Germline pathogenic variants in metaplastic breast cancer patients: a monocentric study and literature review

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Scarce information is available about germline testing in MpBC. We retrospectively reviewed MpBC patients counseled at our Institute and found to harbor germline pathogenic variants (PVs), and we revised literature data. We identified a germline PV in 15 MpBC patients: 13 in BRCA1 (86.7%), one in TP53 (6.7%), one in MLH1 (6.7%) genes. Eight MpBC PV carriers in BRCA1 have been previously described, including a patient with a PV in both BRCA1 and TP53 . MpBC histological subtype in PV carriers was heterogeneous. All MpBCs were TN but 13.3% in our series showed HER2 overexpression. We described the largest series of MpBCs with germline PVs. As previously reported, we observed that BRCA1 is the mainly involved gene in MpBC patients who underwent germline testing according to specific selection criteria. Additional studies on unselected patients are required to assess the authentic role of germline BRCA1 PVs in MpBCs and to explore the possible involvement of other genes in MpBC predisposition. Unraveling a specific MpBC molecular landscape is a starting point for the definition of new therapeutic strategies, since these tumors have a poor prognosis. Biological sciences/Cancer/Breast cancer Health sciences/Pathogenesis/Clinical genetics Metaplastic breast cancer germline genetic testing pathogenic variants BRCA1 gene Figures Figure 1 Figure 2 Introduction Metaplastic breast cancer (MpBC) is an aggressive malignancy characterized by the presence of two or more cell types, most commonly an admixture of epithelial and mesenchymal elements [ 1 ]. MpBC is a rare condition, accounting for about 0.2-5% of all breast cancers (BCs) [ 2 ]. However, it carries the worst prognosis in comparison to other BC types and plays a significant role in global BC mortality [ 3 ]. Indeed, almost all MpBCs are classified as triple-negative breast cancers (TNBCs), meaning that they are characterized by ≤ 1% nuclear expression of hormone receptors (HR) and HER2 negative status, with or without gene amplification [ 4 – 5 ]. TNBC is overall more aggressive than HR positive BC, being responsible for ⁓5% of all cancer-related deaths annually [ 6 ]. Despite the recent achievements in the treatment of BC, the current preferred approach for TNBC remains prevalently chemotherapy-based [ 7 ], or nothing in some low-risk TNBCs [ 8 ]. The majority of TNBCs (⁓95%) are histologically classified as high-grade invasive carcinomas of no special type (NST) and tend to spread very early to lymph nodes and/or distant organs [ 9–10]. Also, MpBC is tipically high-grade but has a more aggressive behavior compared to TNBC with NST, showing great propensity for recurrence and specific chemoresistance, in particular in neo-adjuvant settings [ 11 – 12 ]. The TNBC phenotype appears with an aggressive pattern [ 13 ] and to be closely associated with a hereditary cause of the disease [ 14 ], most frequently the Hereditary Breast and Ovarian Cancer (HBOC) syndrome. HBOC is an autosomal dominant condition caused by germline mutations in BRCA1 and BRCA2 genes. The latest National Comprehensive Cancer Network (NCCN) clinical practice guidelines recommend BRCA1/2 genetic testing for all TNBC patients aged ≤ 60 years [ 15 ]. More specifically, BRCA1 mutation carriers are more likely to develop TNBC than BRCA2 carriers [ 16 ]. In addition to HBOC, early-onset BC is a well-known phenotype also in Li Fraumeni syndrome (LFS), a rare hereditary disorder due to germline mutations in TP53 gene and responsible for epithelial and mesenchymal tumors. Accordingly, genetic testing of TP53 gene is recommended in all patients diagnosed with BC under the age of 31 years, regardless of family history [ 17 ]. As far as MpBC is concerned, only a few studies have been published exploring the association with germline PVs in cancer-related genes. On the whole, due to its rarity, histological diversity and aggressive nature, scarce information is available about genetic predisposition to MpBC. In this study, we revised literature data on MpBC genetic predisposition and we describe our series of MpBC patients found to carry germline PVs. Methods In the present study, we retrospectively searched for patients affected by MpBC who were addressed to genetic counseling at the Division of Cancer Prevention and Genetics of the European Institute of Oncology (IEO) between 2002 and 2022. They underwent germline genetic testing for one or more genes (including BRCA1 , BRCA2 , TP53 , and others) according to their personal/family history of cancer and were found to be carriers of a PV. Histological diagnosis had been performed or reviewed at IEO by pathologists with extensive experience in breast cancer. Variant pathogenicity was assessed based on the ACMG guidelines and using the ClinVar database ( https://www.ncbi.nlm.nih.gov/clinvar/ ). Personal and family history, clinical, histopathological and genetic data were collected and stored in a dedicated institutional database. The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of the European Institute of Oncology (UID 0833, date of approval 23/05/2018). Informed consent was obtained from all subjects involved in the study. We then compared our series of MpBC PV carriers with those reported in the literature. We performed a PubMed search (up to Dec 31, 2022) of the following keywords in the title/abstract of the articles: [germline variant OR germline mutation] AND [metaplastic breast cancer]. Additional papers were identified by a manual search of references from original articles and reviews. Studies not reporting molecular details of the germline PVs identified in MpBCs and/or family history (FH) of breast/ovarian cancers and/or not specifying the selection criteria used to address MpBC patients to genetic testing were excluded from this review. Results We identified 15 female MpBC carriers of a germline PV: 13 in BRCA1 (86.7%), one in TP53 (6.7%) and one in MLH1 (6.7%), as shown in Table 1. All variants were classified as pathogenic (C5) or likely pathogenic (C4). PVs were defined as follows: seven small deletions, two small insertions, two large rearrangements, three nonsense, and one missense. All PVs in BRCA1 and TP53 genes were truncating ( i.e. , predicted to result in a truncated protein product), while the one in MLH1 gene was a missense substitution. Mean age at MpBC diagnosis was 41.5 years (range 27–58). MpBCs were histologically heterogeneous, with the majority showing mesenchymal differentiation (47%) or displaying squamous features (27%). Notably, the TP53 PV carrier developed MpBC with sarcomatoid elements. All patients were diagnosed with a TNBC, except for two cases of HER2 overexpressed BC. Nine out of 15 patients (60%) were also diagnosed with other tumors, before or after MpBC: eight BRCA1 PV carriers developed other BCs, while the MLH1 PV carrier was also affected by colorectal cancer. Eight patients showed family history of BC and/or OC (53%), while the remaining seven patients (47%) did not report any relative affected by BC or OC. Pedigrees of the 15 MpBC patients of our series are shown in Fig. 1. We also performed a detailed literature search to identify previous papers about germline PVs in MpBC, describing also family history of BC/OC and selection criteria used for genetic testing. Eight case reports have been published so far on MpBC patients harboring germline PVs [ 18 – 25 ]. All of them were found to carry a C5 variant in BRCA1 gene; notably, one was also carrier of a C4 splicing variant in TP53 gene (Table 2). The nucleotide changes in BRCA1 gene included five small deletions or insertions leading to frameshift, one nonsense mutation, one large deletion and one missense substitution. Except for this last variant, all PVs were expected to result in a premature termination of the protein. Mean age at MpBC diagnosis of PV carriers was 30 years (range 15–49). All BCs were of TN subtype; however, the histological subtype of MpBC varied greatly among patients. Five out of eight cases (62.5%) were affected by other BCs in addition to the MpBC: all of them were invasive ductal carcinomas but the patient described by Breuer et al ., who was diagnosed with a metachronous bilateral MpBC with squamous differentiation. A positive family history of BC and/or OC was described in five out of eight (62.5%) of the screened MpBC cases. Discussion To the best of our knowledge, we report here the largest monocentric series of MpBC patients harboring a germline PV and fully described in terms of clinical and molecular characteristics, as well as family history of BC/OC. Indeed, only eight single case reports have been published so far with all information. These eight MpBC cases reported in the literature carried PVs almost exclusively in BRCA1 gene, except for the unusual case of a woman affected by both HBOC and LFS [ 25 ]. An additional 54-year-old woman affected by TN MpBC with osseous differentiation has been reported [ 26 ]: a genetic alteration in BRCA1 was identified in the tumor (c.1530del, p.Gly511AlafsTer21), but the patient refused to undergo germline testing and she did not have any family history of malignancies. In addition to these case reports, systematic review of the existing literature revealed several other studies concerning germline PVs of different cancer genes in MpBC patients. However, they did not include molecular details about the detected variants and/or on FH of cancer, and/or did not specify which selection criteria they used to address patients to genetic testing. Therefore, we decided not to include them in our review and we only cite them here. In a recent paper on neoadjuvant chemotherapy in MpBC, Wong et al . (27) reported that two out of 31 (6%) MpBC patients who underwent genetic testing were found to carry a BRCA1 germline mutation, one of which being a large deletion of exons 23–24. Additional studies on target therapies or specific clinical management for BRCA -positive MpBC patients have also been published [ 28 – 29 ]. Moukarzel et al. [ 30 ] identified Homologous Recombination DNA Repair deficiency (HRD) in 15 out of 33 MpBCs (45%). Of relevance, six of the 15 HRD-defective cases harbored a germline PV in BRCA1 (6/15 = 40%) and one in BRCA2 (1/15 = 7%). Moreover, eight additional case reports described MpBC development in patients with a clinical diagnosis of Neurofibromatosis type 1 [ 31 – 38 ]. However, only one of these patients underwent detailed germline analysis and proved to be carrier of a deleterious variant in NF1 gene [ 38 ]. Finally, Rodríguez-Fernández and colleagues [ 39 , 40 ] found a statistically significant difference in frequencies of histological types between BRCA1 carriers vs. non carriers. In particular, they reported 3.2% MpBCs in 93 BRCA1 -positive BCs vs. 0.8% MpBCs in 3157 non BRCA -positive BCs. Taken together, all these evidences from case reports, retrospective reviews and studies on target therapies point to a possible involvement in MpBC genetic predisposition for different cancer-related genes, but mainly for BRCA1 gene. Our results are consistent with literature data: in a series of 15 MpBC patients, the great majority of the identified germline PVs lied in the BRCA1 gene (86.7%), confirming that it could have a crucial role in MpBC predisposition. We also identified a TP53 PV carrier without any alteration in BRCA1 gene. The patient was diagnosed with multiple BCs over time, including a TN MpBC with sarcomatoid features at 52 years of age (Fig. 1, patient ID 14). Interestingly, no FH suggestive for LFS syndrome was observed, even if family was relatively small. Of relevance, we also describe for the first time a germline C4 variant of MLH1 gene in a patient who developed both CRC at 51 and MpBC at 58 years of age (Fig. 1, patient ID 15). Constitutive mutations of mismatch repair genes (including MLH1 , MSH2 , MSH6 and PMS2 ) are known to cause the Lynch syndrome (LS), an inherited condition characterized by an increased risk of developing many tumor types, mainly colorectal and endometrial cancers [ 40 – 41 ]. Whether BC belongs to the LS spectrum is a long-standing question [ 42 – 43 ]; at any rate, MLH1 germline defects have never been reported before in MpBC patients. Proband’s father was affected by both CRC and pancreatic cancer at 72 years of age, and grandmothers from both paternal and maternal sides of the family were reported to be diagnosed with BC (at 40 and 65 years, respectively). Notably, the patient also harbored other two genetic variants (class C3 according to the ACMG classification): the c.5986G > A (p.Ala1996Thr) variant in BRCA2 gene and the c.3313G > A (p.Gly1105Arg) in MSH6 gene. We cannot exclude that the missense substitution in BRCA2 could act as a low penetrance variant for BC risk nor that additional genetic/environmental factor could modulate BC risk in this family. Almost all PVs detected in MpBC patients were expected to result in a truncated protein product, but the c.181T > G C5 missense variant of BRCA1 and the c.375 + 2T > C C4 splicing variant of TP53 reported in the literature, and the c.244A > G C4 missense variant of MLH1 gene described in our series. The most common mutation types were small deletions/insertions leading to frameshift, followed by nonsense. The germline PVs we identified were different compared with those already reported, except for the BRCA1 c.5266dup variant, described both in our series and in a previous report [ 24 ]. In addition, we identified the c.5030_5033del BRCA1 variant in two different MpBC patients. These variants are among the most frequent mutations detected in BRCA1 gene, in Europe or worldwide [ 44 ]. A potential limitation of our study is that we focused on molecular findings only in a small group of patients, making it difficult to perform statistical analysis or extrapolation to other individuals with MpBC. At any rate, no hotspot mutations specific for MpBC seem to be identifiable in BRCA1 gene. Several PVs clustered in exon 11 of BRCA1 , just because it is the largest one of the gene (3426 base pairs). On the whole, the germline variants found in MpBC patients – both in our series and in published case reports - fall within the three regions most frequently mutated in cancer patients. These include the RING (Really Interesting New Gene) domain (exons 2–7), a region encoded by exons 11–13, and the BRCT (BRCA1 C-terminus) domain (exons 16–24) [Clark 2012] (Fig. 2). RING is responsible for the interaction of BRCA1 with BARD1. The region encoded by exons 11–13 contains multiple binding sites for a number of diverse proteins; it includes for example the SCD (serine containing domain), which mediates interaction with PALB2. Finally, the BRCT domain is again critical for tumor suppression, since its main function is modulating phosphoprotein interactions between BRCA1 and proteins phosphorylated by ATM and ATR , two kinases activated by DNA damage. As regards histological classification, MpBCs of PV carriers reported in the literature were extremely heterogeneous, displaying epithelial, mesenchymal and mixed features. Our series showed the same variability: although the most prevalent phenotype was MpBC with mesenchymal differentiation (47%), we did not observe a specific histological subtype in patients with BRCA1 PVs. Notably, the TP53 PV carrier developed MpBC with sarcomatoid elements. All the eight MpBCs described in previous case reports were of TN subtype, as expected from literature data. In our series, TN phenotype was the most frequent subtype as well (86.7%), even though 13.3% of MpBCs showed HER2 overexpression (one with a BRCA1 germline PV and the other with the germline MLH1 PV). In the eight case reports reviewed, family history of BRCA -positive MpBC cases was ascertained: three of them were apparently sporadic, three presented positive FH of BC, one of OC, and one of both BC and OC. Our case series reflects literature data, since about 50% of MpBC cases seem to be sporadic. However, it should be stressed that these are highly selected cases, addressed to genetic counselling and germline testing due to specific clinical criteria, which include but are not limited to FH ( i.e. development of early-onset BC and/or of TNBC ≤ 60 years and/or of bilateral BC and/or presence of family history of BC/OC). Additional studies on larger unselected series of cases are required to better characterize MpBC genetic predisposition. These studies, if conducted on unselected MpBC patients and through careful data collection (family history, histological classification, etc.), are expected to unravel the authentic detection rate of PVs in BRCA1 gene, as well as to explore the possible involvement of additional genes in increasing the risk of developing MpBC. There are multiple evidences suggesting that MpBC and TNBC of NST are two independent and extremely heterogeneous BC subtypes, particularly in their clinical manifestations. Such different features require the urgent definition for new systemic therapeutic strategies. Further studies are needed to uncover the specific genetic landscape of MpBCs, since it would be an interesting starting point for the definition of new therapeutic strategies. Conclusions Taken together, our findings and literature data point to the following conclusions: 1) in MpBC patients described so far, who are highly selected for germline testing of specific genes, BRCA1 seems to play a crucial role in increasing the risk of MpBC development; 2) additional studies on larger, unselected series of patients are necessary to elucidate the authentic role of germline BRCA1 PVs in MpBCs and to explore the possible implication of other genes in MpBC predisposition; 3) almost all PVs detected in MpBC carriers were clearly deleterious and predicted to result in a truncated protein product; 4) no hotspot mutations specific for MpBC seem to be detectable in BRCA1 gene, since the identified PVs are frequently found in HBOC patients or affect the most commonly mutated regions of the protein in cancer patients; 5) BRCA1 PVs do not seem to be associated with a specific histological subtype of MpBC; 6) almost all MpBCs in PV germline carriers are TN, with a few exceptions of HER2 overexpressed cases; 7) unraveling MpBC genetic predisposition and its specific molecular landscape is important for the clinical management of affected patients and families and could be a starting point for the definition of new therapeutic strategies. Declarations Author Contributions: Concept and design, XX; Supervisor board, XX; Iconography and graphic design, XX; Acquisition of data, analysis, and interpretation of data, critical revision of the manuscript for important intellectual content, final approval of manuscript-all authors. Drafting of the manuscript, XX, with input of all authors. All authors have read and agreed to the published version of the manuscript. Funding: This manuscript was partially supported by the Italian ministry of Health with Ricerca Corrente and 5 × 1000 funds. Data Availability Statement: Not publicly available. Conflicts of Interest: The authors declare no conflict of interest. References Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ (eds). WHO classification of tumours of the breast, 4th edition, vol. 4. Geneva, Switzerland WHO Press 2012. Reddy TP, Rosato RR, Xiaoxian Li, Moulder S, Piwnica-Worms H, Chang JC. 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Genet Med. 2020 Apr;22(4):811–812. doi: 10.1038/s41436-019-0716-6 . Rebbeck TR, Friebel TM, Friedman E, Hamann U, Huo D, Kwong A, et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593–620. doi: 10.1002/humu.23406 . Clark CC, Weitzel JN, O'Connor TR. Enhancement of synthetic lethality via combinations of ABT-888, a PARP inhibitor, and carboplatin in vitro and in vivo using BRCA1 and BRCA2 isogenic models. Mol Cancer Ther. 2012 Sep;11(9):1948–58. doi: 10.1158/1535-7163.MCT-11-0597 . Tables Table 1. Germline PVs, family history and clinical, histological characteristics of our series of MpBC patients. Patient ID Gene Germline defect a Location b Variant description Age at diagnosis Laterality Histopathological Classification C Sub-type Other tumors (age) FH d 1 BRCA1 c.(?_-119)_(80+1_81-1)del p.(?) 5'UTR, exons 1 and 2 Large rearr. 44 Left Squamous cell carcinoma TN Right IDC (40); left IDC (42) no 2 BRCA1 c.798_799del p.(Ser267LysfsTer19) Exon 11 Deletion 36 Left Metaplastic carcinoma with heterologous mesenchymal differentiation (matrix-producing) TN Right IDC (24) no 3 BRCA1 c.816_825dup p.(Thr276AlafsTer14) Exon 11 Insertion 37 Left Squamous cell carcinoma TN _ BC/OC 4 BRCA1 c.2934T>G p.(Tyr978Ter) Exon 11 Non-sense 48 Right Squamous cell carcinoma TN Left IDC (30); right IDC (37) BC 5 BRCA1 c.3904G>T p.(Glu1302Ter) Exon 11 Non-sense 47 Left Metaplastic carcinoma with heterologous mesenchymal differentiation (matrix-producing carcinoma) TN _ BC 6 BRCA1 c.3228_3229del p.(Gly1077AlafsTer8) Exon 11 Deletion 35 Left Metaplastic carcinoma with heterologous mesenchymal differentiation (chondroid) TN Right IDC (39) no 7 BRCA1 c.1088del p.(Asn363IlefsTer11) Exon 11 Deletion 52 Left Metaplastic carcinoma with heterologous mesenchymal differentiation (matrix-producing carcinoma) TN _ no 8 BRCA1 c.4186-3156_4357+94dup p.(?) Exon 13 Large rearr. 47 Right Spindle cell carcinoma TN _ no 9 BRCA1 c.4964_4982del p.(Ser1655TyrfsTer16) Exon 16 Deletion 40 Left Mixed metaplastic carcinoma HER2+ Left DCIS (40) BC 10 BRCA1 c.5030_5033del p.(Thr1677IlefsTer2) Exon 17 Deletion 40 Left Metaplastic carcinoma with heterologous mesenchymal differentiation (matrix-producing carcinoma) TN Right IDC (35) OC 11 BRCA1 c.5030_5033del p.