A Systematic Review of Cancer Risks Associated With Mitf Variants

A Systematic Review of Cancer Risks Associated With Mitf Variants | 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 Research Article A Systematic Review of Cancer Risks Associated With Mitf Variants Luigi Monti, Lea Godino, Clio Dessinioti, Alex Stratigos, Olga Papadodima, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9555675/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract The MITF E318K variant has been associated with melanoma risk, while risk associated with other variants or of other cancers remains uncertain. We performed a systematic review with meta-analysis of 11 retrospective case–control studies to evaluate cancer risks associated with germline MITF variants. Across 8,606 melanoma patients and 17,953 controls, the E318K variant was detected in 2.1% and 0.8% of individuals, respectively, corresponding to a significantly increased melanoma risk (OR 2.55, 95% CI 1.90–3.43). The association was stronger in patients with multiple primary melanomas, with carrier frequencies up to 2.6% compared to 1.0% in single melanoma cases and ORs reaching 4.45 in individual studies. Phenotypic analyses showed enrichment of high nevus burden (> 200 nevi), with ORs up to 12.4 in multiple melanoma cohorts. No consistent association with age at onset or pigmentary traits was observed. Evidence for non-melanoma cancers was limited and heterogeneous: a single study reported increased renal cancer risk (OR 7.64), whereas larger cohorts failed to replicate this finding; an association with pheochromocytoma/paraganglioma was observed (OR 3.19) but lacks confirmation. No other MITF variants demonstrated significant cancer risk. These findings support MITF E318K as a moderate-penetrance melanoma susceptibility allele, particularly associated with multiple primary melanomas. Figures Figure 1 Figure 2 Figure 3 INTRODUCTION The Microphthalmia‑associated Transcription Factor ( MITF ) codes for a basic helix–loop–helix leucine zipper (bHLH‑Zip) transcription factor that plays a central role in cell survival, differentiation, proliferation, invasion, senescence, metabolism, and DNA damage repair 1 . By regulating genes involved in melanogenesis, cellular metabolism, DNA repair, and stress responses, MITF acts as a master regulator of melanocytic homeostasis 2 . Germline alterations in the MITF gene (mapped to chromosome 3p13) are classically associated with Waardenburg syndrome type 2 and Tietz syndrome, both characterized by sensorineural hearing loss and pigmentary abnormalities 3 . Further, the MITF gene has been incorporated into diagnostic multigene panels for hereditary cancer predisposition following the demonstration of an association between the E318K variant (exon 10) and an increased risk of cutaneous melanoma and renal cell carcinoma (RCC) 4 – 5 . Subsequent studies have suggested that carriers may benefit from tailored clinical management strategies, including enhanced dermatologic surveillance and renal imaging protocols 6 – 8 . Despite these recommendations, the magnitude of cancer risk associated with MITF E318K remains incompletely defined, with variability across study designs, populations, and ascertainment criteria, and it remains unknown whether other MITF variants confer the same risks. In this context, the primary objective of the present review was to systematically identify and synthesize the available evidence on cancer risks associated with germline MITF variants that can be detected while performing multigene testing, in order to support clinical interpretation and management, as well as to inform future research by highlighting knowledge gaps. MATERIALS AND METHODS Study design The study was designed according to the Guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Protocol Statement to reduce reporting bias 9 . The main steps included search methods, study selection, quality assessment, data extraction, and data synthesis. A Microsoft Excel-based method 10 was used to record and select data in subsequent steps to promote transparency. The protocol was registered on the Open Science Framework (OSF, https://osf.io/3f5pq ). Review questions The question to respond to, formulated according to the PEO (Population, Exposure, Outcomes) methodology ( Supplementary Table 1 ), was: “What are the cancer risks associated with constitutional pathogenic variants of the MITF gene?” Search strategy and study selection Four databases (Pubmed, Scopus, Web of Science and Cochrane) were searched for papers published from January 2011 to July 2025. We chose to start in 2011 because MITF has been proposed as associated with increased cancer risks in that year. A detailed search strategy for all electronic databases is presented in Supplementary Table 2 . The reference lists of all included studies were hand-searched for additional relevant reports or key terms. Targeted internet searching using Google Scholar was also performed to find any additional studies of interest. Grey literature was consulted through the OpenGrey Repository (formerly System for Information on Grey Literature in Europe). All search results were imported into Microsoft Excel to allow their management, and duplicate records were removed before screening. Titles and abstracts were independently screened by two reviewers (LM, GI), followed by full-text assessment of potentially eligible articles. Any disagreements were resolved through discussion with a third reviewer (DT). The selection process and reasons for exclusion were documented in a PRISMA flow diagram. To ensure transparency and reproducibility, all steps of the search and selection process were recorded in an electronic logbook following the Excel-based systematic review method described by Godino (2023) 10 . Eligibility criteria Papers were eligible for inclusion in this systematic review if: written in English or Italian language; published in peer-reviewed journals and reporting original research (using any methods); the study sample explicitly included MITF carriers; it was possible to assess cancer risks from the study data. Papers were excluded from the review if they were: preclinical research studies; pharmacology studies; abstract; case reports or opinion papers; books. Assessment of methodological quality and risk of bias Methodological quality and the risk of bias were independently assessed by LM and CD using the validation tools of Kmet et al and of Hoy et al 11–12 ; any disagreement was discussed until consensus was reached. According to Kmet et al, items concerning methodology and reporting of results were assessed and assigned 0 point (not addressed), 1 point (partially addressed) or 2 points (completely addressed), with total scores reported as percentages; although a minimum score is not enforced for inclusion in a review, 60% is suggested as a reasonable cut-off. As suggested by Hoy et al, a study was considered to have high, moderate or low risk of bias if 3 or less, 4–6 and 7–11 of the assessed items, respectively, were satisfied. Publication bias was assessed using funnel plots. Data analysis and synthesis Two independent researchers (LM, GI) extracted data from the included studies using a pre-defined matrix that considers the following information: author(s) of the study, year of publication, country where the study was conducted, study aim(s), study design, sample size and findings relevant to the review question. The heterogeneity of included studies was determined. A narrative synthesis was conducted to describe the design, implementation, and findings of the studies. Whenever sufficient information was available and data format allowed comparisons, a synthesis of quantitative data through meta-analysis was performed, using germline MITF pathogenic variants as event. Data were analyzed using Review Manager software (Cochrane Collaboration, Copenhagen, Denmark). All quantitative syntheses were restricted to dichotomous outcomes. Pooled odds ratios (Ors) with 95% confidence intervals (Cis) were calculated using a random-effects model, in light of the expected clinical and methodological heterogeneity across studies. Statistical heterogeneity was calculated using the χ 2 test and I 2 test. I 2 values of 75% were considered to indicate low, medium, and high heterogeneity, respectively. The influence of each single study on the results was evaluated by removing each study from consideration one at a time. MITF variants reporting The mRNA reference sequence used is the NM_000248.4, corresponding to the MANE Plus Clinical transcript. RESULTS Search results The results of the literature search are summarized in the PRISMA flow diagram (Fig. 1 ). The database search identified 777 records, of which 395 were removed as duplicates, leaving 382 records for title and abstract screening. Following this initial screening, 39 articles were read in detail by researchers, and 11 met the inclusion criteria and were included in the systematic review. Characteristics of included studies All the 11 included studies 4 – 5 , 13 – 21 were retrospective series, published between 2011 and 2020, and examined cancer risk associated with MITF variants. Two studies were monocentric (one from France and one from Spain), while eight were multicentric (from United States, Canada, Brazil, Australia, Italy, Poland, Switzerland, Denmark). Nine studies focused only on cancer risk associated with the E318K variant, while the other two included the estimation of cancer risks associated with also other two MITF variants (c.1081G > A;p.Val320Ile and c.938-325G > A). Eight studies evaluated only melanoma cohorts, while the other three studies evaluated cohorts of different cancer types. Overall, the risk of bias of the included studies was low and the methodology quality was high. For most studies (10/11, 91.0%) 5, 13–20 , data collection, sample characteristics and recruitment were considered appropriate. One study 4 showed a lower methodological quality score (62.5%) and was classified as having a moderate risk of bias. Despite this limitation, the study was retained in the systematic review, as it was the first to report an association between MITF variants and cancer risk and provided unique data not available in the other included studies, thereby contributing to a broader interpretation of the evidence. The main characteristics and findings of the included studies are detailed in Table 1 . Table 1 Main characteristics of included studies. Author, date Country Population Disease assessed Research design Aim Main findings Kmet et al. (2004) score Bertoletto et al. 2011 5 France 829 cases, 1659 controls Melanoma and RCC a Multicentric, Case–control study To examine E318K MITF prevalence in patients with melanoma and/or renal cell carcinoma (RCC) The MITF E318K variant was associated with an increased risk of melanoma, renal cell carcinoma (RCC), and melanoma plus RCC. 10/16; 62.5% Berwick et al. 2014 11 Australia, Italy, Canada, USA 1194 cases, 2430 controls Melanoma Multicentric, Case–control study To assess E318K effect on melanoma risk and the interaction with other genetic risk factors The MITF E318K variant was associated with an increased risk of melanoma. The association was strongest among individuals with a low‑risk phenotype. 