional variants in PTPN11 -related NS/JMML (16,51), nor with those arising as somatic mutations in cancer (COSMIC database) ( Supplementary Table 5 ). CNS tumors were the most frequent type of neoplasia in both literature and the FPG cohort (Fig. 1 A-C). Notably, the observed spectrum of PTPN11 -related tumors differed from that associated with pathogenic variants in SOS1 (Fig. 1 B); importantly, no central nervous system tumors were observed in individuals with SOS1 variants. Solid tumors identified in other less frequent NS and NS-like gene are reported in Supplementary Table 10 . Costello syndrome Among the 49 CS individuals reported with a solid tumor in the literature, only 27 had a confirmed molecular diagnosis ( Supplementary Table 6 ). The p.Gly12Ser amino acid substitution was the most common variant (~ 66.7%, 18/27), followed by p.Gly12Ala (~ 25.9%, 7/27), and p.Gly12Cys (~ 7.4%, 2/27). Among 33 cases reported in literature with RMS, only 19 were confirmed by genetic diagnosis (n = 11 embryonal RMS; n = 2 spindle RMS; n = 6 unspecified). Nevertheless, RMS was the most frequent tumor (~ 70%), followed by bladder neoplasia (~ 14%), NB (~ 11%), and gastric neoplasia (~ 3%). Other tumors, such as vestibular schwannoma, fibrosarcoma and hepatoblastoma, have only been reported in anecdotal cases without a confirmed molecular diagnosis. Integrating data from the literature with our monocentric cohort identified p.Gly12Ala as a high-risk variant ( p = 0.016; two-tailed Fisher’s Exact test) ( Supplementary Table 7 ). Conversely, we did not find an association between the p.Gly13Cys variant and tumor development ( p = 0.06). The overall distribution of variants in CS patients, stratified by the presence or absence of tumors, is illustrated in Fig. 4 . Cardiofaciocutaneous syndrome To our knowledge, solid tumors have been reported in five cases of CFCS (Supplementary Table 8). Among three patients who developed multiple giant cell lesions of the jaw, two carried a BRAF variant resulting in the p.Gln257Arg substitution, while the other one carried a missense change in MAP2K1 (p.Tyr130Cys) ( 24 ). The fourth patient heterozygous for the same MAP2K1 variant, developed metastatic hepatoblastoma ( 28 ). Finally, chondroblastoma, a benign but locally aggressive neoplasm, was diagnosed in a patient without a confirmed molecular diagnosis. Due to the limited number of patients with solid tumors, no cancer susceptibility variants were identified in individuals with CFCS or other RASopathies, except for NSML ( Supplementary Table 9) . DISCUSSION The RAS-MAPK pathway plays a central role in tumorigenesis, with somatic mutations in the three members of the RAS family of proto-oncogenes involved in nearly one-third of human cancers ( 42 ). The occurrence of cancer in RASopathies has been supported by numerous case reports and some case series in the literature ( 7 , 15 ). Kratz and colleagues reported a cumulative cancer incidence of ~ 4% in NS and ~ 15% in CS within the first two decades of life, with a peak during adolescence ( 7 ). These data were retrospectively collected from a cohort of 1,941 individuals with a clinical diagnosis of RASopathy ( 7 ). Considering the very low number of tumors reported in the CFCS group, a precise estimate of the tumor risk in this condition could not be established. More recently, the same research group investigated the presence of malignancies in a cohort of 735 RASopathy patients. In that study, molecularly confirmed cases collected from 25 laboratories performing genetic screening in Germany were matched with those of the German Childhood Cancer Registry (GCCR), showing that the overall cancer risk during childhood was 10.5-fold higher compared to the general population ( 8 ). More specifically, individuals with NS and CS showed an 8-fold and 42.4-fold increased risk, respectively, compared to age-matched populations ( 8 ). No tumors were documented in 53 subjects of the cohort with CFCS as well as in a single CBLS patient. The study provided an enormous contribution in stimulating awareness on performing cancer-screening programs in patients with RASopathies. At the same time, it was limited by the exclusion of subjects older than 14 years and the lack of information from patient medical records, since the case-identifying resource was a childhood cancer registry. In addition, patients carrying variants in RASopathy-genes identified after 2015, such as RIT1 , RRAS2 , MRAS , MAPK1 , YWHAZ , LZTR1 , were not included. A recent review by the same authors confirmed that children with RASopathies, except those with LS, face a significantly increased cancer risk compared to the age-matched general population, and provided updated consensus recommendations for cancer surveillance in these categories ( 9 , 30 ). Considering the limited data available in the literature, a major goal of the present study was to define the prevalence and spectrum of solid tumors in a large and unselected monocentric cohort of RASopathy patients (FPG cohort), not including NF1 and LS cases. We also aimed to compare the findings of the FPG cohort with those reported in literature, by providing a systematic review. In the FPG cohort, at least one solid tumor was documented in 10.8% of individuals with NS, 47.8% of those with CS, and 7.3% of those with CFCS, significantly higher compared to those previously reported ( 7 , 12 , 30 ). The discrepancy might stem from both center-dependent ( e.g. , advancements in diagnostic techniques) and center-independent ( e.g. , implementation of surveillance protocols) factors. Consistently with previous findings, we observed an early age at tumor diagnosis in patients with RASopathies, with a median age of 13.5 years in CS and 19 years in NS ( 7 ), likely due to the intrinsic oncogenic potential of hyperactive RAS-MAPK signaling. Interestingly, in the FPG cohort 34.7% and 5.4% of patients with CS and NS, respectively, developed at least one tumor in the first two decades of life; the number of CFCS patients with cancer was too low to draw any definitive conclusion. Regarding the tumor spectrum in RASopathies reported in literature, PTPN11 -positive NS cases have primarily been linked to malignant tumors of the nervous system (including DNET, glioma, and NB) whereas SOS1 -positive NS cases have been predominantly associated with RMS and giant cell lesions of the jaw ( 7 , 8 , 12 , 15 ). We documented low-grade gliomas as the most common malignancy observed in the PTPN11- NS sub-cohort (9.3%), while no cases of DNET were documented, and only one patient developed NB (i.e. retropharyngeal ganglioneuroblastoma). Only 1 patient with PTPN11- NS developed a high-grade glioma requiring chemotherapy (temozolomide) and radiotherapy (54 Gray). The most updated recommendations concerning tumor screening for NS proposed by Perrino et al., do not suggest specific screening for non-hematologic malignancy ( 9 ). However, given the high prevalence of low CNS tumors reported to date also in our FPG cohort, a personalized screening protocol may be discussed in future dedicated consensus. In the SOS1 -related NS sub-cohort, RMS was not reported. A giant cell lesion of the jaw was diagnosed in one NS patient carrying a RIT1 variant (p.Ala57Gly). Notably, to the best of our knowledge, this is the first case in literature reported with this association. Literature data support the evidence that in CS, RMS is the most common tumor of childhood with average onset age of six years of age, followed by NB and bladder neoplasia from childhood through adolescence ( 7 , 11 , 25 , 26 ). While most malignancies are diagnosed during childhood, transitional cell carcinoma of the bladder has been reported exclusively in adulthood ( 43 ). In the CS FPG cohort, asymptomatic bladder tumors were the most common neoplasia, followed by breast intraductal papillomas, NB, and RMS. ( 43 , 44 ) PUNLMP and low-grade bladder carcinoma have been diagnosed in individuals as young as 10 and 12 years, respectively, underscores the importance of active surveillance ( 26 , 30 ) in line with recent recommendations ( 4 , 9 , 25 ). Although somatic mutations in HRAS are well-established as playing a pivotal role in embryonal RMS ( 7 , 25 ), the latter being the most reported CS-associated neoplasia in literature, in the FPG cohort RMS was detected only in one patient (vaginal embryonal RMS). Despite the differences in the prevalence of tumors between CS-FPG cohort and literature, the existing surveillance protocols for these solid tumors remain strongly recommended, with clinical evaluation and routine ultrasound monitoring being the gold standard investigation ( 25 , 30 , 33 ). Of note, six patients in the CS FPG cohort developed more than one tumor. Among them, two patients experienced at least one relapse (1 intraductal breast papillary neoplasia, 1 urothelial carcinoma) and one patient experienced spontaneous regression of NB (Table 1 ). Another major finding of this study was the identification of candidate variants that might be associated with a higher risk of solid tumor development. These include p.Asp106Ala and p.Ser502Thr in PTPN11 , p.Glu846Lys in SOS1 , p.Gly12Arg in NRAS , and p.Gly12Ala in HRAS . Interestingly, PTPN11 variants associated with solid tumors differ from the mutational hotspots identified in PTPN11 -related NS/JMML (16,18,51) or in sporadic cancer (COSMIC database). Noteworthy, we identified a mother and daughter carrying the p.Glu139Asp variant in PTPN11 , who developed in situ melanoma and multiple tumors of the central nervous system, respectively. Among RAS gene variants, the p.Gly12Arg substitution in NRAS is a well-established oncogenic change that frequently occurs as a somatic event in cancer, particularly in hematologic malignancies (COSMIC database). Based on available data, among the six amino acid substitutions resulting from single-base changes at this codon, p.Gly12Arg has the lowest prevalence in cancer (Gly12Asp > Gly12Ser > Gly12Cys > Gly12Ala > Gly12Val > Gly12Arg), suggesting a relatively mild oncogenic potential. However, when p.Gly12Arg occurs as a constitutional variant, it confers an increased cancer susceptibility ( 25 ). Similarly, the p.Gly12Ala substitution in HRAS represents the rarest variant found in sporadic cancer among missense substitutions at this codon (Gly12Val > Gly12Ser > Gly12Asp > Gly12Cys > Gly12Arg > Gly12Ala). Notably, our single patient carrying this variant has not developed any solid tumor to date (last follow up performed at age 12 years). Finally, no systematic studies investigated the prevalence of cancer in CFCS, with only anecdotal reports documenting cases with hepatoblastoma, granuloma, chondroblastoma, and neoplasia of the jaw ( 9 , 23 , 27 ). In our CFCS cohort, solid tumors were observed in 7.3% of individuals, including relapsing lesions in one patient and one with recurrent tumor. Despite the distinctive skin manifestations of this condition, no cases of melanoma or skin tumors have been reported either in the literature or in CFCS-FPG cohort. ( 35 ) Study limitations The main limitation of the present study stem in the monocentric nature of the study which implies bias due to personalized and Institutional screening protocols not often applied on large scale. Furthermore, the limited number of tumor and rarity of the condition did not allow to establish a statistically significant genotype-phenotype correlation in the FPG cohort alone. CONCLUSIONS Based on a large, molecularly confirmed monocentric cohort of individuals with RASopathies monitored for solid tumors, this study provides important insights into tumor risk and surveillance. Comparison with literature data highlights a strong association between NS and low-grade CNS tumors, as well as between CS and bladder tumors. Differences in tumor prevalence may reflect variability in surveillance protocols at our institution. Consistent with previous reports, we observed an earlier onset of solid neoplasms in NS and CS compared with the general population. While the number of reported tumors in the FPG cohort alone was