(Thr1677IlefsTer2) Exon 17 Deletion 28 Left Mixed metaplastic carcinoma TN _ no 12 BRCA1 c.5179A>T p.(Lys1727Ter) Exon 19 Non-sense 27 Left Metaplastic carcinoma with heterologous mesenchymal differentiation (matrix-producing carcinoma and chondroid) TN _ BC 13 BRCA1 c.5266dup p.(Gln1756ProfsTer74) Exon 20 Insertion 32 Right Spindle cell carcinoma TN Left IDC (33) BC/OC 14 TP53 c.635_636del p.(Phe212SerfsTer3) Exon 5 Deletion 52 Left Spindle cell carcinoma TN Left IDC (36, 39, 54); right IDC (37); right DCIS (45, 47); multiple BCCs no 15 MLH1 c.244A>G p.(Thr82Ala) Exon 3 Missense 58 Left Metaplastic carcinoma with heterologous mesenchymal differentiation (rhabdomyoid) HER2+ CRC (51) BC BC: breast cancer; BCC: basal cell carcinoma; CRC: colorectal cancer; DCIS: ductal carcinoma in situ; FH: family history; IDC: infiltrating ductal carcinoma; MpBC: metaplastic breast cancer; N/A: not applicable; NOS: not otherwise specified; OC: ovarian cancer; TN: triple negative. a cDNA and protein changes are named according to HGVS nomenclature. Reference sequences: BRCA1 NM_007294.4; TP53 NM_000546.5; MLH1 NM_000249.4 b After exon 3, subsequent exon numbers of BRCA1 gene are increased by one, due to historical misannotation of an additional “exon 4” c Classification into seven sub-categories following the WHO guidelines [1; 3] d Family history of BC or OC in 1 st and 2 nd degree relatives on the maternal side or until 3 rd degree relatives on the paternal side (pathology-confirmed or self-reported cancer diagnoses) Table 2. Germline PVs, family history and clinical, histological characteristics of MpBC patients reported in the literature. Reference Gene Germline defect a Location b Variant description Age at diagnosis Laterality Histology Sub-type Other tumors (age) FH c Rashid 2011 BRCA1 c.68_69del p.(Glu23ValfsTer17) Exon 2 Deletion 22 Left Mixed metaplastic carcinoma (epithelial and mesenchymal components) TN _ No Nöel 2010 BRCA1 c.66dup p.(Glu23ArgfsTer18) Exon 2 Insertion 49 Right Low-grade adenosquamous carcinoma TN Right IDC (36) No Breuer 2007 BRCA1 c.181T>G p.(Cys61Gly) Exon 5 Missense 25 Right Squamous cell carcinoma TN Left MBC with squamous cells (28) BC Yamashita 2021 BRCA1 c.188T>A p.(Leu63Ter) Exon 5 Non-sense 39 Left Mixed metaplastic carcinoma (invasive ductal carcinoma and mesenchymal component with chondroid differentiation) TN Left IDC (39) BC/OC Vohra 2022 BRCA1 c.1961dup p.(Tyr655ValfsTer18) Exon 11 Insertion 15 Right Metaplastic carcinoma with heterologous mesenchymal differentiation TN _ No Ghilli 2017 BRCA1 c.4754_4755del p.(Pro1585ArgfsTer36) Exon 16 Deletion 35 Right Mixed metaplastic carcinoma (epithelial and mesenchymal components TN Right IDC (35) BC Suspitsin 2011 BRCA1 c.5266dup p.(Gln1756ProfsTer74) Exon 20 Insertion 35 Left Mixed metaplastic carcinoma (epithelial and mesenchymal components TN _ OC Bell 2014 BRCA1 TP53 c.81-?_134+?del p.(Cys27Ter) c.375+2T>C p.(?) Exon 3 Intron 4 Large rearr. Splicing 20 Right Metaplastic carcinoma, NOS TN Right IDC (20) BC BC: breast cancer; FH: family history; IDC: infiltrating ductal carcinoma; MpBC: metaplastic breast cancer;N/A: not applicable; NOS: not otherwise specified; OC: ovarian cancer; TN: triple negative. a cDNA and protein changes are named according to HGVS nomenclature. Reference sequences: BRCA1 NM_007294.4; TP53 NM_000546.5 b After exon 3, subsequent exon numbers of BRCA1 gene are increased by one, due to historical misannotation of an additional “exon 4” c Classification into seven sub-categories following the WHO guidelines [1; 3] d Pathology-confirmed or self-reported cancer diagnoses Additional Declarations There is no duality of interest Cite Share Download PDF Status: Published Journal Publication published 18 Jul, 2023 Read the published version in European Journal of Human Genetics → Version 1 posted Editorial decision: revise 27 Apr, 2023 Review # 2 received at journal 25 Apr, 2023 Reviewer # 2 agreed at journal 19 Apr, 2023 Review # 1 received at journal 31 Mar, 2023 Reviewer # 1 agreed at journal 31 Mar, 2023 Reviewers invited by journal 13 Mar, 2023 Submission checks completed at journal 11 Mar, 2023 Editor assigned by journal 08 Mar, 2023 First submitted to journal 08 Mar, 2023 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. 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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-2668559","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":182717776,"identity":"ebc0fcba-75e6-4d98-a021-75c84b5dd059","order_by":0,"name":"Giovanni 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IRCCS","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Massimo","middleName":"","lastName":"Barberis","suffix":""},{"id":182717790,"identity":"fc3b6232-cf93-4259-a464-b3560a770811","order_by":14,"name":"Aliana Guerrieri-Gonzaga","email":"","orcid":"","institution":"European Institute of Oncology, IRCCS","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Aliana","middleName":"","lastName":"Guerrieri-Gonzaga","suffix":""},{"id":182717791,"identity":"5bf6d0f3-b9a2-48c4-af85-314d9d95018b","order_by":15,"name":"Bernardo Bonanni","email":"","orcid":"https://orcid.org/0000-0003-3589-2128","institution":"European Institue of Oncology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Bernardo","middleName":"","lastName":"Bonanni","suffix":""}],"badges":[],"createdAt":"2023-03-08 08:31:38","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2668559/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2668559/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41431-023-01429-2","type":"published","date":"2023-07-18T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":34419186,"identity":"4f67b5ea-3a3d-4b8c-9667-551610656e63","added_by":"auto","created_at":"2023-03-17 14:24:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":185121,"visible":true,"origin":"","legend":"\u003cp\u003ePedigrees of MpBC PV carriers described in our series.\u003c/p\u003e\n\u003cp\u003eID number of the proband is shown on the top left corner of each family tree. Index case is indicated by an arrow. Tumors and ages at diagnosis are displayed under affected individuals.\u003c/p\u003e\n\u003cp\u003eBC: breast cancer; CNS: central nervous system; CRC: colorectal cancer; GC: gastric cancer; EC: endometrial cancer; NOS: not otherwise specified; OC: ovarian cancer; PanC: pancreatic cancer; PrC: prostate cancer.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-2668559/v1/ceba9cbe8a6f9dbd34aefde1.png"},{"id":34419187,"identity":"e344324f-8194-489f-aca9-50274fdd4662","added_by":"auto","created_at":"2023-03-17 14:24:49","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":68252,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of unique germline\u0026nbsp;\u003cem\u003eBRCA1\u003c/em\u003e\u0026nbsp;PVs\u0026nbsp;identified\u0026nbsp;in MpBC patients (modified from \u003cem\u003eBRCA\u003c/em\u003e Exchange https://brcaexchange.org/). Alternate exons are shown as rectangles, with the corresponding number underneath. Donor splice sites are depicted in violet, acceptor splice site in blue. After exon 3, subsequent exon numbers are increased by one, due to historical mis-annotation of an additional “exon 4”. Exon 11 is not to scale, since it covers \u0026gt;65% of \u003cem\u003eBRCA1\u003c/em\u003e sequence.\u003c/p\u003e\n\u003cp\u003ePVs described in our series are indicated in bold; PVs reported in previous case reports are in normal type.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003ereported twice in our series\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003ereported both in our series and in [24]\u003c/p\u003e\n\u003cp\u003eThe three regions of BRCA1 protein that are mutated in cancer patients with a higher frequency [44] are indicated above the graph.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-2668559/v1/e8a9950e87de790050f17d31.png"},{"id":40356818,"identity":"03c62b6d-119a-4c2b-8973-16db393fc85e","added_by":"auto","created_at":"2023-07-21 07:14:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":566733,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2668559/v1/a187802b-a8ee-4ee1-b096-b155a9e654ea.pdf"}],"financialInterests":"There is no duality of interest","formattedTitle":"Germline pathogenic variants in metaplastic breast cancer patients: a monocentric study and literature review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMetaplastic breast cancer (MpBC) is an aggressive malignancy characterized by the presence of two or more cell types, most commonly an admixture of epithelial and mesenchymal elements [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. MpBC is a rare condition, accounting for about 0.2-5% of all breast cancers (BCs) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, it carries the worst prognosis in comparison to other BC types and plays a significant role in global BC mortality [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Indeed, almost all MpBCs are classified as triple-negative breast cancers (TNBCs), meaning that they are characterized by \u0026le;\u0026thinsp;1% nuclear expression of hormone receptors (HR) and HER2 negative status, with or without gene amplification [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. TNBC is overall more aggressive than HR positive BC, being responsible for ⁓5% of all cancer-related deaths annually [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Despite the recent achievements in the treatment of BC, the current preferred approach for TNBC remains prevalently chemotherapy-based [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], or nothing in some low-risk TNBCs [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The majority of TNBCs (⁓95%) are histologically classified as high-grade invasive carcinomas of no special type (NST) and tend to spread very early to lymph nodes and/or distant organs [ 9\u0026ndash;10]. Also, MpBC is tipically high-grade but has a more aggressive behavior compared to TNBC with NST, showing great propensity for recurrence and specific chemoresistance, in particular in neo-adjuvant settings [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe TNBC phenotype appears with an aggressive pattern [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] and to be closely associated with a hereditary cause of the disease [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], most frequently the Hereditary Breast and Ovarian Cancer (HBOC) syndrome. HBOC is an autosomal dominant condition caused by germline mutations in \u003cem\u003eBRCA1\u003c/em\u003e and \u003cem\u003eBRCA2\u003c/em\u003e genes. The latest National Comprehensive Cancer Network (NCCN) clinical practice guidelines recommend \u003cem\u003eBRCA1/2\u003c/em\u003e genetic testing for all TNBC patients aged\u0026thinsp;\u0026le;\u0026thinsp;60 years [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. More specifically, \u003cem\u003eBRCA1\u003c/em\u003e mutation carriers are more likely to develop TNBC than \u003cem\u003eBRCA2\u003c/em\u003e carriers [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In addition to HBOC, early-onset BC is a well-known phenotype also in Li Fraumeni syndrome (LFS), a rare hereditary disorder due to germline mutations in \u003cem\u003eTP53\u003c/em\u003e gene and responsible for epithelial and mesenchymal tumors. Accordingly, genetic testing of \u003cem\u003eTP53\u003c/em\u003e gene is recommended in all patients diagnosed with BC under the age of 31 years, regardless of family history [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAs far as MpBC is concerned, only a few studies have been published exploring the association with germline PVs in cancer-related genes. On the whole, due to its rarity, histological diversity and aggressive nature, scarce information is available about genetic predisposition to MpBC. In this study, we revised literature data on MpBC genetic predisposition and we describe our series of MpBC patients found to carry germline PVs.