13/16; 81.25% Castro-Vega et al. 2016 17 France 555 cases, 2348 controls PCC/PGL b Monocentric, Case–control study To determinate the prevalence of E318K MITF in a French cohort of Pheochromocytoma/Paraganglioma (PCC/PGL) The MITF E318K variant was associated with an increased risk of pheochromocytoma/paraganglioma (PCC/PGL). 16/16: 100% Ghiorzo et al. 2013 15 Italy 667 cases, 2205 controls Melanoma Multicentric, Case–control study To test prevalence of E318K MITF in 667 Italian melanoma patients The MITF E318K variant was associated with an increased risk of melanoma. 11/16; 68.75% Gromowsky et al. 2014 14 Poland 748 melanoma patients, 683 breast, 753 prostate, 729 colon, 737 lung, 576 kidney, 2114 controls. Melanoma, breast cancer, prostate cancer, colorectal cancer, lung cancer, kidney cancer Multicentric, Case–control study To examine association between E318K and V320I and risk of cancer. Neither MITF E318K nor V320I showed a significant association with melanoma and other cancers. 14/16; 87.5% Lourenço et al. 2020 10 Brazil 247 cases, 280 controls Melanoma Multicentric, Case–control study To identify SNVs on pigmentation-related genes with importance in risk and clinicopathological aspects of CM. The MITF c.938‑325G > A variant did not increase melanoma risk. 15/16; 93.75% Mangas et al. 2016 9 Switzerland 41 cases, 146 controls Melanoma Multicentric, Case–control study To obtain information about genetic predisposition to CM in Ticino. The MITF E318K variant was associated with an increased risk of melanoma. 15/16; 93.75% McMeniman EK, et al. 2019 16 Australia 585 patients, 659 controls Melanoma Multicentric, Case–control study To ascertain whether the level of UV damage at the site of melanomas was associated with genetic polymorphisms. The MITF E318K variant was associated with an increased risk of multiple primary melanomas. 15/16; 93.75% Potrony et al. 2016 13 Spain 531 cases, 2704 controls Melanoma Monocentric, Case–control study To evaluate the penetrance of E318K MITF in patients with melanoma ad assess association with clinical and phenotypic features. The MITF E318K variant was associated with an increased risk of melanoma. 15/16; 93.75% Wadt et al. 2015 12 Denmark 296 cases (276 CM, 20 UM), 1965 controls Melanoma (cutaneous and uveal) Multicentric, Case–control study To examine frequence of melanoma predisposition gene in patients with cutaneous and uveal melanoma. The MITF E318K variant was associated with an increased risk of melanoma. 12/16; 75.0% Yokoyama et al. 2011 4 Australia + UK 3988 patients, 4068 controls Melanoma Multicentric, Case–control study To assess the role of E318K MITF variant to developing melanoma. The MITF E318K variant was associated with an increased risk of melanoma. 14/16; 87.5% a. RCC: renal cells cancer. b. PCC/PGL: Pheochromocytoma/paraganglioma. Risk and features of melanoma in carriers of the E318K variant in the MITF gene. A total of 8,606 melanoma patients were genotyped for the MITF E318K variant, which was detected in 182 patients (2.1%), while 8,424 patients (97.9%) were non-carriers ( MITF E318K wild-type). Out of 17,953 controls, 149 (0.8%) were E318K carriers. Data were subjected to meta-analysis to assess the likelihood of developing melanoma in MITF E318K variant carriers: the presence of the variant was associated with an increased risk of melanoma (OR 2.55, CI 1.90–3.43) (Fig. 2 and Supplementary Table 3 ). Among papers that specify the number of melanomas occurred in individual patients 5 , 17 , 19 – 20 , the risk of developing multiple primary melanomas (MPMs) results higher than that for single melanomas (Fig. 3 and Supplementary Table 3 ). Three studies 4 , 15 , 17 assessed the relationship between the MITF E318K variant and melanoma-related phenotypes ( Supplementary Table 4 ). The variant showed a strong association with very high nevus counts (> 200) in two studies (Potrony et al.: OR 8.4 in all patients and OR 12.4 in MPM cases; Yokohama et al.: OR 2.54), whereas Berwick et al. reported an opposite pattern, linking the variant to the absence of nevi (OR 5.9, CI 1.9–18.0). Regarding pigmentary traits, in the same studies, MITF E318K carriers with non-blue eyes appeared to have a higher melanoma risk, although these associations were not statistically significant. Age at melanoma onset, available for 89 carriers across four studies 4 , 5, 13, 19 , was evenly distributed, with roughly half diagnosed at ≤ 50 years and half after 50. Data on histological subtypes were available for 45 patients from three studies 5 , 17, 19 . Superficial spreading melanoma (SSM) was the most frequently observed subtype, reported in 30 patients (67.0%), followed by nodular melanoma (NM) in 12 cases (27.0%). Other subtypes were less common and included lentigo maligna melanoma (LMM, n = 3.7%)), acral melanoma (AM, n = 2.4%), and mucosal melanoma (MM, n = 1.2%). Association of MITF E318K Variant with other malignancies The link between the MITF E318K variant and the development of non‑melanoma cancers has been examined across several studies, particularly in relation to renal cell carcinoma (RCC), pancreatic cancer, and pheochromocytoma/paraganglioma, as summarized in Supplementary Table 5 . Bertolotto et al. documented a substantial increase in RCC risk, reporting more than a sevenfold elevation among carriers who lacked mutations in established RCC‑predisposing genes (OR 7.64; 95% CI 3.15–18.59) 5 . However, other studies did not replicate this association, not confirming that carriers are at increased risk for renal cancer. Castro‑Vega et al 21 . Reported a significant association with pheochromocytoma/paraganglioma after screening 555 unrelated affected individuals, observing a higher prevalence of the MITF E318K variant (7/555, 1.3%) compared with controls (12/2348, 0.5%, OR 3.19; 95% CI 1.34–7.59; p = 0.005). In contrast, Gromowsky et al 18 . Found no meaningful correlation between the MITF E318K variant and other malignancies, including breast, prostate, colorectal, and lung cancers. Association between other MITF variants and cancer To date, no other MITF variants have been robustly associated with cancer predisposition with sufficient clinical evidence. Gromowsky et al. 18 genotyped a cohort of 6340 cancer patients, including cases of melanoma, kidney, colorectal, lung, breast, and prostate cancer, for the MITF variant c.1081G > A (p.Val320Ile). Only a single carrier of this variant was identified among melanoma patients, while no carriers were observed in any of the other cancer groups. Similarly, Lourenço et al. 14 investigated the potential role of the intronic MITF variant c.938-325G > A, selected from a genome-wide association study (GWAS), in melanoma predisposition. The results did not reach statistical significance (OR 1.28, CI 0.84–1.94; P = 0.06), not supporting an association with melanoma risk. These findings are summarized in Supplementary Table 3. DISCUSSION This systematic review and meta‑analysis provide an updated and comprehensive evaluation of the role of MITF germline variants in cancer predisposition. Across 11 retrospective case-control studies published between 2011 and 2020 4–5, 13–21 , the evidence consistently supports a moderate but clinically relevant association between MITF E318K and melanoma susceptibility, as already emerged in the meta-analysis study by Guhan et al. 22 , while the contribution of other MITF variants to cancer risk remains unsubstantiated. The overall methodological quality of the included studies was high, with low risk of bias in most analyses, strengthening the reliability of the conclusions. The pooled data confirm that MITF E318K carriers exhibit an increased likelihood of developing melanoma, with an OR of 2.55 (CI 1.90–3.43). This magnitude of risk aligns with previous observations positioning MITF E318K as an intermediate‑penetrance allele, comparable to other moderate‑risk melanoma genes 23 . Notably, the association becomes more pronounced in individuals with multiple primary melanomas (MPMs), for whom the risk nearly doubles. This is in line with previous studies that reported the detection of the MITF E318K variant in multiple melanoma patients, as well as the more frequent occurrence of multiple primary melanomas among patients with the variant compared to those without (27% vs 11%, respectively) 4 , 24 – 25 . This finding reinforces the hypothesis that MITF E318K may contribute not only to melanoma initiation but also to a broader phenotype of melanocytic instability, predisposing carriers to recurrent tumorigenesis. Regarding other clinical features of MITF E318K variant carriers, markedly elevated nevus count—particularly > 200 nevi—was consistently associated with the variant in two of the three studies evaluating this phenotype 5 , 17 . High nevus burden is a well‑established melanoma risk factor, and its enrichment among carriers may suggest that MITF E318K influence melanocyte proliferation or survival. However, the study by Berwick et al. 15 reported an opposite trend, linking the variant to the absence of nevi in MPM patients. This discrepancy may reflect methodological differences, population heterogeneity, or unmeasured environmental modifiers, underscoring the need for standardized phenotypic assessment in future research. However, it could also mean that the MITF E318K variant and these clinical features may represent distinct