insufficient to establish definitive genotype-phenotype correlations, integration with literature data allowed identification of potential high-risk variants associated with increased tumor susceptibility. Notably, we report for the first time a giant cell lesion of the jaw in a NS patient carrying a RIT1 variant, and relapsing neoplasia in two CFCS individuals. These findings emphasize the need for multicentric studies to generate real-world data on tumor prevalence in RASopathies, which could inform personalized surveillance strategies to optimize cancer prevention while minimizing unnecessary interventions. Moreover, molecular characterization of tumors may be critical for understanding the interaction between constitutional RASopathy variants and secondary somatic alterations in cancer development. Declarations Acknowledgements We kindly thank the patients and their families. In particular, we thank the family Associations ‘Angeli Noonan’, ‘Associazione Italiana Sindrome Costello CFC’, and ‘Associazione Italiana Sindrome di Noonan RASopatie’. Authors’ contribution GV and VT designed the experimental plan, contributed to data collection, and drafted the manuscript. CR, CB, LP, and EF acquired data, patients’ consent and contributed to the manuscript draft. RO, VG, and DR supervised patients care and revised the manuscript. DPM and RP performed the statistical analysis and contributed to draft the manuscript. MG, AR, MT, and GZ contributed data analysis and critically revised the manuscript. CL and SM conceived the study, contributed to data collection, and critically revised the final draft of the manuscript. All authors approved the final version of the manuscript. Ethics approval and consent to participate The study was performed in accordance with the Declaration of Helsinki and the procedures employed were reviewed and approved by the local appropriate institutional Ethics Committee (ID 4218 Prot. n. 0000628/239). Consent for publication was obtained simultaneously with study consent. Data availability The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interest The authors declare no conflict of interest. Funding information This work was supported, in part, by grants from AIRC (IG 2 8768 to MT), Ministero della Salute (Current Research Funds and 5x1000, to MT; GR-2019-12371203, to CL). ADDITIONAL INFORMATION Supplementary information The online version contains supplementary material available upon request. Correspondence and requests for materials should be addressed to Chiara Leoni. References Ney GM, McKay L, Koschmann C, Mody R, Li Q. The Emerging Role of Ras Pathway Signaling in Pediatric Cancer. Cancer Res [Internet]. 2020 Dec 1 [cited 2024 Mar 13];80(23):5155–63. Available from: https://pubmed.ncbi.nlm.nih.gov/32907837/ Tartaglia M, Aoki Y, Gelb BD. The molecular genetics of RASopathies: An update on novel disease genes and new disorders. Vol. 190, American Journal of Medical Genetics, Part C: Seminars in Medical Genetics. John Wiley and Sons Inc; 2022. p. 425–39. Zenker M. Clinical overview on RASopathies. 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Tables Table 1 A summary of molecular characteristics, histopathologic diagnoses, and management strategies of RASopathy individuals with solid tumors belonging to the FPG cohort. PT ID Sex Genetic variant Age at diagnosis Diagnostic method Diagnosis Histologic exam WHO class Treatment Solid tumor Status* NOONAN SYNDROME NS 1 F PTPN11: c.417G>C, p.Glu139Asp 1 MRI + Bio Neuroblastoma Retropharyngeal ganglioneuroblastoma surgery Remission 11 MRI + Bio CNS tumors Low grade pylocytic astrocytoma surveillance Progression 30 MRI + Bio CNS tumors High grade pylocytic astrocytoma radiotherapy + chemotherapy Stability NS 2 F PTPN11: c.1507G>A, p.Gly503Arg 13 MRI CNS tumors Unclassified astrocytic neoplasia° °histol. performed at 20 yrs of age surveillance Progression NS 3 F PTPN11: c.1510A>G, p.Met504Val 21 MRI CNS tumors Not assessed surveillance NA NS 4 F PTPN11: c.417G>C, p.Glu139Asp 33 Bio Melanoma Melanoma in situ excision with safe margins Remission NS 5 M PTPN11 : c.923A>G, p.Asn308Ser 34 MRI PNS tumors Not assessed surveillance NA 34 MRI CNS tumors Not assessed surveillance NA NS 6 F PTPN11 : c.844A>G, Ile282Val 43 Derm + Bio Melanoma Melanoma in situ excision with safe margins Remission NS 7 M SOS1 : c.1642A>C, p.Ser548Arg 17 Derm + Bio Melanoma Melanoma in situ excision with safe margins Remission NS 8 M RIT1 : c.170C>G, p.Ala57Gly 9 Bio Giant cell lesions Giant cell lesions of the jaw surgery Relapse 10 Bio Giant cell lesions Giant cell lesions of the jaw surgery Relapse 11 Bio Giant cell lesions Giant cell lesions of the jaw surgery Stability COSTELLO SYNDROME (CS) CS 1 F HRAS : c.34G>A, p.Gly12Ser 0,5 EGDS + Bio Gastric neoplasia Gastric leyomyoma endoscopic surgery Remission 12 Cys + Bio Bladder neoplasia Urothelial carcinoma G1/LG (Ta) (ISUP-WHO 2004) endoscopic resection Remission 22 Cys + Bio Bladder neoplasia Urothelial carcinoma G1-2/LG (Ta) (ISUP-WHO 2004) endoscopic resection Remission 17 Cys + Bio Bladder neoplasia PUNLMP endoscopic resection Remission CS 2 M HRAS : c.34G>A, p.Gly12Ser 1 MRI Neuroblastoma Not assessed surveillance Spontaneous Regression 25 Cys + Bio Bladder neoplasia Urothelial carcinoma G1/LG (Ta) (ISUP-WHO 2004) endoscopic resection Remission 31 Cys + Bio Bladder neoplasia Urothelial carcinoma G1/LG (Ta) (ISUP-WHO 2004) endoscopic resection Remission CS 3 F HRAS : c.34G>A, p.Gly12Ser 7 Derm + Bio Skin tumor Melanocytoma surgical excsion Remission CS 4 M HRAS : c.34G>A, p.Gly12Ser 10 Derm + Bio Melanoma Melanoma in situ excision with safe margins Remission 17 Cys + Bio Bladder neoplasia PUNLMP endoscopic resection Remission 19 Cys + Bio Bladder neoplasia Urothelial carcinoma G2/LG (Ta) (ISUP-WHO 2004) endoscopic resection Remission CS 5 F HRAS : c.34G>A, p.Gly12Ser 17 Breast MRI + Bio Breast neoplasia Intraductal breast papillary neoplasia surgical excision Progression 28 MRI Breast neoplasia Intraductal breast papillary neoplasia deceased NA 23 Cys + Bio Bladder neoplasia PUNLMP endoscopic resection Remission CS 6 F HRAS : c.34G>A, p.Gly12Ser 14 Cys + Bio Bladder neoplasia PUNLMP endoscopic resection Remission 17 Breast MRI + Bio Breast neoplasia Intraductal breast papillary neoplasia surveillance Stability CS 7 M HRAS : c.34G>A, p.Gly12Ser 19 Cys + Bio Bladder neoplasia PUNLMP endoscopic resection Remission CS 8 F HRAS : c.34G>A, p.Gly12Ser 22 Cys + Bio Bladder neoplasia Urothelial carcinoma G1/LG (Ta) (ISUP-WHO 2004) endoscopic resection Remission CS 9 F HRAS : c.34G>A, p.Gly12Ser 30 Cys + Bio Bladder neoplasia PUNLMP endoscopic resection Remission 34 Cys + Bio Bladder neoplasia Urothelial carcinoma G1-2/LG (Ta) (ISUP-WHO 2004) endoscopic resection Remission CS 10 F HRAS : c.34G>A, p.Gly12Ser 33 Cys + Bio Bladder neoplasia PUNLMP endoscopic resection Remission 38 Cys + Bio Bladder neoplasia Urothelial carcinoma G1-2/LG (Ta) (ISUP-WHO 2004) endoscopic resection Relapse 40 Cys + Bio Bladder neoplasia Urothelial carcinoma HG(Tx) TURB Stability CS 11 F HRAS : c.34G>A, p.Gly12Ser 1 Cys + Vaginoscopy + Bio Rhabdomyosarcoma RMS Chemotherapy, surgery, brachytherapy Remission CARDIO-FACIO-CUTANEOUS SYNDROME (CFCS) CFCS 1 M BRAF : c.1408A>C, p.Thr470Pro 8 Orthopan + MRI Giant cell lesion Giant cell lesions of the jaw Surgery Relapse 14 Surgery + Bio Giant cell lesion Giant cell lesions of the jaw Surgery Stability CFCS 2 F BRAF : c.1497A>C, p.Lys499Asn 13 MRI + Bio CNS tumors Pilocytic astrocytoma grade I WHO Partial surgical excision Progression 15 MRI + Bio CNS tumors not assessed radiotherapy + chemotherapy Progression 18 MRI CNS tumors Ganglioglioma grade I WHO complete surgical resection Remission CFCS 3 M MAP2K1 : c.389A>G, p.Tyr130Cys 17 MRI PNS tumors Not assessed MRI NA Table 1 Legend: Identifier (ID); Costello syndrome (CS); Cardiofaciocutaneous syndrome (CFCS); Central Nervous System (CNS); Cystoscopy (Cys); Biopsy (Bio); Dermoscopy (Derm); Esophagogastroduodenoscopy (EGDS); International Society of Urological Pathology (ISUP); Magnetic Resonance Imaging (MRI); Noonan syndrome (NS); Not Available (NA); Orthopanoramic (Orthopan); Papillary Urothelial Neoplasm of Low Malignant Potential (PUNLMP); Peripheral Nerve Sheath (PNS); Progression (Progr); Relapse (Rel); Transurethral Resection of Bladder Tumor (TURB); World Health Organization (WHO). *Solid tumor Status definition: Progression : worsening of cancer associated to its growing and spreading to other tissues. Relapse : The return of solid tumor or the signs and symptoms of cancer after a period of improvement. Remission : A decrease in or disappearance of signs and symptoms of cancer. Spontaneous regression : partial or complete disappearance of primary tumor tissue or its metastases in patients who have never been treated. Stability: the term “stability” or “stable disease" refers to a situation where cancer is neither decreasing nor increasing in extent or severity. Table 2. Demographic characterization of the FPG cohort. NS/NS-like disorders ( n=74 ) Gender Age range (median) Median age of onset Earliest diagnosis at y Gene Total n° of patients Patients with tumors 39 F; 35 M 3 - 46 y (15.5 y) 19 y 1 PTPN11* 43 (24 F; 19 M) 6 (4F; 2M) 0 KRAS 5 (3 F; 2 M) 0 0 RAF1 2 (2 F) 0 9 RIT1 4 (2 F; 2 M) 1 (M) 0 LZTR1 3 (1 F; 2M) 0 0 ERF 1 (1 M) 0 0 SHOC2 5 (3 F; 2 M) 0 17 SOS1 10 (4F; 6M) 1 (F) 0 SOS2 1 (1M) 0 CS ( n=23 ) 16 F; 7 M 2 - 40 y (20 y) 14 y 0.5 HRAS Gly12Ser 19 (15F; 4M) 11 (8F; 3M) 0 Gly12Ala 1 (M) 0 0 Gly13Cys 2 (1F; 1M) 0 0 Gln22Lys 1 (1M) 0 CFCS ( n=41 ) 26 F; 15 M 2-39 y (16 y) 13 y 8 BRAF 31 (8F; 11M) 2 (1F; 1M) 0 KRAS 1 (F) 0 17 MAP2K1 7 (4F; 3M) 1 (M) 0 YWHAZ 1 (F) 0 0 MAP2K2 1 (M) 0 Table 2 Legend : CS: Costello Syndrome; CFCS: Cardiofaciocutaneous Syndrome; F: Female; M: Male; n°: number; NS: Noonan Syndome; Y: years. *Amino acid substitutions affecting twelve residues of SHP2, the protein encoded by PTPN11 (Asn58, Gly60, Asp61, Tyr62, Asp106, Glu139, Ile282, Phe285, Asn308, Ser502, Gly503, and Met504), two residues of SOS1 (Arg552 and Glu846), and one NRAS residue (Gly12) occurred in at least two independent NS patients who manifested cancer. Additional Declarations There is no duality of interest Supplementary Files SupplementarymMethodologySolidtumorsinRASopathies.docx Supplementary Materials Methodology SupplementarymaterialsFigure1.docx Supplementary Materials Figure 1 SuppmaterialsTablesSOLIDtumoursinRASopathiesEND.docx Supplementary Materials Tables Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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10:10:44","extension":"html","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":172042,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7979959/v1/ef4769429c9fae13e9c08086.html"},{"id":96302347,"identity":"0c738143-4cf3-4151-ae45-43cd18fd0b05","added_by":"auto","created_at":"2025-11-19 14:41:19","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":710961,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTumor prevalence in \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003ePTPN11\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e and \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eSOS1 \u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003erelated Noonan syndrome patients: combined data from the FPG cohort and from the literature\u003c/strong\u003e. Tumor prevalence in subjects carrying pathogenic \u003cem\u003ePTPN11\u003c/em\u003e(\u003cstrong\u003eA\u003c/strong\u003e) and \u003cem\u003eSOS1\u003c/em\u003e (\u003cstrong\u003eB\u003c/strong\u003e) variants. Tumor prevalence in Noonan syndrome (NS) and NS-like phenotypes (\u003cstrong\u003eC\u003c/strong\u003e) in FPG cohort and literature.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7979959/v1/bf025869c70a772d7a1fbdc8.png"},{"id":96302348,"identity":"35593e7b-6e80-4528-96fb-b5ba580e44e3","added_by":"auto","created_at":"2025-11-19 14:41:19","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":709309,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTumor prevalence in Costello syndrome\u003c/strong\u003e. Tumor prevalence in the FPG cohort (\u003cstrong\u003eA\u003c/strong\u003e), literature (\u003cstrong\u003eB\u003c/strong\u003e), and overall prevalence (both FPG cohort and literature) (\u003cstrong\u003eC\u003c/strong\u003e).