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eIn the present study, we retrospectively searched for patients affected by MpBC who were addressed to genetic counseling at the Division of Cancer Prevention and Genetics of the European Institute of Oncology (IEO) between 2002 and 2022. They underwent germline genetic testing for one or more genes (including \u003cem\u003eBRCA1\u003c/em\u003e, \u003cem\u003eBRCA2\u003c/em\u003e, \u003cem\u003eTP53\u003c/em\u003e, and others) according to their personal/family history of cancer and were found to be carriers of a PV. Histological diagnosis had been performed or reviewed at IEO by pathologists with extensive experience in breast cancer. Variant pathogenicity was assessed based on the ACMG guidelines and using the \u003cem\u003eClinVar\u003c/em\u003e database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/clinvar/\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/clinvar/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Personal and family history, clinical, histopathological and genetic data were collected and stored in a dedicated institutional database. The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of the European Institute of Oncology (UID 0833, date of approval 23/05/2018). Informed consent was obtained from all subjects involved in the study.\u003c/p\u003e \u003cp\u003eWe then compared our series of MpBC PV carriers with those reported in the literature. We performed a PubMed search (up to Dec 31, 2022) of the following keywords in the title/abstract of the articles: [germline variant OR germline mutation] AND [metaplastic breast cancer]. Additional papers were identified by a manual search of references from original articles and reviews. Studies not reporting molecular details of the germline PVs identified in MpBCs and/or family history (FH) of breast/ovarian cancers and/or not specifying the selection criteria used to address MpBC patients to genetic testing were excluded from this review.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eWe identified 15 female MpBC carriers of a germline PV: 13 in \u003cem\u003eBRCA1\u003c/em\u003e (86.7%), one in \u003cem\u003eTP53\u003c/em\u003e (6.7%) and one in \u003cem\u003eMLH1\u003c/em\u003e (6.7%), as shown in Table\u0026nbsp;1. All variants were classified as pathogenic (C5) or likely pathogenic (C4). PVs were defined as follows: seven small deletions, two small insertions, two large rearrangements, three nonsense, and one missense. All PVs in \u003cem\u003eBRCA1\u003c/em\u003e and \u003cem\u003eTP53\u003c/em\u003e genes were truncating (\u003cem\u003ei.e.\u003c/em\u003e, predicted to result in a truncated protein product), while the one in \u003cem\u003eMLH1\u003c/em\u003e gene was a missense substitution.\u003c/p\u003e \u003cp\u003eMean age at MpBC diagnosis was 41.5 years (range 27\u0026ndash;58). MpBCs were histologically heterogeneous, with the majority showing mesenchymal differentiation (47%) or displaying squamous features (27%). Notably, the \u003cem\u003eTP53\u003c/em\u003e PV carrier developed MpBC with sarcomatoid elements. All patients were diagnosed with a TNBC, except for two cases of HER2 overexpressed BC.\u003c/p\u003e \u003cp\u003eNine out of 15 patients (60%) were also diagnosed with other tumors, before or after MpBC: eight \u003cem\u003eBRCA1\u003c/em\u003e PV carriers developed other BCs, while the \u003cem\u003eMLH1\u003c/em\u003e PV carrier was also affected by colorectal cancer.\u003c/p\u003e \u003cp\u003eEight patients showed family history of BC and/or OC (53%), while the remaining seven patients (47%) did not report any relative affected by BC or OC. Pedigrees of the 15 MpBC patients of our series are shown in Fig.\u0026nbsp;1.\u003c/p\u003e \u003cp\u003eWe also performed a detailed literature search to identify previous papers about germline PVs in MpBC, describing also family history of BC/OC and selection criteria used for genetic testing. Eight case reports have been published so far on MpBC patients harboring germline PVs [\u003cspan additionalcitationids=\"CR19 CR20 CR21 CR22 CR23 CR24\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. All of them were found to carry a C5 variant in \u003cem\u003eBRCA1\u003c/em\u003e gene; notably, one was also carrier of a C4 splicing variant in \u003cem\u003eTP53\u003c/em\u003e gene (Table\u0026nbsp;2).\u003c/p\u003e \u003cp\u003eThe nucleotide changes in \u003cem\u003eBRCA1\u003c/em\u003e gene included five small deletions or insertions leading to frameshift, one nonsense mutation, one large deletion and one missense substitution. Except for this last variant, all PVs were expected to result in a premature termination of the protein.\u003c/p\u003e \u003cp\u003eMean age at MpBC diagnosis of PV carriers was 30 years (range 15\u0026ndash;49). All BCs were of TN subtype; however, the histological subtype of MpBC varied greatly among patients.\u003c/p\u003e \u003cp\u003eFive out of eight cases (62.5%) were affected by other BCs in addition to the MpBC: all of them were invasive ductal carcinomas but the patient described by Breuer \u003cem\u003eet al\u003c/em\u003e., who was diagnosed with a metachronous bilateral MpBC with squamous differentiation.\u003c/p\u003e \u003cp\u003eA positive family history of BC and/or OC was described in five out of eight (62.5%) of the screened MpBC cases.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo the best of our knowledge, we report here the largest monocentric series of MpBC patients harboring a germline PV and fully described in terms of clinical and molecular characteristics, as well as family history of BC/OC. Indeed, only eight single case reports have been published so far with all information. These eight MpBC cases reported in the literature carried PVs almost exclusively in \u003cem\u003eBRCA1\u003c/em\u003e gene, except for the unusual case of a woman affected by both HBOC and LFS [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. An additional 54-year-old woman affected by TN MpBC with osseous differentiation has been reported [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]: a genetic alteration in \u003cem\u003eBRCA1\u003c/em\u003e was identified in the tumor (c.1530del, p.Gly511AlafsTer21), but the patient refused to undergo germline testing and she did not have any family history of malignancies.\u003c/p\u003e \u003cp\u003eIn addition to these case reports, systematic review of the existing literature revealed several other studies concerning germline PVs of different cancer genes in MpBC patients. However, they did not include molecular details about the detected variants and/or on FH of cancer, and/or did not specify which selection criteria they used to address patients to genetic testing. Therefore, we decided not to include them in our review and we only cite them here.\u003c/p\u003e \u003cp\u003eIn a recent paper on neoadjuvant chemotherapy in MpBC, Wong \u003cem\u003eet al\u003c/em\u003e. (27) reported that two out of 31 (6%) MpBC patients who underwent genetic testing were found to carry a \u003cem\u003eBRCA1\u003c/em\u003e germline mutation, one of which being a large deletion of exons 23\u0026ndash;24. Additional studies on target therapies or specific clinical management for \u003cem\u003eBRCA\u003c/em\u003e-positive MpBC patients have also been published [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Moukarzel et al. [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] identified Homologous Recombination DNA Repair deficiency (HRD) in 15 out of 33 MpBCs (45%). Of relevance, six of the 15 HRD-defective cases harbored a germline PV in \u003cem\u003eBRCA1\u003c/em\u003e (6/15\u0026thinsp;=\u0026thinsp;40%) and one in \u003cem\u003eBRCA2\u003c/em\u003e (1/15\u0026thinsp;=\u0026thinsp;7%).\u003c/p\u003e \u003cp\u003eMoreover, eight additional case reports described MpBC development in patients with a clinical diagnosis of Neurofibromatosis type 1 [\u003cspan additionalcitationids=\"CR32 CR33 CR34 CR35 CR36 CR37\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. However, only one of these patients underwent detailed germline analysis and proved to be carrier of a deleterious variant in \u003cem\u003eNF1\u003c/em\u003e gene [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Finally, Rodr\u0026iacute;guez-Fern\u0026aacute;ndez and colleagues [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e] found a statistically significant difference in frequencies of histological types between \u003cem\u003eBRCA1\u003c/em\u003e carriers vs. non carriers. In particular, they reported 3.2% MpBCs in 93 \u003cem\u003eBRCA1\u003c/em\u003e-positive BCs \u003cem\u003evs.\u003c/em\u003e 0.8% MpBCs in 3157 non \u003cem\u003eBRCA\u003c/em\u003e-positive BCs.\u003c/p\u003e \u003cp\u003eTaken together, all these evidences from case reports, retrospective reviews and studies on target therapies point to a possible involvement in MpBC genetic predisposition for different cancer-related genes, but mainly for \u003cem\u003eBRCA1\u003c/em\u003e gene.\u003c/p\u003e \u003cp\u003eOur results are consistent with literature data: in a series of 15 MpBC patients, the great majority of the identified germline PVs lied in the \u003cem\u003eBRCA1\u003c/em\u003e gene (86.7%), confirming that it could have a crucial role in MpBC predisposition. We also identified a \u003cem\u003eTP53\u003c/em\u003e PV carrier without any alteration in \u003cem\u003eBRCA1\u003c/em\u003e gene. The patient was diagnosed with multiple BCs over time, including a TN MpBC with sarcomatoid features at 52 years of age (Fig.\u0026nbsp;1, patient ID 14). Interestingly, no FH suggestive for LFS syndrome was observed, even if family was relatively small.