factors that contribute to melanoma development. Pigmentary traits showed weaker and inconsistent associations: non‑blue eye color appeared to modestly increase melanoma risk among carriers although statistical significance was not consistently achieved 5 , 15, 17 . Hair and skin color yielded similarly inconclusive results. These findings suggest that the oncogenic effect of MITF E318K is not primarily mediated through classical melanoma-associated risk phenotypes, despite the gene’s central role in melanocyte biology. Instead, the variant’s functional impact—disruption of SUMOylation and consequent transcriptional dysregulation—may promote melanoma genesis through mechanisms independent of pigmentation 4 , 5 . In addition, in melanocyte models, expression of MITF E318K markedly impaired BRAFV600E-induced senescence, as evidenced by reduced β-galactosidase activity, sustained DNA synthesis, and decreased expression of senescence markers such as p16 and p21 26 . Age at melanoma onset was highly variable 4 – 5 , 13, 19 , indicating that MITF E318K does not strongly influence the timing of disease presentation. This contrasts with high‑penetrance melanoma genes such as CDKN2A , which are typically associated with an early onset of the disease. The balanced age distribution further supports the classification of MITF E318K as a moderate‑risk allele with variable expressivity. Beyond melanoma, the evidence for an association between MITF E318K and non‑melanoma malignancies remains heterogeneous. A markedly increased risk of renal cell carcinoma (RCC) was reported only in one study, particularly among individuals lacking mutations in known RCC‑predisposing genes 5 . However, subsequent studies did not replicate this association in sporadic RCC cohorts 18 , suggesting that the risk cannot be generalized and may be confined to specific genetic or familial contexts. Regarding other cancers, the association with pheochromocytoma/paraganglioma reported by Castro‑Vega et al. 21 is intriguing and biologically plausible, given the role of MITF in neural crest–derived lineages. However, this finding has not yet been replicated, and its clinical significance remains uncertain. Conversely, large‑scale analyses found no evidence linking the variant to other malignancies, suggesting that any broader oncogenic effect is likely absent 18 , 27 . Importantly, no other MITF variants demonstrated a convincing association with cancer predisposition. Both the c.1081G > A (p.Val320Ile) variant and the intronic c.938‑325G > A variant failed to show significant enrichment in cancer cohorts, reinforcing the unique relevance of the E318K substitution 14 , 18 . Taken together, these evidences support MITF E318K as a moderate‑penetrance melanoma susceptibility allele with a particularly strong association with multiple primary melanomas and high nevus burden. Several limitations of the available literature should be acknowledged. First, the included studies differed in terms of study design, cohort composition, ascertainment strategies, and analytical approaches, which limits the comparability of results. Second, although this systematic review was conducted in accordance with rigorous methodological guidelines, it remains possible that some relevant studies were unintentionally missed during the search process, potentially affecting the completeness of the evidence synthesis. Additional case series, ideally based on well‑characterized cohorts with adequate follow‑up, would be essential to refine current risk estimates and reduce the likelihood that existing data do not accurately reflect the true clinical scenario. Its role in non‑melanoma cancers remains suggestive but not definitive, warranting further investigation into larger, well‑characterized cohorts. Future studies should prioritize standardized phenotyping, exploration of gene–gene and gene–environment interactions, functional analyses to clarify the biological mechanisms underlying the variant’s pleiotropic effects and exploration of the potential interaction of the MITF E318K variant with two major melanoma driver mutations, such as those of BRAF and/or NRAS . In light of the evidence currently available and acknowledging these limitations, it appears reasonable in clinical practice to exclusively consider the MITF E318K variant when evaluating cancer risk in individuals undergoing multigene tumor predisposition panel testing, and to restrict such considerations to melanoma risk. Nevertheless, this approach should be interpreted cautiously and may require revision as additional data become available. CONCLUSION In conclusion, the available evidence suggests that the MITF E318K variant may be regarded as a moderate‑penetrance allele associated with an increased susceptibility to melanoma, particularly for multiple primary melanomas and a high nevus burden. Although emerging data suggest possible associations with selected non‑melanoma malignancies, these findings remain inconsistent and require confirmation in larger, and genetically diverse cohorts. The absence of robust evidence for other MITF variants further underscores the unique relevance of the E318K substitution in cancer predisposition. Continued research efforts integrating standardized phenotyping, functional studies, and comprehensive genomic analyses will be essential to clarify the biological mechanisms underlying MITF ‑related oncogenesis and to refine risk assessment strategies for carriers. ETHIC STATEMENT This study is a systematic review of previously published studies and does not involve human participants or animals. Therefore, ethical approval and informed consent were not required. Declarations ETHIC STATEMENT This study is a systematic review of previously published studies and does not involve human participants or animals. Therefore, ethical approval and informed consent were not required. FUNDINGS The work reported in this publication was funded by the Italian Ministry of Health, RC-2026-2801373. DATA AVAILABILITY STATEMENT The data that support the findings of this study are available from the corresponding author upon reasonable request. CONFLICT OF INTERESTS The authors declare no conflicts of interest. ACKNOWLEDGEMENTS This work was funded by the European Union under Grant Agreement no. 101183265 – Joint Action JANE‑2. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or HaDEA. Neither the European Union nor the granting authority can be held responsible for them. The authors also acknowledge Carmela Caprara for her support in project management and coordination. AUTHOR CONTRIBUTIONS Conceptualization: GI, DT; methodology: LG, SM, GI, DT; investigation and data curation: all authors; writing—original draft preparation: LM; writing—review and editing: LM, LG, SM, GI, DT; all authors have read and agreed to the published version of the manuscript. 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Nurse Res 31(1):40–46. 10.7748/nr.2023.e1866 Kmet LM, Lee RC, Cook L, AHFMR Alberta Heritage Foundation for Medical Research (2004) Standard quality assessment criteria for evaluating primary research papers from a variety of fields. HTA Initiat 13:1–28 Hoy D, Brooks P, Woolf A et al (2012) Assessing risk of bias in prevalence studies: Modification of an existing tool and evidence of Interrater agreement. J Clin Epidemiol 65:934–939 Mangas C, Potrony M, Mainetti C, Bianchi E, Carrozza Merlani P, Mancarella Eberhardt A, Maspoli-Postizzi E, Marazza G, Marcollo-Pini A, Pelloni F, Sessa C, Simona B, Puig-Butillé JA, Badenas C, Puig S, Br (2016) J Dermatol 175(5):1030–1037. 10.1111/bjd.14897. Epub 2016 Aug 31. PMID: 27473757 Lourenço GJ, Oliveira C, Carvalho BS, Torricelli C, Silva JK, Gomez GVB, Rinck-Junior JA, Oliveira WL, Vazquez VL, Serrano SV, Moraes AM, Lima CSP (2020) Inherited variations in human pigmentation-related genes modulate cutaneous melanoma risk and clinicopathological features in Brazilian population. Sci Rep 10(1):12129. 10.1038/s41598-020-68945-9. PMID: 32699307; PMCID: PMC7376158 Berwick M, MacArthur J, Orlow I, Kanetsky P, Begg CB, Luo L, Reiner A, Sharma A, Armstrong BK, Kricker A, Cust AE, Marrett LD, Gruber SB, Anton-Culver H, Zanetti R, Rosso S, Gallagher RP, Dwyer T, Venn A, Busam K, From L, White K, Thomas NE, GEM Study Group (2014) MITF E318K’s effect on melanoma risk is independent of, but modified by, other risk factors. Pigment Cell Melanoma Res 27(3):485–488. 10.1111/pcmr.12215. Epub 2014 Jan 30. PMID: 24406078; PMCID: PMC3988207 Wadt KA, Aoude LG, Krogh L, Sunde L, Bojesen A, Grønskov K, Wartacz N, Ek J, Tolstrup-Andersen M, Klarskov-Andersen M, Borg Å, Heegaard S, Kiilgaard JF, Hansen TV, Klein K, Jönsson G, Drzewiecki KT, Dunø M, Hayward NK, Gerdes AM (2015) Molecular characterization of melanoma cases in Denmark suspected of genetic predisposition. PLoS ONE 10(3):e0122662. 10.1371/journal.pone.0122662. PMID: 25803691; PMCID: PMC4372390 Potrony M, Puig-Butille JA, Aguilera P, Badenas C, Tell-Marti G, Carrera C, Del Javier L, Conejo-Mir J, Malvehy J, Puig S (2016) Prevalence of MITF p.E318K in Patients With Melanoma Independent of the Presence of CDKN2A Causative Mutations. JAMA Dermatol. ;152(4):405 – 12. 10.1001/jamadermatol.2015.4356 . PMID: 26650189 Gromowski T, Masojć B, Scott RJ, Cybulski C, Górski B, Kluźniak W, Paszkowska-Szczur K, Rozmiarek A, Dębniak B, Maleszka R, Kładny J, Lubiński J, Dębniak T (2014) Prevalence of the E318K and V320I MITF germline mutations in Polish cancer patients and multiorgan cancer risk-a population-based study. Cancer Genet. ;207(4):128 – 32. Doi: 10.1016/j.cancergen.2014.03.003. Epub 2014 Mar 15. PMID: 24767713 Ghiorzo P, Pastorino L, Queirolo P, Bruno W, Tibiletti MG, Nasti S, Andreotti V, Genoa Pancreatic Cancer Study Group, Paillerets BB (2013) Bianchi Scarrà G. Prevalence of the E318K MITF germline mutation in Italian melanoma patients: associations with histological subtypes and family cancer history. Pigment Cell Melanoma Res 26(2):259–262. 10.1111/pcmr.12047. Epub 2012 Dec 10. PMID: 23167872 McMeniman EK, Duffy DL, Jagirdar K, Lee KJ, Peach E, McInerney-Leo AM, De’Ambrosis B, Rayner JE, Smithers BM, Soyer HP, Sturm RA (2020) The interplay of sun damage and genetic risk in Australian multiple and single primary melanoma cases and controls. Br J Dermatol 183(2):357–366. 