\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7979959/v1/ac15046533c06bccff21b515.png"},{"id":96364487,"identity":"567d31d0-0994-4010-a742-68fc73dee8ee","added_by":"auto","created_at":"2025-11-20 10:09:20","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":56270,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA: \u003c/strong\u003eRelative prevalence (%) of \u003cem\u003ePTPN11\u003c/em\u003e variants between subjects with NS diagnosed with (blue bar \u003cem\u003eN=88\u003c/em\u003e) or without (yellow bar \u003cem\u003eN=3068\u003c/em\u003e) a solid tumour, considering the present cohort and previously published reports. \u003cstrong\u003eB:\u003c/strong\u003e Relative prevalence (%) of \u003cem\u003eSOS1\u003c/em\u003evariants between subjects with NS diagnosed with (blue bar \u003cem\u003eN=22\u003c/em\u003e) or without (yellow bar \u003cem\u003eN=422\u003c/em\u003e) a solid tumour, considering the present cohort and previously published reports. *statistically significant variant from two-tailed Fisher’s exact test or Chi-square test.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7979959/v1/6730e0718a8ec785132a13a9.png"},{"id":96302355,"identity":"ff1052bb-f30a-4a1b-8cb1-02de3340ba3d","added_by":"auto","created_at":"2025-11-19 14:41:19","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":71855,"visible":true,"origin":"","legend":"\u003cp\u003eRelative prevalence (%) of \u003cem\u003eHRAS\u003c/em\u003e variants in subjects with CS diagnosed with (outer circle, \u003cem\u003en=38\u003c/em\u003e) or without (inner circle, \u003cem\u003en=319\u003c/em\u003e) a solid tumour, considering the present cohort and previously published reports (Astiazaran-symonds et al. BR J Cancer. 2023 jun;128(11):2089-2096) *statistically significant variant from two-tailed fisher’s exact test or chi-square test (c).\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7979959/v1/e411dc2b44740f2f45108536.png"},{"id":99817436,"identity":"9d63aa47-ba81-4e23-a7e9-cee55860813b","added_by":"auto","created_at":"2026-01-08 14:49:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2858250,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7979959/v1/1b90d7f4-b069-4c12-aef2-87ce94a4d21e.pdf"},{"id":96302345,"identity":"bf825e30-bb33-4be0-ac31-f923a7c52726","added_by":"auto","created_at":"2025-11-19 14:41:19","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":46971,"visible":true,"origin":"","legend":"Supplementary Materials Methodology","description":"","filename":"SupplementarymMethodologySolidtumorsinRASopathies.docx","url":"https://assets-eu.researchsquare.com/files/rs-7979959/v1/d28806be7e10a3a70823c7cb.docx"},{"id":96365286,"identity":"842e8e0f-64b1-485f-9dd6-e581f87f679d","added_by":"auto","created_at":"2025-11-20 10:10:14","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":41629,"visible":true,"origin":"","legend":"Supplementary Materials Figure 1","description":"","filename":"SupplementarymaterialsFigure1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7979959/v1/a6e0b368115f2d5f122e24de.docx"},{"id":96302352,"identity":"543fd39f-281f-4b7e-acad-68ea9f71b310","added_by":"auto","created_at":"2025-11-19 14:41:19","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":50023,"visible":true,"origin":"","legend":"Supplementary Materials Tables","description":"","filename":"SuppmaterialsTablesSOLIDtumoursinRASopathiesEND.docx","url":"https://assets-eu.researchsquare.com/files/rs-7979959/v1/15dfb305cc4e353198ebed0d.docx"}],"financialInterests":"There is no duality of interest","formattedTitle":"Solid Tumors in RASopathies: Insights from a Large Monocentric Cohort and Systematic Review of the Literature","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eHyperactive RAS-MAPK signaling is recognized as one of the most important events contributing to oncogenesis (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Its key role in cancer has been established in a broad range of pediatric and adult malignancies, where mutations in proto-oncogenes such as \u003cem\u003ePTPN11, KRAS, NRAS, HRAS\u003c/em\u003e, and \u003cem\u003eBRAF\u003c/em\u003e, and in the \u003cem\u003eNF1\u003c/em\u003e, \u003cem\u003eLZTR1\u003c/em\u003e and \u003cem\u003eCBL\u003c/em\u003e tumor suppressor genes represent the most common events (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). While these oncogenic mutations have generally a somatic origin, constitutive variants in the same genes are responsible for a group of multisystemic developmental disorders, the RASopathies, that are characterized by variable predisposition to malignancies (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eRASopathies exhibit overlapping phenotypes and multi-organ involvement with major shared features including growth failure, distinctive facial gestalt, variable degree of developmental delay/intellectual disability, a wide range of congenital and evolutive cardiac defects, ectodermal manifestations, and muscular-skeletal involvement (\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). This family of \u0026ldquo;systemic\u0026rdquo;, constitutional disorders include Noonan syndrome (NS, MIM #PS163950),, Costello syndrome (CS, MIM #218040), cardiofaciocutaneous syndrome (CFCS, MIM #PS115150), Mazzanti syndrome (MIM #PS607721), Noonan syndrome with multiple lentigines (NSML, MIM #151100), neurofibromatosis type 1 (NF1, MIM #162200), Legius syndrome (LS, MIM #611431), CBL-associated syndrome (CBLS, MIM #613563), and the recently recognized \u003cem\u003eMAPK1\u003c/em\u003e-associated syndrome (MIM #619087) and ERF Noonan-like syndrome (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eGiven the critical role of RAS signaling in oncogenesis, RASopathies account for the most prevalent cancer predisposition syndromes (\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Several studies have documented a significantly increased, though variable, incidence of both myeloproliferative disorders and solid tumors in affected individuals(\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), with an overall 10.5-fold increased cancer risk compared to age-matched populations (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Cancer predisposition is well-established in NF1, CS, CBLS, and certain forms of NS linked to specific \u003cem\u003ePTPN11\u003c/em\u003e pathogenic variants (PVs), whereas both hematologic malignancies and solid tumors are less frequently reported in NS caused by pathogenic variants (PVs) in other disease-causing genes, as well as other RASopathies(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)Solid tumors are observed in NF1, CS, and NS, more rarely. In NF1, most tumors involve the nervous system, including gliomas, benign neurofibromas, and malignant peripheral sheath tumors (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). In NS, the most frequent solid tumors reported are low- to high-grade gliomas, neuroblastoma (NB), rhabdomyosarcoma (RMS), and giant cell lesions primarily affecting the jaw(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan additionalcitationids=\"CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Whereas in CS, NB, RMS, and transitional cell carcinoma of the bladder (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Reports of solid tumors in CFCS and other RASopathies remain anecdotal (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eGiven the heterogeneity in risk of tumor development, providing appropriate care is challenging. Surveillance protocols vary according to countries, professional\u0026rsquo;s opinions, and type of genetic alteration (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). The association of a mildly increased cancer risk with specific genetic variants has raised awareness, suggesting the need for a personalized screening to promptly guide accurate diagnostic and therapeutic approaches (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eWe analyzed the prevalence of solid tumors in a large monocentric cohort of individuals with RASopathies and compared these findings with available data from retrospective analyses obtained through a systematic literature review of RASopathy-related cancer-cases. For each syndrome, we evaluated tumor prevalence and types. Moreover, we compared the molecular spectrum of germline variants in RASopathy genes in patients with and without co-occurrence of cancer to identify variants putatively associated with cancer predisposition.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003ePatients\u0026rsquo; cohort\u003c/h2\u003e\u003cp\u003e Individuals with RASopathies, except NF1, followed at the Center for Rare Diseases and Birth Defects, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, from November 2007 to July 2023, were recruited for this study. Enrollment criteria included a clinical and molecular diagnosis of RASopathy. Written informed consent was obtained from the participating patients, caregivers, or legal guardians. The study protocol was approved by the local Ethics Committee (Protocol Number: 0033977/21, ID 4218).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eData collection and investigations conducted\u003c/h3\u003e\n\u003cp\u003eData were both retrospectively and prospectively collected and stored in a dedicated database. All medical records were reviewed, and a questionnaire was administered during the last clinical evaluation to assess: i) personal history of solid tumor; ii) family history of cancer in first- and second-degree relatives in patients who had developed tumors; iii) risk factors associated to solid tumors development. Information on age of tumor onset, type of tumor (macroscopic diagnosis and histological characterization) and treatment was also collected. Each enrolled patient was examined by experienced pediatricians and geneticists and underwent active surveillance according to the available guidelines (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e), expert consensus for solid tumor development in RASopathies(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e) and tailored surveillance protocol according to local institutional expert consensus (\u003cb\u003eSupplementary Materials Methodology\u003c/b\u003e). (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/p\u003e\n\u003ch3\u003eGermline genetic testing\u003c/h3\u003e\n\u003cp\u003eGermline genetic assessment was performed on DNA extracted from peripheral blood samples using parallel sequencing using customized gene panels upon clinical suspicion of RASopathy. MLPA was performed to exclude structural variants involving RASopathy tumor suppressor genes. Sequencing data processing, and variant call and annotation were performed using an in-house implemented bioinformatics pipeline. The gene panels were designed and updated during the timeframe of the study according to ClinGen guidelines and literature (\u003cb\u003esee Supplementary Materials Methodology\u003c/b\u003e).\u003c/p\u003e\n\u003ch3\u003eSystematic literature review\u003c/h3\u003e\n\u003cp\u003e Bibliographic search was performed following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and checklist for reporting this review. In detail, a comprehensive literature review was done separately for NS, CFCS, and CS. The literature search was performed between May 2023 and December 2023 on PubMed using specific queries (see \u003cb\u003eSupplementary Materials Methodology\u003c/b\u003e).\u003c/p\u003e\u003cp\u003eWe evaluated articles obtained from the latest systematic reviews on cancer in RASopathies to identify any potentially overlooked papers during the PubMed search. Abstracts were read to evaluate the relevance to the research topic. For publications, the following year limits were applied: CS (1977\u0026ndash;2023), NS (2001\u0026ndash;2023), NSML (2002\u0026ndash;2023), and CFCS (2006\u0026ndash;2023).