\u003c/p\u003e \u003cp\u003eOf relevance, we also describe for the first time a germline C4 variant of \u003cem\u003eMLH1\u003c/em\u003e gene in a patient who developed both CRC at 51 and MpBC at 58 years of age (Fig.\u0026nbsp;1, patient ID 15). Constitutive mutations of mismatch repair genes (including \u003cem\u003eMLH1\u003c/em\u003e, \u003cem\u003eMSH2\u003c/em\u003e, \u003cem\u003eMSH6\u003c/em\u003e and \u003cem\u003ePMS2\u003c/em\u003e) are known to cause the Lynch syndrome (LS), an inherited condition characterized by an increased risk of developing many tumor types, mainly colorectal and endometrial cancers [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Whether BC belongs to the LS spectrum is a long-standing question [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]; at any rate, \u003cem\u003eMLH1\u003c/em\u003e germline defects have never been reported before in MpBC patients. Proband\u0026rsquo;s father was affected by both CRC and pancreatic cancer at 72 years of age, and grandmothers from both paternal and maternal sides of the family were reported to be diagnosed with BC (at 40 and 65 years, respectively). Notably, the patient also harbored other two genetic variants (class C3 according to the ACMG classification): the c.5986G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Ala1996Thr) variant in \u003cem\u003eBRCA2\u003c/em\u003e gene and the c.3313G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Gly1105Arg) in \u003cem\u003eMSH6\u003c/em\u003e gene. We cannot exclude that the missense substitution in \u003cem\u003eBRCA2\u003c/em\u003e could act as a low penetrance variant for BC risk nor that additional genetic/environmental factor could modulate BC risk in this family.\u003c/p\u003e \u003cp\u003eAlmost all PVs detected in MpBC patients were expected to result in a truncated protein product, but the c.181T\u0026thinsp;\u0026gt;\u0026thinsp;G C5 missense variant of \u003cem\u003eBRCA1\u003c/em\u003e and the c.375\u0026thinsp;+\u0026thinsp;2T\u0026thinsp;\u0026gt;\u0026thinsp;C C4 splicing variant of \u003cem\u003eTP53\u003c/em\u003e reported in the literature, and the c.244A\u0026thinsp;\u0026gt;\u0026thinsp;G C4 missense variant of \u003cem\u003eMLH1\u003c/em\u003e gene described in our series. The most common mutation types were small deletions/insertions leading to frameshift, followed by nonsense.\u003c/p\u003e \u003cp\u003eThe germline PVs we identified were different compared with those already reported, except for the \u003cem\u003eBRCA1\u003c/em\u003e c.5266dup variant, described both in our series and in a previous report [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. In addition, we identified the c.5030_5033del \u003cem\u003eBRCA1\u003c/em\u003e variant in two different MpBC patients. These variants are among the most frequent mutations detected in \u003cem\u003eBRCA1\u003c/em\u003e gene, in Europe or worldwide [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA potential limitation of our study is that we focused on molecular findings only in a small group of patients, making it difficult to perform statistical analysis or extrapolation to other individuals with MpBC.\u003c/p\u003e \u003cp\u003eAt any rate, no hotspot mutations specific for MpBC seem to be identifiable in \u003cem\u003eBRCA1\u003c/em\u003e gene. Several PVs clustered in exon 11 of \u003cem\u003eBRCA1\u003c/em\u003e, just because it is the largest one of the gene (3426 base pairs). On the whole, the germline variants found in MpBC patients \u0026ndash; both in our series and in published case reports - fall within the three regions most frequently mutated in cancer patients. These include the RING (Really Interesting New Gene) domain (exons 2\u0026ndash;7), a region encoded by exons 11\u0026ndash;13, and the BRCT (BRCA1 C-terminus) domain (exons 16\u0026ndash;24) [Clark 2012] (Fig.\u0026nbsp;2). RING is responsible for the interaction of \u003cem\u003eBRCA1\u003c/em\u003e with \u003cem\u003eBARD1.\u003c/em\u003e The region encoded by exons 11\u0026ndash;13 contains multiple binding sites for a number of diverse proteins; it includes for example the SCD (serine containing domain), which mediates interaction with \u003cem\u003ePALB2.\u003c/em\u003e Finally, the BRCT domain is again critical for tumor suppression, since its main function is modulating phosphoprotein interactions between \u003cem\u003eBRCA1\u003c/em\u003e and proteins phosphorylated by \u003cem\u003eATM\u003c/em\u003e and \u003cem\u003eATR\u003c/em\u003e, two kinases activated by DNA damage.\u003c/p\u003e \u003cp\u003eAs regards histological classification, MpBCs of PV carriers reported in the literature were extremely heterogeneous, displaying epithelial, mesenchymal and mixed features. Our series showed the same variability: although the most prevalent phenotype was MpBC with mesenchymal differentiation (47%), we did not observe a specific histological subtype in patients with \u003cem\u003eBRCA1\u003c/em\u003e PVs. Notably, the \u003cem\u003eTP53\u003c/em\u003e PV carrier developed MpBC with sarcomatoid elements. All the eight MpBCs described in previous case reports were of TN subtype, as expected from literature data. In our series, TN phenotype was the most frequent subtype as well (86.7%), even though 13.3% of MpBCs showed HER2 overexpression (one with a \u003cem\u003eBRCA1\u003c/em\u003e germline PV and the other with the germline \u003cem\u003eMLH1\u003c/em\u003e PV).\u003c/p\u003e \u003cp\u003eIn the eight case reports reviewed, family history of \u003cem\u003eBRCA\u003c/em\u003e-positive MpBC cases was ascertained: three of them were apparently sporadic, three presented positive FH of BC, one of OC, and one of both BC and OC.\u003c/p\u003e \u003cp\u003eOur case series reflects literature data, since about 50% of MpBC cases seem to be sporadic. However, it should be stressed that these are highly selected cases, addressed to genetic counselling and germline testing due to specific clinical criteria, which include but are not limited to FH (\u003cem\u003ei.e.\u003c/em\u003e development of early-onset BC and/or of TNBC\u0026thinsp;\u0026le;\u0026thinsp;60 years and/or of bilateral BC and/or presence of family history of BC/OC).\u003c/p\u003e \u003cp\u003eAdditional studies on larger unselected series of cases are required to better characterize MpBC genetic predisposition. These studies, if conducted on unselected MpBC patients and through careful data collection (family history, histological classification, etc.), are expected to unravel the authentic detection rate of PVs in \u003cem\u003eBRCA1\u003c/em\u003e gene, as well as to explore the possible involvement of additional genes in increasing the risk of developing MpBC.\u003c/p\u003e \u003cp\u003eThere are multiple evidences suggesting that MpBC and TNBC of NST are two independent and extremely heterogeneous BC subtypes, particularly in their clinical manifestations. Such different features require the urgent definition for new systemic therapeutic strategies. Further studies are needed to uncover the specific genetic landscape of MpBCs, since it would be an interesting starting point for the definition of new therapeutic strategies.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eTaken together, our findings and literature data point to the following conclusions: 1) in MpBC patients described so far, who are highly selected for germline testing of specific genes, \u003cem\u003eBRCA1\u003c/em\u003e seems to play a crucial role in increasing the risk of MpBC development; 2) additional studies on larger, unselected series of patients are necessary to elucidate the authentic role of germline \u003cem\u003eBRCA1\u003c/em\u003e PVs in MpBCs and to explore the possible implication of other genes in MpBC predisposition; 3) almost all PVs detected in MpBC carriers were clearly deleterious and predicted to result in a truncated protein product; 4) no hotspot mutations specific for MpBC seem to be detectable in \u003cem\u003eBRCA1\u003c/em\u003e gene, since the identified PVs are frequently found in HBOC patients or affect the most commonly mutated regions of the protein in cancer patients; 5) \u003cem\u003eBRCA1\u003c/em\u003e PVs do not seem to be associated with a specific histological subtype of MpBC; 6) almost all MpBCs in PV germline carriers are TN, with a few exceptions of HER2 overexpressed cases; 7) unraveling MpBC genetic predisposition and its specific molecular landscape is important for the clinical management of affected patients and families and could be a starting point for the definition of new therapeutic strategies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e Concept and design, XX; Supervisor board, XX; Iconography and graphic design, XX; Acquisition of data, analysis, and interpretation of data, critical revision of the manuscript for important intellectual content, final approval of manuscript-all authors. Drafting of the manuscript, XX, with input of all authors. All authors have read and agreed to the published version of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This manuscript was partially supported by the Italian ministry of Health with Ricerca Corrente and 5 \u0026times; 1000 funds.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement:\u003c/strong\u003e Not publicly available.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e The authors declare no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ (eds). WHO classification of tumours of the breast, 4th edition, vol.\u0026nbsp;4. 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Genet Med. 2020 Apr;22(4):811\u0026ndash;812. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41436-019-0716-6\u003c/span\u003e\u003cspan address=\"10.1038/s41436-019-0716-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRebbeck TR, Friebel TM, Friedman E, Hamann U, Huo D, Kwong A, et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593\u0026ndash;620. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/humu.23406\u003c/span\u003e\u003cspan address=\"10.1002/humu.23406\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eClark CC, Weitzel JN, O'Connor TR. Enhancement of synthetic lethality via combinations of ABT-888, a PARP inhibitor, and carboplatin in vitro and in vivo using BRCA1 and BRCA2 isogenic models. Mol Cancer Ther. 2012 Sep;11(9):1948\u0026ndash;58. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1158/1535-7163.MCT-11-0597\u003c/span\u003e\u003cspan address=\"10.1158/1535-7163.MCT-11-0597\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Germline PVs, family history and clinical, histological characteristics of our series of MpBC patients.