10.1111/bjd.18777. Epub 2020 Feb 5. PMID: 31794051 Castro-Vega LJ, Kiando SR, Burnichon N, Buffet A, Amar L, Simian C, Berdelou A, Galan P, Schlumberger M, Bouatia-Naji N, Favier J, Bressac-de Paillerets B, Gimenez-Roqueplo AP, The MITF (2016) p.E318K Variant, as a Risk Factor for Pheochromocytoma and Paraganglioma. J Clin Endocrinol Metab 101(12):4764–4768. 10.1210/jc.2016-2103. Epub 2016 Sep 28. PMID: 27680874 Guhan SM, Artomov M, McCormick S et al (2020) Cancer risks associated with the germline MITF(E318K) variant. Sci Rep 10:17051. https://doi.org/10.1038/s41598-020-74237-z Potrony M, Badenas C, Aguilera P, Puig-Butille JA, Carrera C, Malvehy J, Puig S (2015) Update in genetic susceptibility in melanoma. Ann Transl Med 3(15):210. 10.3978/j.issn.2305 PMID: 26488006; PMCID: PMC4583600 Sturm RA, Fox C, McClenahan P, Jagirdar K, Ibarrola-Villava M, Banan P, Abbott NC, Ribas G, Gabrielli B, Duffy DL, Peter Soyer H (2014) Phenotypic characterization of nevus and tumor patterns in MITF E318K mutation carrier melanoma patients. J Invest Dermatol 134(1):141–149. https://doi.org/10.1038/jid.2013.272 Ciccarese G, Dalmasso B, Bruno W, Queirolo P, Pastorino L, Andreotti V, Spagnolo F, Tanda E, Ponti G, Massone C, Drago F, Parodi A, Ghigliotti G, Pizzichetta MA, Ghiorzo P (2020) Clinical, pathological and dermoscopic phenotype of MITF p.E318K carrier cutaneous melanoma patients. J translational Med 18(1):78 & Italian Melanoma Intergroup (I.M.I.). https://doi.org/10.1186/s12967-020-02253-8 Bonet, C., Luciani, F., Ottavi, J. F., Leclerc, J., Jouenne, F. M., Boncompagni, M.,Bille, K., Hofman, V., Bossis, G., Marco de Donatis, G., Strub, T., Cheli, Y., Ohanna,M., Luciano, F., Marchetti, S., Rocchi, S., Birling, M. C., Avril, M. F., Poulalhon,N., Luc, T., … Bertolotto, C. (2017). Deciphering the Role of Oncogenic MITFE318K in Senescence Delay and Melanoma Progression. Journal of the National Cancer Institute,109(8), 10.1093/jnci/djw340. https://doi.org/10.1093/jnci/djw340 Shevach JW, Xu J, Snyder N, Wei J, Shi Z, Tran H, Zheng SL, Beebe-Dimmer JL, Cooney KA (2025) Established Cancer Predisposition Genes in Single and Multiple Cancer Diagnoses. JAMA Oncol 11(10):1222–1230. https://doi.org/10.1001/jamaoncol.2025.2879 Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterials.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 14 May, 2026 Reviewers agreed at journal 03 May, 2026 Reviewers invited by journal 01 May, 2026 Editor assigned by journal 30 Apr, 2026 Submission checks completed at journal 30 Apr, 2026 First submitted to journal 28 Apr, 2026 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. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9555675","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":633570097,"identity":"e00ba70b-4755-4d8e-a897-7bfd847e959d","order_by":0,"name":"Luigi Monti","email":"","orcid":"","institution":"IRCCS Azienda Ospedaliero-Universitaria di Bologna","correspondingAuthor":false,"prefix":"","firstName":"Luigi","middleName":"","lastName":"Monti","suffix":""},{"id":633570098,"identity":"a7568163-3325-49e6-bc6f-99d929026191","order_by":1,"name":"Lea Godino","email":"","orcid":"","institution":"IRCCS Azienda Ospedaliero-Universitaria di Bologna","correspondingAuthor":false,"prefix":"","firstName":"Lea","middleName":"","lastName":"Godino","suffix":""},{"id":633570099,"identity":"4e1e9967-e8d8-4543-8132-7f7705449806","order_by":2,"name":"Clio Dessinioti","email":"","orcid":"","institution":"National and Kapodistrian University of Athens","correspondingAuthor":false,"prefix":"","firstName":"Clio","middleName":"","lastName":"Dessinioti","suffix":""},{"id":633570100,"identity":"3bf01e51-6254-448a-8bfa-1503574ae6fb","order_by":3,"name":"Alex Stratigos","email":"","orcid":"","institution":"National and Kapodistrian University of Athens","correspondingAuthor":false,"prefix":"","firstName":"Alex","middleName":"","lastName":"Stratigos","suffix":""},{"id":633570104,"identity":"91616a74-8ddd-4e4f-8fc9-fd81aba5aa7f","order_by":4,"name":"Olga Papadodima","email":"","orcid":"","institution":"National Hellenic Research Foundation","correspondingAuthor":false,"prefix":"","firstName":"Olga","middleName":"","lastName":"Papadodima","suffix":""},{"id":633570108,"identity":"35146f5f-f347-41cb-b4f4-769a9799da87","order_by":5,"name":"Alexander Pintzas","email":"","orcid":"","institution":"National Hellenic Research Foundation","correspondingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"","lastName":"Pintzas","suffix":""},{"id":633570112,"identity":"1d03b710-1133-4e9e-abef-054f53de58b9","order_by":6,"name":"Delia Nicoară","email":"","orcid":"","institution":"The Oncology Institute \"Prof.Dr.Ion Chiricuță\" Cluj-Napoca (IOCN)","correspondingAuthor":false,"prefix":"","firstName":"Delia","middleName":"","lastName":"Nicoară","suffix":""},{"id":633570116,"identity":"32431b1b-610c-4380-9479-9f8d896d802b","order_by":7,"name":"Stefania Boccia","email":"","orcid":"","institution":"IRCCS, Fondazione Policlinico Universitario A. 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Bologna","correspondingAuthor":true,"prefix":"","firstName":"Giovanni","middleName":"","lastName":"Innella","suffix":""},{"id":633570124,"identity":"98fe79a8-0a51-4523-9cdf-df06c3ae1a9a","order_by":12,"name":"Daniela Turchetti","email":"","orcid":"","institution":"IRCCS Azienda Ospedaliero-Universitaria di Bologna","correspondingAuthor":false,"prefix":"","firstName":"Daniela","middleName":"","lastName":"Turchetti","suffix":""}],"badges":[],"createdAt":"2026-04-28 14:53:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9555675/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9555675/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":109014659,"identity":"a7d5122b-31b7-49ca-8f2c-6f03405100c2","added_by":"auto","created_at":"2026-05-11 17:21:54","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":373212,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA 2020 flow diagram of the selection process of the articles.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-9555675/v1/ce883e745e5466f101fe4e98.png"},{"id":109068220,"identity":"744bda65-efa3-4290-beac-48e1ea1becea","added_by":"auto","created_at":"2026-05-12 10:04:44","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":660520,"visible":true,"origin":"","legend":"\u003cp\u003eMeta-analysis Odds Ratio of the Association between \u003cem\u003eMITF\u003c/em\u003e E318K variant and personal history of melanoma.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-9555675/v1/fc201d6e18787193d370e954.jpeg"},{"id":109014661,"identity":"15821133-82b5-45b0-88ed-feb0c9c038e5","added_by":"auto","created_at":"2026-05-11 17:21:54","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":771356,"visible":true,"origin":"","legend":"\u003cp\u003eMeta-analysis Odds Ratio of the Association between \u003cem\u003eMITF\u003c/em\u003e E318K variant and personal history of single Melanoma (a) and multiple Melanoma (b).\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-9555675/v1/1b910de102a8d8b8d1d472b9.png"},{"id":109204739,"identity":"f2f441bb-fbb0-47ef-a089-448963217d22","added_by":"auto","created_at":"2026-05-13 15:01:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1867118,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9555675/v1/a5640adc-42eb-4903-a294-c61be2bf9129.pdf"},{"id":109068236,"identity":"53caedb6-fa8f-407e-9ec7-604d4a8e8bad","added_by":"auto","created_at":"2026-05-12 10:04:49","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":5791455,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-9555675/v1/89794d5b970a9ce5910ceb4c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eA Systematic Review of Cancer Risks Associated With Mitf Variants\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eThe \u003cem\u003eMicrophthalmia‑associated Transcription Factor\u003c/em\u003e (\u003cem\u003eMITF\u003c/em\u003e) codes for a basic helix\u0026ndash;loop\u0026ndash;helix leucine zipper (bHLH‑Zip) transcription factor that plays a central role in cell survival, differentiation, proliferation, invasion, senescence, metabolism, and DNA damage repair\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. By regulating genes involved in melanogenesis, cellular metabolism, DNA repair, and stress responses, MITF acts as a master regulator of melanocytic homeostasis\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eGermline alterations in the \u003cem\u003eMITF\u003c/em\u003e gene (mapped to chromosome 3p13) are classically associated with Waardenburg syndrome type 2 and Tietz syndrome, both characterized by sensorineural hearing loss and pigmentary abnormalities\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Further, the \u003cem\u003eMITF\u003c/em\u003e gene has been incorporated into diagnostic multigene panels for hereditary cancer predisposition following the demonstration of an association between the E318K variant (exon 10) and an increased risk of cutaneous melanoma and renal cell carcinoma (RCC)\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Subsequent studies have suggested that carriers may benefit from tailored clinical management strategies, including enhanced dermatologic surveillance and renal imaging protocols\u003csup\u003e\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Despite these recommendations, the magnitude of cancer risk associated with \u003cem\u003eMITF\u003c/em\u003e E318K remains incompletely defined, with variability across study designs, populations, and ascertainment criteria, and it remains unknown whether other \u003cem\u003eMITF\u003c/em\u003e variants confer the same risks.\u003c/p\u003e \u003cp\u003eIn this context, the primary objective of the present review was to systematically identify and synthesize the available evidence on cancer risks associated with germline \u003cem\u003eMITF\u003c/em\u003e variants that can be detected while performing multigene testing, in order to support clinical interpretation and management, as well as to inform future research by highlighting knowledge gaps.