\u003c/p\u003e\u003cp\u003eResults considered eligible for evaluation were finally exported into two datasets (Microsoft Excel files) to identify duplicates and unique records (\u003cb\u003eSupplementary Fig.\u0026nbsp;1\u003c/b\u003e).\u003c/p\u003e\n\u003ch3\u003eData extraction and synthesis of the systematic literature review\u003c/h3\u003e\n\u003cp\u003eData extraction and analysis were performed by four researchers assigned to the two different main topics (NS and CFC/CS). Working in pairs (CR and SM, VT and GV, respectively), four reviewers independently completed the assessment for each topic and two senior reviewers reconciled disagreements (CL and SM). The following information was extracted from the included articles: first author, publication year, publication source, study type, number of patients with NS, CS or CFCS, number of patients with cancer, type of cancer, and cancer histology (when available). Moreover, when provided, the following additional patient data were gathered: gender, vital status, age at diagnosis and eventually death, diagnostic method, genetic testing, and identified variants, when available.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eVariant assessment\u003c/h2\u003e\u003cp\u003eVariants reported in the relevant literature to be causative of NS, CFCS and CS were collected. Variants in the included articles were classified using the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) Standards and Guidelines for the Interpretation of Sequence Variants and the ClinGen RASopathy Expert Panel Consensus Methods for Variant Interpretation (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). In addition, the germline and somatic mutational spectra for \u003cem\u003ePTPN11, SOS1\u003c/em\u003e, and \u003cem\u003eHRAS\u003c/em\u003e genes were extracted from the literature and from the public COSMIC database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://cancer.sanger.ac.uk/cosmic\u003c/span\u003e\u003cspan address=\"https://cancer.sanger.ac.uk/cosmic\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). For prevalence calculations, familial cases were counted as a single patient.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003eQualitative variables were presented as absolute frequencies and percentages, and proportions were compared using either the Chi-square or Fisher\u0026rsquo;s exact test, as appropriate. Quantitative variables were described as medians with interquartile ranges (first and third quartiles). All statistical tests were two-sided, with a p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 considered statistically significant. The analyses were conducted using Stata software (StataCorp. 2023. Stata Statistical Software: Release 18. College Station, TX: StataCorp LP).\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003eMolecular spectrum and occurrence of solid tumors in a large monocentric cohort of individuals with RASopathies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA cohort comprising 138 individuals with RASopathies (Fondazione Policlinico Gemelli cohort, FPG cohort, hereafter) was included in the study. Details on the gene involved, age at diagnosis, method used for tumor diagnosis, histology, treatment, and outcome are reported in Table \u003cspan\u003e1\u003c/span\u003e, while demographic data about FPG cohort are detailed in Table \u003cspan\u003e2\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eIn the NS cohort, which also includes NS-like phenotypes associated with pathogenic variants in \u003cem\u003eSHOC2\u003c/em\u003e and \u003cem\u003eERF\u003c/em\u003e, ~\u0026thinsp;10.8% of patients (8/74) were diagnosed with a solid tumor (Table \u003cspan\u003e1\u003c/span\u003e\u0026ndash;\u003cspan\u003e2\u003c/span\u003e and Fig. \u003cspan\u003e1\u003c/span\u003eA-C\u003cstrong\u003e)\u003c/strong\u003e. As expected, \u003cem\u003ePTPN11\u003c/em\u003e was the most frequently implicated gene. Notably, in one family (NS#1 and NS#4), the mother and her daughter, who shared the p.Glu139Asp amino acid substitution, developed solid tumors. In detail, the daughter had a retropharyngeal ganglioneuroblastoma and a low-grade pilocytic astrocytoma, while a melanoma \u003cem\u003ein situ\u003c/em\u003e was diagnosed in the mother. In this cohort, a statistically significant association between p.Glu139Asp and solid tumors (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.02;) was observed. CNS tumor progression was observed in two separate patients affected with a low grade pilocytic astrocytoma and an unclassified astrocytic tumor, respectively (Table \u003cspan\u003e1\u003c/span\u003e). In one case the relapse occurred following chemotherapy treatment, and in the other one during active surveillance (NS#1 and NS#2). See Table \u003cspan\u003e1\u003c/span\u003e for all tumors detected in the NS cohort.\u003c/p\u003e\n\u003cp\u003eApproximately 47.8% (11/23) of the CS patients in the FPG cohort developed a benign or malignant neoplasia. Notably, five subjects showed the occurrence of multiple primary tumors in different districts (CS#1, CS#2, CS#4, CS#5, CS#6) (Fig.\u0026nbsp;\u003cspan\u003e2\u003c/span\u003eA-B, Table\u0026nbsp;\u003cspan\u003e1\u003c/span\u003e\u0026ndash;\u003cspan\u003e2\u003c/span\u003e and \u003cstrong\u003eSupplementary Table\u0026nbsp;2\u003c/strong\u003e). Bladder tumors [7 urothelial carcinoma (G1-2) and 7 papillary urothelial neoplasia of low malignant potential-PUNLMP] were the most frequent neoplasia observed in the CS cohort. Spontaneous regression of adrenal neuroblastoma was recorded for CS#2. CS#5 presented with multiple neoplasms involving the bladder (PUNLMP), and breast (relapse of intraductal breast neoplasia detected after 11 years from surgical intervention). All patients were alive at last follow-up, except for CS#5 who passed unexpectedly due to sudden cardiac death at the age of 28 years.\u003c/p\u003e\n\u003cp\u003eFinally, solid tumors were reported in ~\u0026thinsp;7.3% of CFCS cases in the FPG cohort (3/41 (Table\u0026nbsp;\u003cspan\u003e1\u003c/span\u003e\u0026ndash;\u003cspan\u003e2\u003c/span\u003e). Two patients carried a pathogenic variant in \u003cem\u003eBRAF\u003c/em\u003e and developed relapsing neoplastic lesions. The first subject, a male who harbored the p.Thr470Pro amino acid substitution, developed giant cell lesions of the jaw at 8 years of age, which recurred at 14 years of age. The second patient, a female carrier of the p.Lys499Asn change, developed a pylocytic astrocytoma at 13 years of age, which recurred twice, at 15 and 18 years of age. The third individual, carrier of the p.Tyr130Cys variant in the \u003cem\u003eMAP2K1\u003c/em\u003e gene, developed multiple peripheral nerve sheath tumors at 17 years of age \u003cstrong\u003e(\u003c/strong\u003eTable\u0026nbsp;\u003cspan\u003e1\u003c/span\u003e\u0026ndash;\u003cspan\u003e2\u003c/span\u003e, \u003cstrong\u003eSuppl. Table\u0026nbsp;3)\u003c/strong\u003e.\u003c/p\u003e\n\u003cdiv id=\"Sec11\"\u003e\n \u003ch2\u003eLiterature review and comparison with data from our monocentric cohort\u003c/h2\u003e\n \u003cp\u003eA systematic literature review was performed on patients with NS, CS, NSML, CBLS, LS, and CFCS with co-occurrence of solid tumors.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\"\u003e\n \u003ch2\u003eNoonan syndrome\u003c/h2\u003e\n \u003cp\u003eThe cohort including NS and clinically related phenotypes comprised 3,002 published cases with a confirmed molecular diagnosis. Among them, 79 developed a solid neoplasia (~\u0026thinsp;2.6%) (\u003cem\u003ePTPN11\u003c/em\u003e, n\u0026thinsp;=\u0026thinsp;45; \u003cem\u003eSOS1\u003c/em\u003e, n\u0026thinsp;=\u0026thinsp;21; \u003cem\u003eRIT1\u003c/em\u003e, n\u0026thinsp;=\u0026thinsp;3; \u003cem\u003eKRAS\u003c/em\u003e, n\u0026thinsp;=\u0026thinsp;2; \u003cem\u003eNRAS\u003c/em\u003e, n\u0026thinsp;=\u0026thinsp;2; \u003cem\u003eCBL\u003c/em\u003e, n\u0026thinsp;=\u0026thinsp;1; \u003cem\u003eLZTR1\u003c/em\u003e, n\u0026thinsp;=\u0026thinsp;1; \u003cem\u003eMRAS\u003c/em\u003e, n\u0026thinsp;=\u0026thinsp;1; \u003cem\u003eRAF1\u003c/em\u003e, n\u0026thinsp;=\u0026thinsp;1; \u003cem\u003eRRAS2\u003c/em\u003e, n\u0026thinsp;=\u0026thinsp;1; \u003cem\u003eSHOC2\u003c/em\u003e, n\u0026thinsp;=\u0026thinsp;1) (\u003cstrong\u003eSupplementary Table\u0026nbsp;4)\u003c/strong\u003e. In most cases, the prevalence of specific PVs does not differ substantially between the two NS populations (with \u003cem\u003evs\u003c/em\u003e. without tumors). For example, SHP2 substitutions at codon 308 (p.Asn308Asp or p.Asn308Ser), representing the most common defects in the entire NS population, occurred in ~\u0026thinsp;28.9% of \u003cem\u003ePTPN11\u003c/em\u003e-positive NS patients who developed cancer and in ~\u0026thinsp;29.4% of subjects with no cancer history (Fig.\u0026nbsp;\u003cspan\u003e3\u003c/span\u003eA-B).\u003c/p\u003e\n \u003cp\u003eIn contrast, a subset of PVs appeared to confer an increased risk of cancer development, such as SHP2 p.Asp106Ala and p.Ser502Thr (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.02 and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, respectively; SOS1 p.Glu846Lys (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and NRAS p.Gly12Arg (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.002) (\u003cstrong\u003eSupplementary Table\u0026nbsp;5\u003c/strong\u003e). The association of these changes with increased cancer susceptibility was confirmed combining prevalence in literature data and in data from our monocentric cohort (Fig.\u0026nbsp;\u003cspan\u003e1\u003c/span\u003eA-C). Moreover, a few additional SHP2 residues showed a trend to be associated with cancer in NS patients (Gly\u003csup\u003e60\u003c/sup\u003e, Ile\u003csup\u003e282\u003c/sup\u003e, Phe\u003csup\u003e285\u003c/sup\u003e; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.11, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.10, and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.12, respectively). Of note, these candidate tumor susceptibility changes did not overlap with those occurring as constitutional variants in \u003cem\u003ePTPN11\u003c/em\u003e-related NS/JMML (16,51), nor with those arising as somatic mutations in cancer (COSMIC database) (\u003cstrong\u003eSupplementary Table\u0026nbsp;5\u003c/strong\u003e).\u003c/p\u003e\n \u003cp\u003eCNS tumors were the most frequent type of neoplasia in both literature and the FPG cohort (Fig.\u0026nbsp;\u003cspan\u003e1\u003c/span\u003eA-C).\u003c/p\u003e\n \u003cp\u003eNotably, the observed spectrum of \u003cem\u003ePTPN11\u003c/em\u003e-related tumors differed from that associated with pathogenic variants in SOS1 (Fig.\u0026nbsp;\u003cspan\u003e1\u003c/span\u003eB); importantly, no central nervous system tumors were observed in individuals with SOS1 variants. Solid tumors identified in other less frequent NS and NS-like gene are reported in \u003cstrong\u003eSupplementary Table\u0026nbsp;10\u003c/strong\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\"\u003e\n \u003ch2\u003eCostello syndrome\u003c/h2\u003e\n \u003cp\u003eAmong the 49 CS individuals reported with a solid tumor in the literature, only 27 had a confirmed molecular diagnosis (\u003cstrong\u003eSupplementary Table\u0026nbsp;6\u003c/strong\u003e). The p.Gly12Ser amino acid substitution was the most common variant (~\u0026thinsp;66.7%, 18/27), followed by p.Gly12Ala (~\u0026thinsp;25.9%, 7/27), and p.Gly12Cys (~\u0026thinsp;7.4%, 2/27). Among 33 cases reported in literature with RMS, only 19 were confirmed by genetic diagnosis (n\u0026thinsp;=\u0026thinsp;11 embryonal RMS; n\u0026thinsp;=\u0026thinsp;2 spindle RMS; n\u0026thinsp;=\u0026thinsp;6 unspecified). Nevertheless, RMS was the most frequent tumor (~\u0026thinsp;70%), followed by bladder neoplasia (~\u0026thinsp;14%), NB (~\u0026thinsp;11%), and gastric neoplasia (~\u0026thinsp;3%). Other tumors, such as vestibular schwannoma, fibrosarcoma and hepatoblastoma, have only been reported in anecdotal cases without a confirmed molecular diagnosis.