\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"870\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient ID\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.551724137931035%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGene\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.35632183908046%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGermline defect\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.988505747126437%\"\u003e\n \u003cp\u003e\u003cstrong\u003eLocation\u003csup\u003eb\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.954022988505747%\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariant\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003edescription\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.735632183908047%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at diagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.586206896551724%\"\u003e\n \u003cp\u003e\u003cstrong\u003eLaterality\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.919540229885058%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistopathological Classification\u003csup\u003eC\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSub-type\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003e\u003cstrong\u003eOther tumors (age)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003e\u003cstrong\u003eFH\u003csup\u003ed\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.551724137931035%\"\u003e\n \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.35632183908046%\"\u003e\n \u003cp\u003ec.(?_-119)_(80+1_81-1)del\u003c/p\u003e\n \u003cp\u003ep.(?)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.988505747126437%\"\u003e\n \u003cp\u003e5\u0026apos;UTR, exons 1 and 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.954022988505747%\"\u003e\n \u003cp\u003eLarge rearr.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.735632183908047%\"\u003e\n \u003cp\u003e44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.586206896551724%\"\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.919540229885058%\"\u003e\n \u003cp\u003e\u0026nbsp;Squamous cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003eTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003eRight IDC (40); left IDC (42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.551724137931035%\"\u003e\n \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.35632183908046%\"\u003e\n \u003cp\u003ec.798_799del\u003c/p\u003e\n \u003cp\u003ep.(Ser267LysfsTer19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.988505747126437%\"\u003e\n \u003cp\u003eExon 11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.954022988505747%\"\u003e\n \u003cp\u003eDeletion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.735632183908047%\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.586206896551724%\"\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.919540229885058%\"\u003e\n \u003cp\u003eMetaplastic carcinoma with heterologous mesenchymal differentiation (matrix-producing)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003eTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003eRight IDC (24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.551724137931035%\"\u003e\n \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.35632183908046%\"\u003e\n \u003cp\u003ec.816_825dup\u003c/p\u003e\n \u003cp\u003ep.(Thr276AlafsTer14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.988505747126437%\"\u003e\n \u003cp\u003eExon 11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.954022988505747%\"\u003e\n \u003cp\u003eInsertion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.735632183908047%\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.586206896551724%\"\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.919540229885058%\"\u003e\n \u003cp\u003e\u0026nbsp;Squamous cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003eTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003e_\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003eBC/OC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.551724137931035%\"\u003e\n \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.35632183908046%\"\u003e\n \u003cp\u003ec.2934T\u0026gt;G\u003c/p\u003e\n \u003cp\u003ep.(Tyr978Ter)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.988505747126437%\"\u003e\n \u003cp\u003eExon 11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.954022988505747%\"\u003e\n \u003cp\u003eNon-sense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.735632183908047%\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.586206896551724%\"\u003e\n \u003cp\u003eRight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.919540229885058%\"\u003e\n \u003cp\u003e\u0026nbsp;Squamous cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003eTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003eLeft IDC (30); right IDC (37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003eBC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.551724137931035%\"\u003e\n \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.35632183908046%\"\u003e\n \u003cp\u003ec.3904G\u0026gt;T\u003c/p\u003e\n \u003cp\u003ep.(Glu1302Ter)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.988505747126437%\"\u003e\n \u003cp\u003eExon 11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.954022988505747%\"\u003e\n \u003cp\u003eNon-sense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.735632183908047%\"\u003e\n \u003cp\u003e47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.586206896551724%\"\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.919540229885058%\"\u003e\n \u003cp\u003eMetaplastic carcinoma with heterologous mesenchymal differentiation (matrix-producing carcinoma)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003eTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003e_\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003eBC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.551724137931035%\"\u003e\n \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.35632183908046%\"\u003e\n \u003cp\u003ec.3228_3229del\u003c/p\u003e\n \u003cp\u003ep.(Gly1077AlafsTer8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.988505747126437%\"\u003e\n \u003cp\u003eExon 11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.954022988505747%\"\u003e\n \u003cp\u003eDeletion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.735632183908047%\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.586206896551724%\"\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.919540229885058%\"\u003e\n \u003cp\u003eMetaplastic carcinoma with heterologous mesenchymal differentiation (chondroid)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003eTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003eRight IDC (39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.551724137931035%\"\u003e\n \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.35632183908046%\"\u003e\n \u003cp\u003ec.1088del\u003c/p\u003e\n \u003cp\u003ep.(Asn363IlefsTer11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.988505747126437%\"\u003e\n \u003cp\u003eExon 11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.954022988505747%\"\u003e\n \u003cp\u003eDeletion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.735632183908047%\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.586206896551724%\"\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.919540229885058%\"\u003e\n \u003cp\u003eMetaplastic carcinoma with heterologous mesenchymal differentiation (matrix-producing carcinoma)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003eTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003e_\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.551724137931035%\"\u003e\n \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.35632183908046%\"\u003e\n \u003cp\u003ec.4186-3156_4357+94dup\u003c/p\u003e\n \u003cp\u003ep.(?)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.988505747126437%\"\u003e\n \u003cp\u003eExon 13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.954022988505747%\"\u003e\n \u003cp\u003eLarge rearr.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.735632183908047%\"\u003e\n \u003cp\u003e47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.586206896551724%\"\u003e\n \u003cp\u003eRight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.919540229885058%\"\u003e\n \u003cp\u003eSpindle cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003eTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003e_\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.551724137931035%\"\u003e\n \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.35632183908046%\"\u003e\n \u003cp\u003ec.4964_4982del\u003c/p\u003e\n \u003cp\u003ep.(Ser1655TyrfsTer16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.988505747126437%\"\u003e\n \u003cp\u003eExon 16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.954022988505747%\"\u003e\n \u003cp\u003eDeletion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.735632183908047%\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.586206896551724%\"\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.919540229885058%\"\u003e\n \u003cp\u003eMixed metaplastic carcinoma\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003eHER2+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003eLeft DCIS (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003eBC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.551724137931035%\"\u003e\n \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.35632183908046%\"\u003e\n \u003cp\u003ec.5030_5033del\u003c/p\u003e\n \u003cp\u003ep.(Thr1677IlefsTer2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.988505747126437%\"\u003e\n \u003cp\u003eExon 17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.954022988505747%\"\u003e\n \u003cp\u003eDeletion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.735632183908047%\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.586206896551724%\"\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.919540229885058%\"\u003e\n \u003cp\u003eMetaplastic carcinoma with heterologous mesenchymal differentiation (matrix-producing carcinoma)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003eTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003eRight IDC (35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003eOC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.551724137931035%\"\u003e\n \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.35632183908046%\"\u003e\n \u003cp\u003ec.5030_5033del\u003c/p\u003e\n \u003cp\u003ep.(Thr1677IlefsTer2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.988505747126437%\"\u003e\n \u003cp\u003eExon 17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.954022988505747%\"\u003e\n \u003cp\u003eDeletion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.735632183908047%\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.586206896551724%\"\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.919540229885058%\"\u003e\n \u003cp\u003eMixed metaplastic carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003eTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003e_\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.551724137931035%\"\u003e\n \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.35632183908046%\"\u003e\n \u003cp\u003ec.5179A\u0026gt;T\u003c/p\u003e\n \u003cp\u003ep.