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003eStudy design\u003c/h2\u003e\n\u003cp\u003eThe study was designed according to the Guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Protocol Statement to reduce reporting bias\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. The main steps included search methods, study selection, quality assessment, data extraction, and data synthesis. A Microsoft Excel-based method\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e was used to record and select data in subsequent steps to promote transparency. The protocol was registered on the Open Science Framework (OSF, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://osf.io/3f5pq\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eReview questions\u003c/h3\u003e\n\u003cp\u003eThe question to respond to, formulated according to the PEO (Population, Exposure, Outcomes) methodology (\u003cspan class=\"Underline\"\u003eSupplementary Table\u0026nbsp;1\u003c/span\u003e), was: \u003cem\u003e\u0026ldquo;What are the cancer risks associated with constitutional pathogenic variants of the MITF gene?\u0026rdquo;\u003c/em\u003e\u003c/p\u003e\n\u003ch3\u003eSearch strategy and study selection\u003c/h3\u003e\n\u003cp\u003eFour databases (Pubmed, Scopus, Web of Science and Cochrane) were searched for papers published from January 2011 to July 2025. We chose to start in 2011 because \u003cem\u003eMITF\u003c/em\u003e has been proposed as associated with increased cancer risks in that year. A detailed search strategy for all electronic databases is presented in \u003cspan class=\"Underline\"\u003eSupplementary Table\u0026nbsp;2\u003c/span\u003e. The reference lists of all included studies were hand-searched for additional relevant reports or key terms. Targeted internet searching using Google Scholar was also performed to find any additional studies of interest. Grey literature was consulted through the OpenGrey Repository (formerly System for Information on Grey Literature in Europe).\u003c/p\u003e\n\u003cp\u003eAll search results were imported into Microsoft Excel to allow their management, and duplicate records were removed before screening. Titles and abstracts were independently screened by two reviewers (LM, GI), followed by full-text assessment of potentially eligible articles. Any disagreements were resolved through discussion with a third reviewer (DT).\u003c/p\u003e\n\u003cp\u003eThe selection process and reasons for exclusion were documented in a PRISMA flow diagram. To ensure transparency and reproducibility, all steps of the search and selection process were recorded in an electronic logbook following the Excel-based systematic review method described by Godino (2023)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003eEligibility criteria\u003c/h3\u003e\n\u003cp\u003ePapers were eligible for inclusion in this systematic review if:\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003e\n\u003cp\u003ewritten in English or Italian language;\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003epublished in peer-reviewed journals and reporting original research (using any methods);\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ethe study sample explicitly included \u003cem\u003eMITF\u003c/em\u003e carriers;\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eit was possible to assess cancer risks from the study data.\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003ePapers were excluded from the review if they were:\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003e\n\u003cp\u003epreclinical research studies;\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003epharmacology studies;\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eabstract;\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ecase reports or opinion papers;\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ebooks.\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ol\u003e\n\u003ch3\u003eAssessment of methodological quality and risk of bias\u003c/h3\u003e\n\u003cp\u003eMethodological quality and the risk of bias were independently assessed by LM and CD using the validation tools of Kmet et al and of Hoy et al \u003csup\u003e11\u0026ndash;12\u003c/sup\u003e; any disagreement was discussed until consensus was reached. According to Kmet et al, items concerning methodology and reporting of results were assessed and assigned 0 point (not addressed), 1 point (partially addressed) or 2 points (completely addressed), with total scores reported as percentages; although a minimum score is not enforced for inclusion in a review, 60% is suggested as a reasonable cut-off. As suggested by Hoy et al, a study was considered to have high, moderate or low risk of bias if 3 or less, 4\u0026ndash;6 and 7\u0026ndash;11 of the assessed items, respectively, were satisfied. Publication bias was assessed using funnel plots.\u003c/p\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003eData analysis and synthesis\u003c/h2\u003e\n\u003cp\u003eTwo independent researchers (LM, GI) extracted data from the included studies using a pre-defined matrix that considers the following information: author(s) of the study, year of publication, country where the study was conducted, study aim(s), study design, sample size and findings relevant to the review question. The heterogeneity of included studies was determined. A narrative synthesis was conducted to describe the design, implementation, and findings of the studies. Whenever sufficient information was available and data format allowed comparisons, a synthesis of quantitative data through meta-analysis was performed, using germline \u003cem\u003eMITF\u003c/em\u003e pathogenic variants as event. Data were analyzed using Review Manager software (Cochrane Collaboration, Copenhagen, Denmark). All quantitative syntheses were restricted to dichotomous outcomes. Pooled odds ratios (Ors) with 95% confidence intervals (Cis) were calculated using a random-effects model, in light of the expected clinical and methodological heterogeneity across studies. Statistical heterogeneity was calculated using the \u0026chi;\u003csup\u003e2\u003c/sup\u003e test and I\u003csup\u003e2\u003c/sup\u003e test. I\u003csup\u003e2\u003c/sup\u003e values of \u0026lt;\u0026thinsp;25%, 25%\u0026ndash;75% or \u0026gt;\u0026thinsp;75% were considered to indicate low, medium, and high heterogeneity, respectively. The influence of each single study on the results was evaluated by removing each study from consideration one at a time.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMITF\u003c/strong\u003e \u003cstrong\u003evariants reporting\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe mRNA reference sequence used is the NM_000248.4, corresponding to the MANE Plus Clinical transcript.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eSearch results\u003c/h2\u003e \u003cp\u003eThe results of the literature search are summarized in the PRISMA flow diagram (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The database search identified 777 records, of which 395 were removed as duplicates, leaving 382 records for title and abstract screening. Following this initial screening, 39 articles were read in detail by researchers, and 11 met the inclusion criteria and were included in the systematic review.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of included studies\u003c/h2\u003e \u003cp\u003eAll the 11 included studies\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan additionalcitationids=\"CR14 CR15 CR16 CR17 CR18 CR19 CR20\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e were retrospective series, published between 2011 and 2020, and examined cancer risk associated with \u003cem\u003eMITF\u003c/em\u003e variants. Two studies were monocentric (one from France and one from Spain), while eight were multicentric (from United States, Canada, Brazil, Australia, Italy, Poland, Switzerland, Denmark). Nine studies focused only on cancer risk associated with the E318K variant, while the other two included the estimation of cancer risks associated with also other two \u003cem\u003eMITF\u003c/em\u003e variants (c.1081G\u0026thinsp;\u0026gt;\u0026thinsp;A;p.Val320Ile and c.938-325G\u0026thinsp;\u0026gt;\u0026thinsp;A). Eight studies evaluated only melanoma cohorts, while the other three studies evaluated cohorts of different cancer types.\u003c/p\u003e \u003cp\u003eOverall, the risk of bias of the included studies was low and the methodology quality was high. For most studies (10/11, 91.0%)\u003csup\u003e5, 13\u0026ndash;20\u003c/sup\u003e, data collection, sample characteristics and recruitment were considered appropriate. One study\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e showed a lower methodological quality score (62.5%) and was classified as having a moderate risk of bias. Despite this limitation, the study was retained in the systematic review, as it was the first to report an association between \u003cem\u003eMITF\u003c/em\u003e variants and cancer risk and provided unique data not available in the other included studies, thereby contributing to a broader interpretation of the evidence.\u003c/p\u003e \u003cp\u003eThe main characteristics and findings of the included studies are detailed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMain characteristics of included studies.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAuthor, date\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCountry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePopulation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDisease assessed\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eResearch design\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAim\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMain findings\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eKmet et al. (2004) score\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBertoletto et al. 2011\u003c/b\u003e\u003csup\u003e\u003cb\u003e5\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFrance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e829 cases,\u003c/p\u003e \u003cp\u003e1659 controls\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMelanoma and RCC\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMulticentric, Case\u0026ndash;control study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTo examine E318K MITF prevalence in patients with melanoma and/or renal cell carcinoma (RCC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThe \u003cem\u003eMITF\u003c/em\u003e E318K variant was associated with an increased risk of melanoma, renal cell carcinoma (RCC), and melanoma plus RCC.