\u003c/p\u003e\n \u003cp\u003eIntegrating data from the literature with our monocentric cohort identified p.Gly12Ala as a high-risk variant (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016; two-tailed Fisher\u0026rsquo;s Exact test) (\u003cstrong\u003eSupplementary Table\u0026nbsp;7\u003c/strong\u003e). Conversely, we did not find an association between the p.Gly13Cys variant and tumor development (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.06). The overall distribution of variants in CS patients, stratified by the presence or absence of tumors, is illustrated in Fig.\u0026nbsp;\u003cspan\u003e4\u003c/span\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\"\u003e\n \u003ch2\u003eCardiofaciocutaneous syndrome\u003c/h2\u003e\n \u003cp\u003eTo our knowledge, solid tumors have been reported in five cases of CFCS \u003cstrong\u003e(Supplementary Table\u0026nbsp;8).\u003c/strong\u003e Among three patients who developed multiple giant cell lesions of the jaw, two carried a \u003cem\u003eBRAF\u003c/em\u003e variant resulting in the p.Gln257Arg substitution, while the other one carried a missense change in \u003cem\u003eMAP2K1\u003c/em\u003e (p.Tyr130Cys) (\u003cspan\u003e24\u003c/span\u003e). The fourth patient heterozygous for the same \u003cem\u003eMAP2K1\u003c/em\u003e variant, developed metastatic hepatoblastoma (\u003cspan\u003e28\u003c/span\u003e). Finally, chondroblastoma, a benign but locally aggressive neoplasm, was diagnosed in a patient without a confirmed molecular diagnosis.\u003c/p\u003e\n \u003cp\u003eDue to the limited number of patients with solid tumors, no cancer susceptibility variants were identified in individuals with CFCS or other RASopathies, except for NSML (\u003cstrong\u003eSupplementary Table\u0026nbsp;9)\u003c/strong\u003e.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe RAS-MAPK pathway plays a central role in tumorigenesis, with somatic mutations in the three members of the \u003cem\u003eRAS\u003c/em\u003e family of proto-oncogenes involved in nearly one-third of human cancers (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e). The occurrence of cancer in RASopathies has been supported by numerous case reports and some case series in the literature (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eKratz and colleagues reported a cumulative cancer incidence of ~\u0026thinsp;4% in NS and ~\u0026thinsp;15% in CS within the first two decades of life, with a peak during adolescence (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). These data were retrospectively collected from a cohort of 1,941 individuals with a clinical diagnosis of RASopathy (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Considering the very low number of tumors reported in the CFCS group, a precise estimate of the tumor risk in this condition could not be established. More recently, the same research group investigated the presence of malignancies in a cohort of 735 RASopathy patients. In that study, molecularly confirmed cases collected from 25 laboratories performing genetic screening in Germany were matched with those of the German Childhood Cancer Registry (GCCR), showing that the overall cancer risk during childhood was 10.5-fold higher compared to the general population (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). More specifically, individuals with NS and CS showed an 8-fold and 42.4-fold increased risk, respectively, compared to age-matched populations (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). No tumors were documented in 53 subjects of the cohort with CFCS as well as in a single CBLS patient. The study provided an enormous contribution in stimulating awareness on performing cancer-screening programs in patients with RASopathies. At the same time, it was limited by the exclusion of subjects older than 14 years and the lack of information from patient medical records, since the case-identifying resource was a childhood cancer registry. In addition, patients carrying variants in RASopathy-genes identified after 2015, such as \u003cem\u003eRIT1\u003c/em\u003e, \u003cem\u003eRRAS2\u003c/em\u003e, \u003cem\u003eMRAS\u003c/em\u003e, \u003cem\u003eMAPK1\u003c/em\u003e, \u003cem\u003eYWHAZ\u003c/em\u003e, \u003cem\u003eLZTR1\u003c/em\u003e, were not included. A recent review by the same authors confirmed that children with RASopathies, except those with LS, face a significantly increased cancer risk compared to the age-matched general population, and provided updated consensus recommendations for cancer surveillance in these categories (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eConsidering the limited data available in the literature, a major goal of the present study was to define the prevalence and spectrum of solid tumors in a large and unselected monocentric cohort of RASopathy patients (FPG cohort), not including NF1 and LS cases. We also aimed to compare the findings of the FPG cohort with those reported in literature, by providing a systematic review.\u003c/p\u003e\u003cp\u003eIn the FPG cohort, at least one solid tumor was documented in 10.8% of individuals with NS, 47.8% of those with CS, and 7.3% of those with CFCS, significantly higher compared to those previously reported (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). The discrepancy might stem from both center-dependent (\u003cem\u003ee.g.\u003c/em\u003e, advancements in diagnostic techniques) and center-independent (\u003cem\u003ee.g.\u003c/em\u003e, implementation of surveillance protocols) factors. Consistently with previous findings, we observed an early age at tumor diagnosis in patients with RASopathies, with a median age of 13.5 years in CS and 19 years in NS (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), likely due to the intrinsic oncogenic potential of hyperactive RAS-MAPK signaling. Interestingly, in the FPG cohort 34.7% and 5.4% of patients with CS and NS, respectively, developed at least one tumor in the first two decades of life; the number of CFCS patients with cancer was too low to draw any definitive conclusion.\u003c/p\u003e\u003cp\u003eRegarding the tumor spectrum in RASopathies reported in literature, \u003cem\u003ePTPN11\u003c/em\u003e-positive NS cases have primarily been linked to malignant tumors of the nervous system (including DNET, glioma, and NB) whereas \u003cem\u003eSOS1\u003c/em\u003e-positive NS cases have been predominantly associated with RMS and giant cell lesions of the jaw (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). We documented low-grade gliomas as the most common malignancy observed in the \u003cem\u003ePTPN11-\u003c/em\u003eNS sub-cohort (9.3%), while no cases of DNET were documented, and only one patient developed NB (i.e. retropharyngeal ganglioneuroblastoma). Only 1 patient with \u003cem\u003ePTPN11-\u003c/em\u003eNS developed a high-grade glioma requiring chemotherapy (temozolomide) and radiotherapy (54 Gray).\u003c/p\u003e\u003cp\u003eThe most updated recommendations concerning tumor screening for NS proposed by Perrino et al., do not suggest specific screening for non-hematologic malignancy (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). However, given the high prevalence of low CNS tumors reported to date also in our FPG cohort, a personalized screening protocol may be discussed in future dedicated consensus.\u003c/p\u003e\u003cp\u003eIn the \u003cem\u003eSOS1\u003c/em\u003e-related NS sub-cohort, RMS was not reported.\u003c/p\u003e\u003cp\u003eA giant cell lesion of the jaw was diagnosed in one NS patient carrying a \u003cem\u003eRIT1\u003c/em\u003e variant (p.Ala57Gly). Notably, to the best of our knowledge, this is the first case in literature reported with this association. Literature data support the evidence that in CS, RMS is the most common tumor of childhood with average onset age of six years of age, followed by NB and bladder neoplasia from childhood through adolescence (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). While most malignancies are diagnosed during childhood, transitional cell carcinoma of the bladder has been reported exclusively in adulthood (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn the CS FPG cohort, asymptomatic bladder tumors were the most common neoplasia, followed by breast intraductal papillomas, NB, and RMS. (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e)\u003c/p\u003e\u003cp\u003ePUNLMP and low-grade bladder carcinoma have been diagnosed in individuals as young as 10 and 12 years, respectively, underscores the importance of active surveillance (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e) in line with recent recommendations (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAlthough somatic mutations in \u003cem\u003eHRAS\u003c/em\u003e are well-established as playing a pivotal role in embryonal RMS (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e), the latter being the most reported CS-associated neoplasia in literature, in the FPG cohort RMS was detected only in one patient (vaginal embryonal RMS). Despite the differences in the prevalence of tumors between CS-FPG cohort and literature, the existing surveillance protocols for these solid tumors remain strongly recommended, with clinical evaluation and routine ultrasound monitoring being the gold standard investigation (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eOf note, six patients in the CS FPG cohort developed more than one tumor. Among them, two patients experienced at least one relapse (1 intraductal breast papillary neoplasia, 1 urothelial carcinoma) and one patient experienced spontaneous regression of NB (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAnother major finding of this study was the identification of candidate variants that might be associated with a higher risk of solid tumor development. These include p.Asp106Ala and p.Ser502Thr in \u003cem\u003ePTPN11\u003c/em\u003e, p.Glu846Lys in \u003cem\u003eSOS1\u003c/em\u003e, p.Gly12Arg in \u003cem\u003eNRAS\u003c/em\u003e, and p.Gly12Ala in \u003cem\u003eHRAS\u003c/em\u003e. Interestingly, \u003cem\u003ePTPN11\u003c/em\u003e variants associated with solid tumors differ from the mutational hotspots identified in \u003cem\u003ePTPN11\u003c/em\u003e-related NS/JMML (16,18,51) or in sporadic cancer (COSMIC database). Noteworthy, we identified a mother and daughter carrying the p.Glu139Asp variant in \u003cem\u003ePTPN11\u003c/em\u003e, who developed \u003cem\u003ein situ\u003c/em\u003e melanoma and multiple tumors of the central nervous system, respectively.\u003c/p\u003e\u003cp\u003eAmong \u003cem\u003eRAS\u003c/em\u003e gene variants, the p.Gly12Arg substitution in NRAS is a well-established oncogenic change that frequently occurs as a somatic event in cancer, particularly in hematologic malignancies (COSMIC database). Based on available data, among the six amino acid substitutions resulting from single-base changes at this codon, p.Gly12Arg has the lowest prevalence in cancer (Gly12Asp\u0026thinsp;\u0026gt;\u0026thinsp;Gly12Ser\u0026thinsp;\u0026gt;\u0026thinsp;Gly12Cys\u0026thinsp;\u0026gt;\u0026thinsp;Gly12Ala\u0026thinsp;\u0026gt;\u0026thinsp;Gly12Val\u0026thinsp;\u0026gt;\u0026thinsp;Gly12Arg), suggesting a relatively mild oncogenic potential. However, when p.Gly12Arg occurs as a constitutional variant, it confers an increased cancer susceptibility (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Similarly, the p.Gly12Ala substitution in \u003cem\u003eHRAS\u003c/em\u003e represents the rarest variant found in sporadic cancer among missense substitutions at this codon (Gly12Val\u0026thinsp;\u0026gt;\u0026thinsp;Gly12Ser\u0026thinsp;\u0026gt;\u0026thinsp;Gly12Asp\u0026thinsp;\u0026gt;\u0026thinsp;Gly12Cys\u0026thinsp;\u0026gt;\u0026thinsp;Gly12Arg\u0026thinsp;\u0026gt;\u0026thinsp;Gly12Ala). Notably, our single patient carrying this variant has not developed any solid tumor to date (last follow up performed at age 12 years).