(Lys1727Ter)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.988505747126437%\"\u003e\n \u003cp\u003eExon 19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.954022988505747%\"\u003e\n \u003cp\u003eNon-sense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.735632183908047%\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.586206896551724%\"\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.919540229885058%\"\u003e\n \u003cp\u003eMetaplastic carcinoma with heterologous mesenchymal differentiation (matrix-producing carcinoma and chondroid)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003eTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003e_\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003eBC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.551724137931035%\"\u003e\n \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.35632183908046%\"\u003e\n \u003cp\u003ec.5266dup\u003c/p\u003e\n \u003cp\u003ep.(Gln1756ProfsTer74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.988505747126437%\"\u003e\n \u003cp\u003eExon 20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.954022988505747%\"\u003e\n \u003cp\u003eInsertion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.735632183908047%\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.586206896551724%\"\u003e\n \u003cp\u003eRight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.919540229885058%\"\u003e\n \u003cp\u003eSpindle cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003eTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003eLeft IDC (33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003eBC/OC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.551724137931035%\"\u003e\n \u003cp\u003e\u003cem\u003eTP53\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.35632183908046%\"\u003e\n \u003cp\u003ec.635_636del\u003c/p\u003e\n \u003cp\u003ep.(Phe212SerfsTer3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.988505747126437%\"\u003e\n \u003cp\u003eExon 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.954022988505747%\"\u003e\n \u003cp\u003eDeletion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.735632183908047%\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.586206896551724%\"\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.919540229885058%\"\u003e\n \u003cp\u003eSpindle cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003eTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003eLeft IDC (36, 39, 54); right IDC (37); right DCIS (45, 47); multiple BCCs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.551724137931035%\"\u003e\n \u003cp\u003e\u003cem\u003eMLH1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.35632183908046%\"\u003e\n \u003cp\u003ec.244A\u0026gt;G\u003c/p\u003e\n \u003cp\u003ep.(Thr82Ala)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.988505747126437%\"\u003e\n \u003cp\u003eExon 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.954022988505747%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.735632183908047%\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.586206896551724%\"\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.919540229885058%\"\u003e\n \u003cp\u003eMetaplastic carcinoma with heterologous mesenchymal differentiation\u003c/p\u003e\n \u003cp\u003e(rhabdomyoid)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.436781609195402%\"\u003e\n \u003cp\u003eHER2+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003eCRC (51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.517241379310345%\"\u003e\n \u003cp\u003eBC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eBC: breast cancer; BCC: basal cell carcinoma;\u0026nbsp;CRC: colorectal cancer;\u0026nbsp;DCIS: ductal carcinoma in situ; FH: family history;\u0026nbsp;IDC:\u0026nbsp;infiltrating ductal carcinoma; MpBC: metaplastic breast cancer; N/A: not applicable; NOS: not otherwise specified; OC: ovarian cancer; TN: triple negative.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003ecDNA and protein changes are named according to HGVS nomenclature. Reference sequences:\u0026nbsp;\u003cem\u003eBRCA1\u003c/em\u003e NM_007294.4; \u003cem\u003eTP53\u003c/em\u003e NM_000546.5; \u003cem\u003eMLH1\u003c/em\u003e NM_000249.4\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003eAfter exon 3, subsequent exon numbers of \u003cem\u003eBRCA1\u003c/em\u003e gene are increased by one, due to historical misannotation of an additional \u0026ldquo;exon 4\u0026rdquo;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ec\u003c/sup\u003eClassification into seven sub-categories following the WHO guidelines [1; 3]\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ed\u003c/sup\u003eFamily history of BC or OC in 1\u003csup\u003est\u003c/sup\u003e and 2\u003csup\u003end\u003c/sup\u003e degree relatives on the maternal side or until 3\u003csup\u003erd\u003c/sup\u003e degree relatives on the paternal side (pathology-confirmed or self-reported cancer diagnoses)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Germline PVs, family history and clinical, histological characteristics of MpBC patients reported in the literature.\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"897\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.567296996662959%\"\u003e\n \u003cp\u003e\u003cstrong\u003eReference\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.341490545050056%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGene\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.681868743047831%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGermline defect\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.453837597330367%\"\u003e\n \u003cp\u003e\u003cstrong\u003eLocation\u003csup\u003eb\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.454949944382648%\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariant\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003edescription\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.567296996662959%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at diagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.340378197997775%\"\u003e\n \u003cp\u003e\u003cstrong\u003eLaterality\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.682981090100112%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistology\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2280311457174635%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSub-type\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.453837597330367%\"\u003e\n \u003cp\u003e\u003cstrong\u003eOther tumors (age)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2280311457174635%\"\u003e\n \u003cp\u003e\u003cstrong\u003eFH\u003csup\u003ec\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.567296996662959%\"\u003e\n \u003cp\u003eRashid 2011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.341490545050056%\"\u003e\n \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.681868743047831%\"\u003e\n \u003cp\u003ec.68_69del\u003c/p\u003e\n \u003cp\u003ep.(Glu23ValfsTer17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.453837597330367%\"\u003e\n \u003cp\u003eExon 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.454949944382648%\"\u003e\n \u003cp\u003eDeletion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.567296996662959%\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.340378197997775%\"\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.682981090100112%\"\u003e\n \u003cp\u003eMixed metaplastic carcinoma (epithelial and mesenchymal components)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2280311457174635%\"\u003e\n \u003cp\u003eTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.453837597330367%\"\u003e\n \u003cp\u003e_\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2280311457174635%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.567296996662959%\"\u003e\n \u003cp\u003eN\u0026ouml;el 2010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.341490545050056%\"\u003e\n \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.681868743047831%\"\u003e\n \u003cp\u003ec.66dup\u003c/p\u003e\n \u003cp\u003ep.(Glu23ArgfsTer18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.453837597330367%\"\u003e\n \u003cp\u003eExon 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.454949944382648%\"\u003e\n \u003cp\u003eInsertion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.567296996662959%\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.340378197997775%\"\u003e\n \u003cp\u003eRight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.682981090100112%\"\u003e\n \u003cp\u003eLow-grade adenosquamous carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2280311457174635%\"\u003e\n \u003cp\u003eTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.453837597330367%\"\u003e\n \u003cp\u003eRight IDC (36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2280311457174635%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.567296996662959%\"\u003e\n \u003cp\u003eBreuer 2007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.341490545050056%\"\u003e\n \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.681868743047831%\"\u003e\n \u003cp\u003ec.181T\u0026gt;G\u003c/p\u003e\n \u003cp\u003ep.(Cys61Gly)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.453837597330367%\"\u003e\n \u003cp\u003eExon 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.454949944382648%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.567296996662959%\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.340378197997775%\"\u003e\n \u003cp\u003eRight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.682981090100112%\"\u003e\n \u003cp\u003eSquamous cell\u003c/p\u003e\n \u003cp\u003ecarcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2280311457174635%\"\u003e\n \u003cp\u003eTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.453837597330367%\"\u003e\n \u003cp\u003eLeft MBC with squamous cells (28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2280311457174635%\"\u003e\n \u003cp\u003eBC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.567296996662959%\"\u003e\n \u003cp\u003eYamashita 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.341490545050056%\"\u003e\n \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.681868743047831%\"\u003e\n \u003cp\u003ec.188T\u0026gt;A\u003c/p\u003e\n \u003cp\u003ep.