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e10/16; 62.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBerwick et al. 2014\u003c/b\u003e\u003csup\u003e\u003cb\u003e11\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAustralia, Italy, Canada, USA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1194 cases, 2430 controls\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMelanoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMulticentric, Case\u0026ndash;control study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTo assess E318K effect on melanoma risk and the interaction with other genetic risk factors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThe \u003cem\u003eMITF\u003c/em\u003e E318K variant was associated with an increased risk of melanoma. The association was strongest among individuals with a low‑risk phenotype.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e13/16; 81.25%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCastro-Vega et al. 2016\u003c/b\u003e\u003csup\u003e\u003cb\u003e17\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFrance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e555 cases, 2348 controls\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePCC/PGL\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMonocentric, Case\u0026ndash;control study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTo determinate the prevalence of E318K \u003cem\u003eMITF\u003c/em\u003e in a French cohort of Pheochromocytoma/Paraganglioma (PCC/PGL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThe \u003cem\u003eMITF\u003c/em\u003e E318K variant was associated with an increased risk of pheochromocytoma/paraganglioma (PCC/PGL).\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e16/16: 100%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGhiorzo et al. 2013\u003c/b\u003e\u003csup\u003e\u003cb\u003e15\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eItaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e667 cases, 2205 controls\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMelanoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMulticentric, Case\u0026ndash;control study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTo test prevalence of E318K \u003cem\u003eMITF\u003c/em\u003e in 667 Italian melanoma patients\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThe \u003cem\u003eMITF\u003c/em\u003e E318K variant was associated with an increased risk of melanoma.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e11/16; 68.75%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGromowsky et al. 2014\u003c/b\u003e\u003csup\u003e\u003cb\u003e14\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePoland\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e748 melanoma patients, 683 breast, 753 prostate, 729 colon, 737 lung, 576 kidney, 2114 controls.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMelanoma, breast cancer, prostate cancer, colorectal cancer, lung cancer, kidney cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMulticentric, Case\u0026ndash;control study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTo examine association between E318K and V320I and risk of cancer.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNeither \u003cem\u003eMITF\u003c/em\u003e E318K nor V320I showed a significant association with melanoma and other cancers.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e14/16; 87.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLouren\u0026ccedil;o et al. 2020\u003c/b\u003e\u003csup\u003e\u003cb\u003e10\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBrazil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e247 cases, 280 controls\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMelanoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMulticentric, Case\u0026ndash;control study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTo identify SNVs on pigmentation-related genes with importance in risk and clinicopathological aspects of CM.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThe \u003cem\u003eMITF\u003c/em\u003e c.938‑325G\u0026thinsp;\u0026gt;\u0026thinsp;A variant did not increase melanoma risk.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e15/16; 93.75%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMangas et al. 2016\u003c/b\u003e\u003csup\u003e\u003cb\u003e9\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSwitzerland\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41 cases, 146 controls\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMelanoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMulticentric, Case\u0026ndash;control study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTo obtain information about genetic predisposition to CM in Ticino.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThe \u003cem\u003eMITF\u003c/em\u003e E318K variant was associated with an increased risk of melanoma.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e15/16; 93.75%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMcMeniman EK, et al. 2019\u003c/b\u003e\u003csup\u003e\u003cb\u003e16\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAustralia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e585 patients, 659 controls\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMelanoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMulticentric, Case\u0026ndash;control study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTo ascertain whether the level of UV damage at the site of melanomas was associated with genetic polymorphisms.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThe \u003cem\u003eMITF\u003c/em\u003e E318K variant was associated with an increased risk of multiple primary melanomas.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e15/16; 93.75%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePotrony et al. 2016\u003c/b\u003e\u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSpain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e531 cases, 2704 controls\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMelanoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMonocentric, Case\u0026ndash;control study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTo evaluate the penetrance of E318K \u003cem\u003eMITF\u003c/em\u003e in patients with melanoma ad assess association with clinical and phenotypic features.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThe \u003cem\u003eMITF\u003c/em\u003e E318K variant was associated with an increased risk of melanoma.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e15/16; 93.75%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWadt et al. 2015\u003c/b\u003e\u003csup\u003e\u003cb\u003e12\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDenmark\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e296 cases (276 CM, 20 UM), 1965 controls\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMelanoma (cutaneous and uveal)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMulticentric, Case\u0026ndash;control study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTo examine frequence of melanoma predisposition gene in patients with cutaneous and uveal melanoma.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThe \u003cem\u003eMITF\u003c/em\u003e E318K variant was associated with an increased risk of melanoma.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12/16; 75.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eYokoyama et al. 2011\u003c/b\u003e\u003csup\u003e\u003cb\u003e4\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAustralia\u0026thinsp;+\u0026thinsp;UK\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3988 patients, 4068 controls\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMelanoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMulticentric, Case\u0026ndash;control study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTo assess the role of E318K \u003cem\u003eMITF\u003c/em\u003e variant to developing melanoma.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThe \u003cem\u003eMITF\u003c/em\u003e E318K variant was associated with an increased risk of melanoma.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e14/16; 87.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003ea. RCC: renal cells cancer.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eb. PCC/PGL: Pheochromocytoma/paraganglioma.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eRisk and features of melanoma in carriers of the E318K variant in the\u003c/b\u003e \u003cb\u003eMITF\u003c/b\u003e \u003cb\u003egene.\u003c/b\u003e\u003c/p\u003e \u003cp\u003eA total of 8,606 melanoma patients were genotyped for the \u003cem\u003eMITF\u003c/em\u003e E318K variant, which was detected in 182 patients (2.1%), while 8,424 patients (97.9%) were non-carriers (\u003cem\u003eMITF\u003c/em\u003e E318K wild-type). Out of 17,953 controls, 149 (0.8%) were E318K carriers. Data were subjected to meta-analysis to assess the likelihood of developing melanoma in \u003cem\u003eMITF\u003c/em\u003e E318K variant carriers: the presence of the variant was associated with an increased risk of melanoma (OR 2.55, CI 1.90\u0026ndash;3.43) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eSupplementary Table\u0026nbsp;3\u003c/span\u003e). Among papers that specify the number of melanomas occurred in individual patients \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, the risk of developing multiple primary melanomas (MPMs) results higher than that for single melanomas (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eSupplementary Table\u0026nbsp;3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThree studies\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e assessed the relationship between the \u003cem\u003eMITF\u003c/em\u003e E318K variant and melanoma-related phenotypes (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eSupplementary Table\u0026nbsp;4\u003c/span\u003e). The variant showed a strong association with very high nevus counts (\u0026gt;\u0026thinsp;200) in two studies (Potrony et al.: OR 8.4 in all patients and OR 12.4 in MPM cases; Yokohama et al.: OR 2.54), whereas Berwick et al. reported an opposite pattern, linking the variant to the absence of nevi (OR 5.9, CI 1.9\u0026ndash;18.0). Regarding pigmentary traits, in the same studies, \u003cem\u003eMITF\u003c/em\u003e E318K carriers with non-blue eyes appeared to have a higher melanoma risk, although these associations were not statistically significant. Age at melanoma onset, available for 89 carriers across four studies\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, 5, 13, 19\u003c/sup\u003e, was evenly distributed, with roughly half diagnosed at \u0026le;\u0026thinsp;50 years and half after 50.