\u003c/p\u003e\u003cp\u003eFinally, no systematic studies investigated the prevalence of cancer in CFCS, with only anecdotal reports documenting cases with hepatoblastoma, granuloma, chondroblastoma, and neoplasia of the jaw (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). In our CFCS cohort, solid tumors were observed in 7.3% of individuals, including relapsing lesions in one patient and one with recurrent tumor. Despite the distinctive skin manifestations of this condition, no cases of melanoma or skin tumors have been reported either in the literature or in CFCS-FPG cohort. (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e)\u003c/p\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eStudy limitations\u003c/h2\u003e\u003cp\u003eThe main limitation of the present study stem in the monocentric nature of the study which implies bias due to personalized and Institutional screening protocols not often applied on large scale. Furthermore, the limited number of tumor and rarity of the condition did not allow to establish a statistically significant genotype-phenotype correlation in the FPG cohort alone.\u003c/p\u003e\u003c/div\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eBased on a large, molecularly confirmed monocentric cohort of individuals with RASopathies monitored for solid tumors, this study provides important insights into tumor risk and surveillance. Comparison with literature data highlights a strong association between NS and low-grade CNS tumors, as well as between CS and bladder tumors. Differences in tumor prevalence may reflect variability in surveillance protocols at our institution. Consistent with previous reports, we observed an earlier onset of solid neoplasms in NS and CS compared with the general population. While the number of reported tumors in the FPG cohort alone was insufficient to establish definitive genotype-phenotype correlations, integration with literature data allowed identification of potential high-risk variants associated with increased tumor susceptibility. Notably, we report for the first time a giant cell lesion of the jaw in a NS patient carrying a \u003cem\u003eRIT1\u003c/em\u003e variant, and relapsing neoplasia in two CFCS individuals. These findings emphasize the need for multicentric studies to generate real-world data on tumor prevalence in RASopathies, which could inform personalized surveillance strategies to optimize cancer prevention while minimizing unnecessary interventions. Moreover, molecular characterization of tumors may be critical for understanding the interaction between constitutional RASopathy variants and secondary somatic alterations in cancer development.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe kindly thank the patients and their families. In particular, we thank the family Associations \u0026lsquo;Angeli Noonan\u0026rsquo;, \u0026lsquo;Associazione Italiana Sindrome Costello CFC\u0026rsquo;, and \u0026lsquo;Associazione Italiana Sindrome di Noonan RASopatie\u0026rsquo;.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGV and VT designed the experimental plan, contributed to data collection, and drafted the manuscript. CR, CB, LP, and EF acquired data, patients\u0026rsquo; consent and contributed to the manuscript draft. RO, VG, and DR supervised patients care and revised the manuscript. DPM and RP performed the statistical analysis and contributed to draft the manuscript. MG, AR, MT, and GZ contributed data analysis and critically revised the manuscript. CL and SM conceived the study, contributed to data collection, and critically revised the final draft of the manuscript. All authors approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was performed in accordance with the Declaration of Helsinki and the procedures employed were reviewed and approved by the local appropriate institutional Ethics Committee (ID 4218 Prot. n. 0000628/239). Consent for publication was obtained simultaneously with study consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported, in part, by grants from AIRC (IG 2 8768 to MT), Ministero della Salute (Current Research Funds and 5x1000, to MT; GR-2019-12371203, to CL).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eADDITIONAL INFORMATION\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe online version contains supplementary material available upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrespondence\u0026nbsp;\u003c/strong\u003eand requests for materials should be addressed to Chiara Leoni.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eNey GM, McKay L, Koschmann C, Mody R, Li Q. 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J Eur Acad Dermatol Venereol [Internet]. 2021 Jan 1 [cited 2024 Mar 14];35(1):e83\u0026ndash;5. Available from: https://pubmed.ncbi.nlm.nih.gov/32679607/\u003c/li\u003e\n\u003cli\u003eGelb BD, Cav\u0026eacute; H, Dillon MW, Gripp KW, Lee JA, Mason-Suares H, et al. ClinGen\u0026rsquo;s RASopathy Expert Panel consensus methods for variant interpretation. Genet Med [Internet]. 2018 Nov 1 [cited 2024 Mar 14];20(11):1334\u0026ndash;45. Available from: https://pubmed.ncbi.nlm.nih.gov/29493581/\u003c/li\u003e\n\u003cli\u003eAltm\u0026uuml;ller F, Lissewski C, Bertola D, Flex E, Stark Z, Spranger S, et al. Genotype and phenotype spectrum of NRAS germline variants. European Journal of Human Genetics [Internet]. 2017 Jun 1 [cited 2025 May 21];25(7):823\u0026ndash;31. Available from: https://pubmed.ncbi.nlm.nih.gov/28594414/\u003c/li\u003e\n\u003cli\u003eJacquinet A, Bonnard A, Capri Y, Martin D, Sadzot B, Bianchi E, et al. Oligo-astrocytoma in LZTR1-related Noonan syndrome. Eur J Med Genet [Internet]. 2020 Jan 1 [cited 2025 May 21];63(1). Available from: https://pubmed.ncbi.nlm.nih.gov/30664951/\u003c/li\u003e\n\u003cli\u003eHarms FL, Alawi M, Amor DJ, Tan TY, Cuturilo G, Lissewski C, et al. The novel RAF1 mutation p.(Gly361Ala) located outside the kinase domain of the CR3 region in two patients with Noonan syndrome, including one with a rare brain tumor. Am J Med Genet A. 2018 Feb 1;176(2):470\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eZeng L, Wang J, Zhu H, Huang Y, Deng Y, Wei P, et al. The RRAS2 pathogenic variant (c.67G\u0026gt;T; p. Gly23Cys) produces Noonan syndrome with embryonal rhabdomyosarcoma. Mol Genet Genomic Med [Internet]. 2024 Jan 1 [cited 2025 May 21];12(1). Available from: https://pubmed.ncbi.nlm.nih.gov/37942564/41. \u003c/li\u003e\n\u003cli\u003eLi S, Balmain A, Counter CM. A model for RAS mutation patterns in cancers: finding the sweet spot. Nat Rev Cancer [Internet]. 2018 Dec 1 [cited 2024 Mar 14];18(12):767\u0026ndash;77. Available from: https://pubmed.ncbi.nlm.nih.gov/30420765/\u003c/li\u003e\n\u003cli\u003eWhite SM, Graham JM, Kerr B, Gripp K, Weksberg R, Cytrynbaum C, et al. The adult phenotype in Costello syndrome. Am J Med Genet. 2005 Jul 15;136 A(2):128\u0026ndash;35. \u003c/li\u003e\n\u003cli\u003eLeoni C, Paradiso FV, Foschi N, Tedesco M, Pierconti F, Silvaroli S, et al. Prevalence of bladder cancer in Costello syndrome: New insights to drive clinical decision-making. Clin Genet. 2022 Apr 1;101(4):454\u0026ndash;8. \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e A summary of molecular characteristics, histopathologic diagnoses, and management strategies of RASopathy individuals with solid tumors belonging to the FPG cohort.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"left\" width=\"999\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePT ID\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGenetic variant\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at diagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiagnostic method\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 227px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistologic exam WHO class\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSolid tumor Status*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"10\" valign=\"top\" style=\"width: 999px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNOONAN SYNDROME\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNS 1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 37px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cem\u003ePTPN11:\u003c/em\u003e c.417G\u0026gt;C, p.Glu139Asp\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMRI + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eNeuroblastoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 227px;\"\u003e\n \u003cp\u003eRetropharyngeal ganglioneuroblastoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003esurgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMRI + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCNS tumors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 227px;\"\u003e\n \u003cp\u003eLow grade pylocytic astrocytoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003esurveillance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eProgression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMRI + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCNS tumors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 227px;\"\u003e\n \u003cp\u003eHigh grade pylocytic astrocytoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eradiotherapy + chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eStability\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNS 2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cem\u003ePTPN11:\u003c/em\u003e c.1507G\u0026gt;A, p.Gly503Arg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCNS tumors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 227px;\"\u003e\n \u003cp\u003eUnclassified astrocytic neoplasia\u0026deg;\u0026nbsp;\u003cbr\u003e\u0026nbsp;\u0026deg;histol. performed at 20 yrs of age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003esurveillance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eProgression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNS 3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cem\u003ePTPN11:\u003c/em\u003e c.1510A\u0026gt;G, p.Met504Val\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCNS tumors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 227px;\"\u003e\n \u003cp\u003eNot assessed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003esurveillance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNS 4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cem\u003ePTPN11:\u003c/em\u003e c.417G\u0026gt;C, p.Glu139Asp\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eBio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMelanoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 227px;\"\u003e\n \u003cp\u003eMelanoma \u003cem\u003ein situ\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eexcision with safe margins\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNS 5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 37px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cem\u003ePTPN11\u003c/em\u003e: c.923A\u0026gt;G, p.Asn308Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003ePNS tumors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 227px;\"\u003e\n \u003cp\u003eNot assessed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003esurveillance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCNS tumors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 227px;\"\u003e\n \u003cp\u003eNot assessed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003esurveillance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNS 6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cem\u003ePTPN11\u003c/em\u003e: c.844A\u0026gt;G, Ile282Val\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eDerm + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMelanoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 227px;\"\u003e\n \u003cp\u003eMelanoma \u003cem\u003ein situ\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eexcision with safe margins\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNS 7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cem\u003eSOS1\u003c/em\u003e: c.1642A\u0026gt;C, p.Ser548Arg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eDerm + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMelanoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 227px;\"\u003e\n \u003cp\u003eMelanoma \u003cem\u003ein situ\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eexcision with safe margins\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNS 8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 37px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cem\u003eRIT1\u003c/em\u003e: c.170C\u0026gt;G, p.Ala57Gly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eBio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eGiant cell lesions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 227px;\"\u003e\n \u003cp\u003eGiant cell lesions of the jaw\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003esurgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRelapse\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eBio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eGiant cell lesions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 227px;\"\u003e\n \u003cp\u003eGiant cell lesions of the jaw\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003esurgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRelapse\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eBio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eGiant cell lesions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 227px;\"\u003e\n \u003cp\u003eGiant cell lesions of the jaw\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003esurgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eStability\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"10\" style=\"width: 999px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCOSTELLO SYNDROME (CS)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCS 1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 37px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cem\u003eHRAS\u003c/em\u003e: c.34G\u0026gt;A, p.Gly12Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0,5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eEGDS + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eGastric neoplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eGastric leyomyoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eendoscopic surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCys + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eBladder neoplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eUrothelial carcinoma G1/LG (Ta) (ISUP-WHO 2004)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eendoscopic resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCys + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eBladder neoplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eUrothelial carcinoma G1-2/LG (Ta) (ISUP-WHO 2004)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eendoscopic resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCys + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eBladder neoplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003ePUNLMP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eendoscopic resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCS 2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 37px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cem\u003eHRAS\u003c/em\u003e: c.34G\u0026gt;A, p.Gly12Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eNeuroblastoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eNot assessed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003esurveillance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eSpontaneous Regression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCys + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eBladder neoplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eUrothelial carcinoma G1/LG (Ta) (ISUP-WHO 2004)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eendoscopic resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCys + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eBladder neoplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eUrothelial carcinoma G1/LG (Ta) (ISUP-WHO 2004)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eendoscopic resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCS 3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cem\u003eHRAS\u003c/em\u003e: c.34G\u0026gt;A, p.Gly12Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eDerm + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eSkin tumor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eMelanocytoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003esurgical excsion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCS 4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 37px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cem\u003eHRAS\u003c/em\u003e: c.34G\u0026gt;A, p.Gly12Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eDerm + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eMelanoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eMelanoma \u003cem\u003ein situ\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eexcision with safe margins\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCys + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eBladder neoplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003ePUNLMP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eendoscopic resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCys + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eBladder neoplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eUrothelial carcinoma G2/LG (Ta) (ISUP-WHO 2004)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eendoscopic resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCS 5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 37px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cem\u003eHRAS\u003c/em\u003e: c.34G\u0026gt;A, p.Gly12Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eBreast MRI + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eBreast neoplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eIntraductal breast papillary neoplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003esurgical excision\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eProgression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eBreast neoplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eIntraductal breast papillary neoplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003edeceased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCys + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eBladder neoplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003ePUNLMP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eendoscopic resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCS 6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 37px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cem\u003eHRAS\u003c/em\u003e: c.34G\u0026gt;A, p.Gly12Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCys + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eBladder neoplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003ePUNLMP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eendoscopic resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eBreast MRI + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eBreast neoplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eIntraductal breast papillary neoplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003esurveillance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eStability\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCS 7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cem\u003eHRAS\u003c/em\u003e: c.34G\u0026gt;A, p.Gly12Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCys + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eBladder neoplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003ePUNLMP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eendoscopic resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCS 8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cem\u003eHRAS\u003c/em\u003e: c.34G\u0026gt;A, p.Gly12Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCys + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eBladder neoplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eUrothelial carcinoma G1/LG (Ta) (ISUP-WHO 2004)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eendoscopic resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCS 9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 37px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cem\u003eHRAS\u003c/em\u003e: c.34G\u0026gt;A, p.Gly12Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCys + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eBladder neoplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003ePUNLMP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eendoscopic resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCys + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eBladder neoplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eUrothelial carcinoma G1-2/LG (Ta) (ISUP-WHO 2004)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eendoscopic resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCS 10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 37px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cem\u003eHRAS\u003c/em\u003e: c.34G\u0026gt;A, p.Gly12Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCys + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eBladder neoplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003ePUNLMP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eendoscopic resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCys + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eBladder neoplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eUrothelial carcinoma G1-2/LG (Ta) (ISUP-WHO 2004)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eendoscopic resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRelapse\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCys + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eBladder neoplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eUrothelial carcinoma HG(Tx)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eTURB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eStability\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCS 11\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cem\u003eHRAS\u003c/em\u003e: c.34G\u0026gt;A, p.Gly12Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCys + Vaginoscopy + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eRhabdomyosarcoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eRMS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eChemotherapy, surgery, brachytherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"10\" style=\"width: 999px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCARDIO-FACIO-CUTANEOUS\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eSYNDROME (CFCS)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCFCS 1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 37px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cem\u003eBRAF\u003c/em\u003e: c.1408A\u0026gt;C, p.Thr470Pro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eOrthopan + MRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eGiant cell lesion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 227px;\"\u003e\n \u003cp\u003eGiant cell lesions of the jaw\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eSurgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRelapse\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eSurgery + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eGiant cell lesion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 227px;\"\u003e\n \u003cp\u003eGiant cell lesions of the jaw\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eSurgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eStability\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCFCS 2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 37px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cem\u003eBRAF\u003c/em\u003e: c.1497A\u0026gt;C, p.Lys499Asn\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMRI + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCNS tumors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 227px;\"\u003e\n \u003cp\u003ePilocytic astrocytoma grade I WHO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003ePartial surgical excision\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eProgression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMRI + Bio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCNS tumors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 227px;\"\u003e\n \u003cp\u003enot assessed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eradiotherapy + chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eProgression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCNS tumors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 227px;\"\u003e\n \u003cp\u003eGanglioglioma grade I WHO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003ecomplete surgical resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCFCS 3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cem\u003eMAP2K1\u003c/em\u003e: c.389A\u0026gt;G, p.Tyr130Cys\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003ePNS tumors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 227px;\"\u003e\n \u003cp\u003eNot assessed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eMRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eTable 1 Legend:\u003c/strong\u003e Identifier (ID); Costello syndrome (CS); Cardiofaciocutaneous syndrome (CFCS); Central Nervous System (CNS); Cystoscopy (Cys); Biopsy (Bio); Dermoscopy (Derm); Esophagogastroduodenoscopy (EGDS); International Society of Urological Pathology (ISUP); Magnetic Resonance Imaging (MRI); Noonan syndrome (NS); Not Available (NA); Orthopanoramic (Orthopan); Papillary Urothelial Neoplasm of Low Malignant Potential (PUNLMP); Peripheral Nerve Sheath (PNS); Progression (Progr); Relapse (Rel); Transurethral Resection of Bladder Tumor (TURB); World Health Organization (WHO).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e*Solid tumor Status definition: \u003cstrong\u003eProgression\u003c/strong\u003e: worsening of cancer associated to its growing and spreading to other tissues. \u003cstrong\u003eRelapse\u003c/strong\u003e: The return of solid tumor or the signs and symptoms of cancer after a period of improvement.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRemission\u003c/strong\u003e: A decrease in or disappearance of signs and symptoms of cancer. \u003cstrong\u003eSpontaneous regression\u003c/strong\u003e: partial or complete disappearance of primary tumor tissue or its metastases in patients who have never been treated. Stability: the term \u0026ldquo;stability\u0026rdquo; or \u0026ldquo;stable disease\u0026quot; refers to a situation where cancer is neither decreasing nor increasing in extent or severity.\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"780\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"bottom\" style=\"width: 360px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 2. Demographic characterization of the FPG cohort.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 61px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 65px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 87px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"10\" style=\"width: 133px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNS/NS-like disorders (\u003cem\u003en=74\u003c/em\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge range (median)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian age of onset\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEarliest diagnosis at y\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGene\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal n\u0026deg; of patients\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatients with tumors\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"9\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e39 F; \u0026nbsp; \u0026nbsp; 35 M\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"9\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3 - 46 y \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; (15.5 \u0026nbsp;y)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"9\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e19 y\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cem\u003ePTPN11*\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e43 (24 F; 19 M)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e6 (4F; 2M)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cem\u003eKRAS\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e5 (3 F; 2 M)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cem\u003eRAF1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e2 (2 F)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cem\u003eRIT1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e4 (2 F; 2 M)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e1 (M)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cem\u003eLZTR1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e3 (1 F; 2M)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cem\u003eERF\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e1 (1 M)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cem\u003eSHOC2\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e5 (3 F; 2 M)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e17\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cem\u003eSOS1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e10 (4F; 6M)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e1 (F)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cem\u003eSOS2\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e1 (1M)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" style=\"width: 133px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCS (\u003cem\u003en=23\u003c/em\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e16 F; \u0026nbsp; \u0026nbsp; \u0026nbsp;7 M\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2 - 40 y \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; (20 y)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e14 y\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cem\u003eHRAS\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003eGly12Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e19 (15F; 4M)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e11 (8F; 3M)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003eGly12Ala\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e1 (M)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003eGly13Cys\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e2 (1F; 1M)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003eGln22Lys\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e1 (1M)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" style=\"width: 133px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCFCS (\u003cem\u003en=41\u003c/em\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e26 F; \u0026nbsp; \u0026nbsp; \u0026nbsp; 15 M\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2-39 y \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;(16 y)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e13 y\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cem\u003eBRAF\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e31 (8F; 11M)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e2 (1F; 1M)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cem\u003eKRAS\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e1 (F)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e17\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cem\u003eMAP2K1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e7 (4F; 3M)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e1 (M)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cem\u003eYWHAZ\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e1 (F)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cem\u003eMAP2K2\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e1 (M)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"9\" valign=\"top\" style=\"width: 780px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eTable 2 Legend\u003c/em\u003e\u003c/strong\u003e: CS: Costello Syndrome; CFCS: Cardiofaciocutaneous Syndrome; F: Female; M: Male; n\u0026deg;: number; NS: Noonan Syndome; Y: years. *Amino acid substitutions affecting twelve residues of SHP2, the protein encoded by PTPN11 (Asn58, Gly60, Asp61, Tyr62, Asp106, Glu139, Ile282, Phe285, Asn308, Ser502, Gly503, and Met504), two residues of SOS1 (Arg552 and Glu846), and one NRAS residue (Gly12) occurred in at least two independent NS patients who manifested cancer.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"RASopathies, cancer predisposition, high-risk variants, tailored surveillance, Costello syndrome, Noonan syndrome, Cardiofaciocutaneous syndrome","lastPublishedDoi":"10.21203/rs.3.rs-7979959/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7979959/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground.\u003c/h2\u003e\u003cp\u003eThe RAS-MAPK signaling cascade mediates cellular responses to external stimuli, regulating key processes involved in tumorigenesis, including growth, differentiation, and survival. RASopathies are a group of neurodevelopmental disorders caused by dysregulated RAS-MAPK activity and characterized by overlapping clinical presentations. While individuals with Neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Costello syndrome (CS), and CBL-associated syndrome have an established increased cancer risk, data regarding tumor predisposition in other RASopathies remain anecdotal.\u003c/p\u003e\u003ch2\u003eMethods.\u003c/h2\u003e\u003cp\u003eWe investigated the prevalence and spectrum of solid tumors in NS and related RASopathies, excluding NF1, through a retrospective analysis of a large monocentric cohort. These findings were complemented with data from an updated systematic review of the literature.\u003c/p\u003e\u003ch2\u003eResults.\u003c/h2\u003e\u003cp\u003eThis study reports the largest single-center cohort of individuals with RASopathies monitored for solid tumors to date (n\u0026thinsp;=\u0026thinsp;138; age range, 2\u0026ndash;48 years). Solid neoplasms were identified in 10.8% of individuals with NS, 47.8% with CS, and 7.3% with cardiofaciocutaneous syndrome (CFCS). Multiple tumors occurred in 41.6% of CS patients, and one CFCS patient developed relapsing neoplasia. Tumor onset occurred at a younger age compared with the general population, particularly in individuals with CS. Distinct tumor spectra were observed among NS patients carrying \u003cem\u003ePTPN11\u003c/em\u003e and \u003cem\u003eSOS1\u003c/em\u003e pathogenic variants. Moreover, we identified a subset of potentially high-risk variants in RASopathy-causing genes that may confer increased susceptibility to solid tumors.\u003c/p\u003e\u003ch2\u003eConclusion.\u003c/h2\u003e\u003cp\u003e Our findings provide clinically relevant insights into tumor predisposition across RASopathies and underscore the need for tailored surveillance strategies and evidence-based clinical guidelines for each disorder.\u003c/p\u003e","manuscriptTitle":"Solid Tumors in RASopathies: Insights from a Large Monocentric Cohort and Systematic Review of the Literature","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-19 14:41:14","doi":"10.21203/rs.3.rs-7979959/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"17cd5976-0f94-4960-8e2f-abe0ad68fd9c","owner":[],"postedDate":"November 19th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":57732229,"name":"Biological sciences/Genetics/Cancer genomics"},{"id":57732230,"name":"Health sciences/Medical research/Genetics research"}],"tags":[],"updatedAt":"2026-01-08T14:44:09+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-19 14:41:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7979959","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7979959","identity":"rs-7979959","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}