(Leu63Ter)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.453837597330367%\"\u003e\n \u003cp\u003eExon 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.454949944382648%\"\u003e\n \u003cp\u003eNon-sense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.567296996662959%\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.340378197997775%\"\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.682981090100112%\"\u003e\n \u003cp\u003eMixed metaplastic carcinoma (invasive ductal carcinoma and mesenchymal component with chondroid differentiation)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2280311457174635%\"\u003e\n \u003cp\u003eTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.453837597330367%\"\u003e\n \u003cp\u003eLeft IDC (39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2280311457174635%\"\u003e\n \u003cp\u003eBC/OC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.567296996662959%\"\u003e\n \u003cp\u003eVohra 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.341490545050056%\"\u003e\n \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.681868743047831%\"\u003e\n \u003cp\u003ec.1961dup\u003c/p\u003e\n \u003cp\u003ep.(Tyr655ValfsTer18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.453837597330367%\"\u003e\n \u003cp\u003eExon 11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.454949944382648%\"\u003e\n \u003cp\u003eInsertion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.567296996662959%\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.340378197997775%\"\u003e\n \u003cp\u003eRight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.682981090100112%\"\u003e\n \u003cp\u003eMetaplastic carcinoma with heterologous mesenchymal differentiation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2280311457174635%\"\u003e\n \u003cp\u003eTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.453837597330367%\"\u003e\n \u003cp\u003e_\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2280311457174635%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.567296996662959%\"\u003e\n \u003cp\u003eGhilli 2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.341490545050056%\"\u003e\n \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.681868743047831%\"\u003e\n \u003cp\u003ec.4754_4755del\u003c/p\u003e\n \u003cp\u003ep.(Pro1585ArgfsTer36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.453837597330367%\"\u003e\n \u003cp\u003eExon 16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.454949944382648%\"\u003e\n \u003cp\u003eDeletion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.567296996662959%\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.340378197997775%\"\u003e\n \u003cp\u003eRight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.682981090100112%\"\u003e\n \u003cp\u003eMixed metaplastic carcinoma (epithelial and mesenchymal components\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2280311457174635%\"\u003e\n \u003cp\u003eTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.453837597330367%\"\u003e\n \u003cp\u003eRight IDC (35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2280311457174635%\"\u003e\n \u003cp\u003eBC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.567296996662959%\"\u003e\n \u003cp\u003eSuspitsin 2011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.341490545050056%\"\u003e\n \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.681868743047831%\"\u003e\n \u003cp\u003ec.5266dup\u003c/p\u003e\n \u003cp\u003ep.(Gln1756ProfsTer74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.453837597330367%\"\u003e\n \u003cp\u003eExon 20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.454949944382648%\"\u003e\n \u003cp\u003eInsertion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.567296996662959%\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.340378197997775%\"\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.682981090100112%\"\u003e\n \u003cp\u003eMixed metaplastic carcinoma (epithelial and mesenchymal components\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2280311457174635%\"\u003e\n \u003cp\u003eTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.453837597330367%\"\u003e\n \u003cp\u003e_\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2280311457174635%\"\u003e\n \u003cp\u003eOC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.567296996662959%\"\u003e\n \u003cp\u003eBell 2014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.341490545050056%\"\u003e\n \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eTP53\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.681868743047831%\"\u003e\n \u003cp\u003ec.81-?_134+?del\u003c/p\u003e\n \u003cp\u003ep.(Cys27Ter)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ec.375+2T\u0026gt;C\u003c/p\u003e\n \u003cp\u003ep.(?)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.453837597330367%\"\u003e\n \u003cp\u003eExon 3\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eIntron 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.454949944382648%\"\u003e\n \u003cp\u003eLarge rearr.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eSplicing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.567296996662959%\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.340378197997775%\"\u003e\n \u003cp\u003eRight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.682981090100112%\"\u003e\n \u003cp\u003eMetaplastic carcinoma, NOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2280311457174635%\"\u003e\n \u003cp\u003eTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.453837597330367%\"\u003e\n \u003cp\u003eRight IDC (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2280311457174635%\"\u003e\n \u003cp\u003eBC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eBC: breast cancer; FH: family history;\u0026nbsp;IDC:\u0026nbsp;infiltrating ductal carcinoma; MpBC: metaplastic breast cancer;N/A: not applicable; NOS: not otherwise specified; OC: ovarian cancer; TN: triple negative.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003ecDNA and protein changes are named according to HGVS nomenclature. Reference sequences:\u0026nbsp;\u003cem\u003eBRCA1\u003c/em\u003e NM_007294.4; \u003cem\u003eTP53\u003c/em\u003e NM_000546.5\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003eAfter exon 3, subsequent exon numbers of \u003cem\u003eBRCA1\u003c/em\u003e gene are increased by one, due to historical misannotation of an additional \u0026ldquo;exon 4\u0026rdquo;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ec\u003c/sup\u003eClassification into seven sub-categories following the WHO guidelines [1; 3]\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ed\u003c/sup\u003ePathology-confirmed or self-reported cancer diagnoses\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-human-genetics","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"ejhg","sideBox":"Learn more about [European Journal of Human Genetics](http://www.nature.com/ejhg/)","snPcode":"41431","submissionUrl":"https://mts-ejhg.nature.com/cgi-bin/main.plex","title":"European Journal of Human Genetics","twitterHandle":"@ejhg_journal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Metaplastic breast cancer, germline genetic testing, pathogenic variants, BRCA1 gene","lastPublishedDoi":"10.21203/rs.3.rs-2668559/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2668559/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMetaplastic breast cancer (MpBC) is a rare, aggressive type of breast cancer, often classified as triple negative (TN). Scarce information is available about germline testing in MpBC. We retrospectively reviewed MpBC patients counseled at our Institute and found to harbor germline pathogenic variants (PVs), and we revised literature data. We identified a germline PV in 15 MpBC patients: 13 in \u003cem\u003eBRCA1 \u003c/em\u003e(86.7%), one in \u003cem\u003eTP53\u003c/em\u003e (6.7%), one in \u003cem\u003eMLH1\u003c/em\u003e (6.7%) genes. Eight MpBC PV carriers in \u003cem\u003eBRCA1\u003c/em\u003e have been previously described, including a patient with a PV in both \u003cem\u003eBRCA1\u003c/em\u003e and \u003cem\u003eTP53\u003c/em\u003e. MpBC histological subtype in PV carriers was heterogeneous. All MpBCs were TN but 13.3% in our series showed HER2 overexpression.\u003c/p\u003e\n\u003cp\u003eWe described the largest series of MpBCs with germline PVs. As previously reported, we observed that \u003cem\u003eBRCA1\u003c/em\u003e is the mainly involved gene in MpBC patients who underwent germline testing according to specific selection criteria. Additional studies on unselected patients are required to assess the authentic role of germline \u003cem\u003eBRCA1\u003c/em\u003e PVs in MpBCs and to explore the possible involvement of other genes in MpBC predisposition. Unraveling a specific MpBC molecular landscape is a starting point for the definition of new therapeutic strategies, since these tumors have a poor prognosis.\u003c/p\u003e","manuscriptTitle":"Germline pathogenic variants in metaplastic breast cancer patients: a monocentric study and literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-03-17 14:24:43","doi":"10.21203/rs.3.rs-2668559/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2023-04-27T09:22:28+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2023-04-25T10:49:55+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2023-04-19T06:19:26+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2023-03-31T14:04:07+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2023-03-31T10:42:03+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2023-03-13T18:00:43+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-03-12T00:21:48+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-03-08T08:29:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Human Genetics","date":"2023-03-08T08:29:38+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-human-genetics","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"ejhg","sideBox":"Learn more about [European Journal of Human Genetics](http://www.nature.com/ejhg/)","snPcode":"41431","submissionUrl":"https://mts-ejhg.nature.com/cgi-bin/main.plex","title":"European Journal of Human Genetics","twitterHandle":"@ejhg_journal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"27c37867-3439-4fa1-b828-d5bef3d57edb","owner":[],"postedDate":"March 17th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":19846358,"name":"Biological sciences/Cancer/Breast cancer"},{"id":19846359,"name":"Health sciences/Pathogenesis/Clinical genetics"}],"tags":[],"updatedAt":"2023-07-21T07:14:43+00:00","versionOfRecord":{"articleIdentity":"rs-2668559","link":"https://doi.org/10.1038/s41431-023-01429-2","journal":{"identity":"european-journal-of-human-genetics","isVorOnly":false,"title":"European Journal of Human Genetics"},"publishedOn":"2023-07-18 04:00:00","publishedOnDateReadable":"July 18th, 2023"},"versionCreatedAt":"2023-03-17 14:24:43","video":"","vorDoi":"10.1038/s41431-023-01429-2","vorDoiUrl":"https://doi.org/10.1038/s41431-023-01429-2","workflowStages":[]},"version":"v1","identity":"rs-2668559","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2668559","identity":"rs-2668559","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}