\u003c/p\u003e \u003cp\u003eData on histological subtypes were available for 45 patients from three studies\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, 17, 19\u003c/sup\u003e. Superficial spreading melanoma (SSM) was the most frequently observed subtype, reported in 30 patients (67.0%), followed by nodular melanoma (NM) in 12 cases (27.0%). Other subtypes were less common and included lentigo maligna melanoma (LMM, n\u0026thinsp;=\u0026thinsp;3.7%)), acral melanoma (AM, n\u0026thinsp;=\u0026thinsp;2.4%), and mucosal melanoma (MM, n\u0026thinsp;=\u0026thinsp;1.2%).\u003c/p\u003e \u003cp\u003e \u003cb\u003eAssociation of\u003c/b\u003e \u003cb\u003eMITF\u003c/b\u003e \u003cb\u003eE318K Variant with other malignancies\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe link between the \u003cem\u003eMITF\u003c/em\u003e E318K variant and the development of non‑melanoma cancers has been examined across several studies, particularly in relation to renal cell carcinoma (RCC), pancreatic cancer, and pheochromocytoma/paraganglioma, as summarized in \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eSupplementary Table\u0026nbsp;5\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eBertolotto et al. documented a substantial increase in RCC risk, reporting more than a sevenfold elevation among carriers who lacked mutations in established RCC‑predisposing genes (OR 7.64; 95% CI 3.15\u0026ndash;18.59)\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. However, other studies did not replicate this association, not confirming that carriers are at increased risk for renal cancer.\u003c/p\u003e \u003cp\u003eCastro‑Vega et al\u003csup\u003e21\u003c/sup\u003e. Reported a significant association with pheochromocytoma/paraganglioma after screening 555 unrelated affected individuals, observing a higher prevalence of the \u003cem\u003eMITF\u003c/em\u003e E318K variant (7/555, 1.3%) compared with controls (12/2348, 0.5%, OR 3.19; 95% CI 1.34\u0026ndash;7.59; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005).\u003c/p\u003e \u003cp\u003eIn contrast, Gromowsky et al\u003csup\u003e18\u003c/sup\u003e. Found no meaningful correlation between the \u003cem\u003eMITF\u003c/em\u003e E318K variant and other malignancies, including breast, prostate, colorectal, and lung cancers.\u003c/p\u003e \u003cp\u003e \u003cb\u003eAssociation between other\u003c/b\u003e \u003cb\u003eMITF\u003c/b\u003e \u003cb\u003evariants and cancer\u003c/b\u003e\u003c/p\u003e \u003cp\u003eTo date, no other \u003cem\u003eMITF\u003c/em\u003e variants have been robustly associated with cancer predisposition with sufficient clinical evidence. Gromowsky et al.\u003csup\u003e18\u003c/sup\u003e genotyped a cohort of 6340 cancer patients, including cases of melanoma, kidney, colorectal, lung, breast, and prostate cancer, for the \u003cem\u003eMITF\u003c/em\u003e variant c.1081G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Val320Ile). Only a single carrier of this variant was identified among melanoma patients, while no carriers were observed in any of the other cancer groups.\u003c/p\u003e \u003cp\u003eSimilarly, Louren\u0026ccedil;o et al.\u003csup\u003e14\u003c/sup\u003e investigated the potential role of the intronic \u003cem\u003eMITF\u003c/em\u003e variant c.938-325G\u0026thinsp;\u0026gt;\u0026thinsp;A, selected from a genome-wide association study (GWAS), in melanoma predisposition. The results did not reach statistical significance (OR 1.28, CI 0.84\u0026ndash;1.94; P\u0026thinsp;=\u0026thinsp;0.06), not supporting an association with melanoma risk.\u003c/p\u003e \u003cp\u003eThese findings are summarized in \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eSupplementary Table\u0026nbsp;3.\u003c/span\u003e\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis systematic review and meta‑analysis provide an updated and comprehensive evaluation of the role of \u003cem\u003eMITF\u003c/em\u003e germline variants in cancer predisposition. Across 11 retrospective case-control studies published between 2011 and 2020 \u003csup\u003e4\u0026ndash;5, 13\u0026ndash;21\u003c/sup\u003e, the evidence consistently supports a moderate but clinically relevant association between \u003cem\u003eMITF\u003c/em\u003e E318K and melanoma susceptibility, as already emerged in the meta-analysis study by Guhan et al.\u003csup\u003e22\u003c/sup\u003e, while the contribution of other \u003cem\u003eMITF\u003c/em\u003e variants to cancer risk remains unsubstantiated. The overall methodological quality of the included studies was high, with low risk of bias in most analyses, strengthening the reliability of the conclusions.\u003c/p\u003e \u003cp\u003eThe pooled data confirm that \u003cem\u003eMITF\u003c/em\u003e E318K carriers exhibit an increased likelihood of developing melanoma, with an OR of 2.55 (CI 1.90\u0026ndash;3.43). This magnitude of risk aligns with previous observations positioning \u003cem\u003eMITF\u003c/em\u003e E318K as an intermediate‑penetrance allele, comparable to other moderate‑risk melanoma genes\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Notably, the association becomes more pronounced in individuals with multiple primary melanomas (MPMs), for whom the risk nearly doubles. This is in line with previous studies that reported the detection of the \u003cem\u003eMITF\u003c/em\u003e E318K variant in multiple melanoma patients, as well as the more frequent occurrence of multiple primary melanomas among patients with the variant compared to those without (27% vs 11%, respectively)\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. This finding reinforces the hypothesis that \u003cem\u003eMITF\u003c/em\u003e E318K may contribute not only to melanoma initiation but also to a broader phenotype of melanocytic instability, predisposing carriers to recurrent tumorigenesis.\u003c/p\u003e \u003cp\u003eRegarding other clinical features of \u003cem\u003eMITF\u003c/em\u003e E318K variant carriers, markedly elevated nevus count\u0026mdash;particularly\u0026thinsp;\u0026gt;\u0026thinsp;200 nevi\u0026mdash;was consistently associated with the variant in two of the three studies evaluating this phenotype\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, 17\u003c/sup\u003e. High nevus burden is a well‑established melanoma risk factor, and its enrichment among carriers may suggest that \u003cem\u003eMITF\u003c/em\u003e E318K influence melanocyte proliferation or survival. However, the study by Berwick et al.\u003csup\u003e15\u003c/sup\u003e reported an opposite trend, linking the variant to the absence of nevi in MPM patients. This discrepancy may reflect methodological differences, population heterogeneity, or unmeasured environmental modifiers, underscoring the need for standardized phenotypic assessment in future research. However, it could also mean that the \u003cem\u003eMITF\u003c/em\u003e E318K variant and these clinical features may represent distinct factors that contribute to melanoma development. Pigmentary traits showed weaker and inconsistent associations: non‑blue eye color appeared to modestly increase melanoma risk among carriers although statistical significance was not consistently achieved\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, 15, 17\u003c/sup\u003e. Hair and skin color yielded similarly inconclusive results. These findings suggest that the oncogenic effect of \u003cem\u003eMITF\u003c/em\u003e E318K is not primarily mediated through classical melanoma-associated risk phenotypes, despite the gene\u0026rsquo;s central role in melanocyte biology. Instead, the variant\u0026rsquo;s functional impact\u0026mdash;disruption of SUMOylation and consequent transcriptional dysregulation\u0026mdash;may promote melanoma genesis through mechanisms independent of pigmentation\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, 5\u003c/sup\u003e. In addition, in melanocyte models, expression of \u003cem\u003eMITF\u003c/em\u003e E318K markedly impaired BRAFV600E-induced senescence, as evidenced by reduced β-galactosidase activity, sustained DNA synthesis, and decreased expression of senescence markers such as p16 and p21\u003csup\u003e26\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAge at melanoma onset was highly variable\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, 13, 19\u003c/sup\u003e, indicating that \u003cem\u003eMITF\u003c/em\u003e E318K does not strongly influence the timing of disease presentation. This contrasts with high‑penetrance melanoma genes such as \u003cem\u003eCDKN2A\u003c/em\u003e, which are typically associated with an early onset of the disease. The balanced age distribution further supports the classification of \u003cem\u003eMITF\u003c/em\u003e E318K as a moderate‑risk allele with variable expressivity.\u003c/p\u003e \u003cp\u003eBeyond melanoma, the evidence for an association between \u003cem\u003eMITF\u003c/em\u003e E318K and non‑melanoma malignancies remains heterogeneous. A markedly increased risk of renal cell carcinoma (RCC) was reported only in one study, particularly among individuals lacking mutations in known RCC‑predisposing genes\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. However, subsequent studies did not replicate this association in sporadic RCC cohorts\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e, suggesting that the risk cannot be generalized and may be confined to specific genetic or familial contexts.\u003c/p\u003e \u003cp\u003eRegarding other cancers, the association with pheochromocytoma/paraganglioma reported by Castro‑Vega et al.\u003csup\u003e21\u003c/sup\u003e is intriguing and biologically plausible, given the role of \u003cem\u003eMITF\u003c/em\u003e in neural crest\u0026ndash;derived lineages. However, this finding has not yet been replicated, and its clinical significance remains uncertain. Conversely, large‑scale analyses found no evidence linking the variant to other malignancies, suggesting that any broader oncogenic effect is likely absent\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eImportantly, no other \u003cem\u003eMITF\u003c/em\u003e variants demonstrated a convincing association with cancer predisposition. Both the c.1081G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Val320Ile) variant and the intronic c.938‑325G\u0026thinsp;\u0026gt;\u0026thinsp;A variant failed to show significant enrichment in cancer cohorts, reinforcing the unique relevance of the E318K substitution\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTaken together, these evidences support \u003cem\u003eMITF\u003c/em\u003e E318K as a moderate‑penetrance melanoma susceptibility allele with a particularly strong association with multiple primary melanomas and high nevus burden.\u003c/p\u003e \u003cp\u003eSeveral limitations of the available literature should be acknowledged. First, the included studies differed in terms of study design, cohort composition, ascertainment strategies, and analytical approaches, which limits the comparability of results. Second, although this systematic review was conducted in accordance with rigorous methodological guidelines, it remains possible that some relevant studies were unintentionally missed during the search process, potentially affecting the completeness of the evidence synthesis.\u003c/p\u003e \u003cp\u003eAdditional case series, ideally based on well‑characterized cohorts with adequate follow‑up, would be essential to refine current risk estimates and reduce the likelihood that existing data do not accurately reflect the true clinical scenario. Its role in non‑melanoma cancers remains suggestive but not definitive, warranting further investigation into larger, well‑characterized cohorts. Future studies should prioritize standardized phenotyping, exploration of gene\u0026ndash;gene and gene\u0026ndash;environment interactions, functional analyses to clarify the biological mechanisms underlying the variant\u0026rsquo;s pleiotropic effects and exploration of the potential interaction of the \u003cem\u003eMITF\u003c/em\u003e E318K variant with two major melanoma driver mutations, such as those of \u003cem\u003eBRAF\u003c/em\u003e and/or \u003cem\u003eNRAS\u003c/em\u003e.\u003c/p\u003e \u003cp\u003eIn light of the evidence currently available and acknowledging these limitations, it appears reasonable in clinical practice to exclusively consider the \u003cem\u003eMITF\u003c/em\u003e E318K variant when evaluating cancer risk in individuals undergoing multigene tumor predisposition panel testing, and to restrict such considerations to melanoma risk. Nevertheless, this approach should be interpreted cautiously and may require revision as additional data become available.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eIn conclusion, the available evidence suggests that the \u003cem\u003eMITF\u003c/em\u003e E318K variant may be regarded as a moderate‑penetrance allele associated with an increased susceptibility to melanoma, particularly for multiple primary melanomas and a high nevus burden. Although emerging data suggest possible associations with selected non‑melanoma malignancies, these findings remain inconsistent and require confirmation in larger, and genetically diverse cohorts. The absence of robust evidence for other \u003cem\u003eMITF\u003c/em\u003e variants further underscores the unique relevance of the E318K substitution in cancer predisposition. Continued research efforts integrating standardized phenotyping, functional studies, and comprehensive genomic analyses will be essential to clarify the biological mechanisms underlying \u003cem\u003eMITF\u003c/em\u003e‑related oncogenesis and to refine risk assessment strategies for carriers.\u003c/p\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eETHIC STATEMENT\u003c/h2\u003e \u003cp\u003eThis study is a systematic review of previously published studies and does not involve human participants or animals. Therefore, ethical approval and informed consent were not required.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eETHIC STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is a systematic review of previously published studies and does not involve human participants or animals. Therefore, ethical approval and informed consent were not required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDINGS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe work reported in this publication was funded by the Italian Ministry of Health, RC-2026-2801373.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONFLICT OF INTERESTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was funded by the European Union under Grant Agreement no. 101183265 – Joint Action JANE‑2. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or HaDEA. Neither the European Union nor the granting authority can be held responsible for them. The authors also acknowledge Carmela Caprara for her support in project management and coordination.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: GI, DT; methodology: LG, SM, GI, DT; investigation and data curation: all authors; writing—original draft preparation: LM; writing—review and editing: LM, LG, SM, GI, DT; all authors have read and agreed to the published version of the manuscript. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDECLARATION OF GENERATIVE AI USE\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors confirm that no generative artificial intelligence tools were used in the writing, analysis, or preparation of this manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eChauhan JS, H\u0026ouml;lzel M, Lambert JP, Buffa FM, Goding CR (2022) The MITF regulatory network in melanoma. 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Journal of the National Cancer Institute,109(8), 10.1093/jnci/djw340. https://doi.org/10.1093/jnci/djw340\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShevach JW, Xu J, Snyder N, Wei J, Shi Z, Tran H, Zheng SL, Beebe-Dimmer JL, Cooney KA (2025) Established Cancer Predisposition Genes in Single and Multiple Cancer Diagnoses. JAMA Oncol 11(10):1222\u0026ndash;1230. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1001/jamaoncol.2025.2879\u003c/span\u003e\u003cspan address=\"10.1001/jamaoncol.2025.2879\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"familial-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"fame","sideBox":"Learn more about [Familial Cancer](http://link.springer.com/journal/10689)","snPcode":"10689","submissionUrl":"https://submission.nature.com/new-submission/10689/3","title":"Familial Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-9555675/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9555675/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe \u003cem\u003eMITF\u003c/em\u003e E318K variant has been associated with melanoma risk, while risk associated with other variants or of other cancers remains uncertain. We performed a systematic review with meta-analysis of 11 retrospective case\u0026ndash;control studies to evaluate cancer risks associated with germline \u003cem\u003eMITF\u003c/em\u003e variants. Across 8,606 melanoma patients and 17,953 controls, the E318K variant was detected in 2.1% and 0.8% of individuals, respectively, corresponding to a significantly increased melanoma risk (OR 2.55, 95% CI 1.90\u0026ndash;3.43). The association was stronger in patients with multiple primary melanomas, with carrier frequencies up to 2.6% compared to 1.0% in single melanoma cases and ORs reaching 4.45 in individual studies. Phenotypic analyses showed enrichment of high nevus burden (\u0026gt;\u0026thinsp;200 nevi), with ORs up to 12.4 in multiple melanoma cohorts. No consistent association with age at onset or pigmentary traits was observed. Evidence for non-melanoma cancers was limited and heterogeneous: a single study reported increased renal cancer risk (OR 7.64), whereas larger cohorts failed to replicate this finding; an association with pheochromocytoma/paraganglioma was observed (OR 3.19) but lacks confirmation. No other \u003cem\u003eMITF\u003c/em\u003e variants demonstrated significant cancer risk. These findings support MITF \u003cem\u003eE318K\u003c/em\u003e as a moderate-penetrance melanoma susceptibility allele, particularly associated with multiple primary melanomas.\u003c/p\u003e","manuscriptTitle":"A Systematic Review of Cancer Risks Associated With Mitf Variants","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-11 17:21:45","doi":"10.21203/rs.3.rs-9555675/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-05-14T10:18:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"130746861934208656463362997407753554797","date":"2026-05-03T09:24:44+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-05-01T12:52:42+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-30T07:21:55+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-30T07:21:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"Familial Cancer","date":"2026-04-28T14:41:59+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"familial-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"fame","sideBox":"Learn more about [Familial Cancer](http://link.springer.com/journal/10689)","snPcode":"10689","submissionUrl":"https://submission.nature.com/new-submission/10689/3","title":"Familial Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"f8d92ff3-895f-4024-a558-e83b28ddbf42","owner":[],"postedDate":"May 11th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"","date":"2026-05-14T10:18:03+00:00","index":7,"fulltext":""},{"type":"reviewerAgreed","content":"130746861934208656463362997407753554797","date":"2026-05-03T09:24:44+00:00","index":6,"fulltext":""},{"type":"reviewersInvited","content":"4","date":"2026-05-01T12:52:42+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-30T07:21:55+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-30T07:21:33+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-11T17:21:46+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-11 17:21:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9555675","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9555675","identity":"rs-9555675","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}