Valentina Silvestri1, Veronica Zelli1, Virginia Valentini1, Piera Rizzolo1, Anna Sara Navazio1, Anna Coppa2, Simona Agata3, Cristina Oliani4, Daniela Barana4, Tiziana Castrignanò5, Alessandra Viel6, Antonio Russo7, Maria Grazia Tibiletti8, Ines Zanna9, Giovanna Masala9, Laura Cortesi10, Siranoush Manoukian11, Jacopo Azzollini11, Bernard Peissel11, Bernardo Bonanni12, Paolo Peterlongo13, Paolo Radice14, Domenico Palli9, Giuseppe Giannini1, Giovanni Chillemi5, Marco Montagna3, Laura Ottini1. 1. Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy. 2. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy. 3. Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV, Padua, Italy. 4. Oncology Unit, Local Health and Social Care Unit ULSS5 Ovest Vicentino, Montecchio Maggiore, Italy. 5. Supercomputing Applications and Innovation Department, Interuniversity Consortium for Super Computing CINECA, Rome, Italy. 6. Unit of Functional Onco-Genomics and Genetics, Aviano Oncology Reference Center CRO, National Cancer Institute, Aviano, Italy. 7. Section of Medical Oncology, Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy. 8. Unit of Pathology, Circolo Hospital, Varese, Italy. 9. Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute ISPO, Florence, Italy. 10. Department of Oncology and Haematology, University of Modena and Reggio Emilia, Modena, Italy. 11. Unit of Medical Genetics, Department of Preventive and Predictive Medicine, National Cancer Institute INT, Milan, Italy. 12. Division of Cancer Prevention and Genetics, European Institute of Oncology IEO, Milan, Italy. 13. Italian Foundation for Cancer Research (FIRC) Institute of Molecular Oncology INT, Milan, Italy. 14. Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, National Cancer Institute INT, Milan, Italy.
Abstract
BACKGROUND: Male breast cancer (MBC) is a rare disease whose etiology appears to be largely associated with genetic factors. BRCA1 and BRCA2 mutations account for about 10% of all MBC cases. Thus, a fraction of MBC cases are expected to be due to genetic factors not yet identified. To further explain the genetic susceptibility for MBC, whole-exome sequencing (WES) and targeted gene sequencing were applied to high-risk, BRCA1/2 mutation-negative MBC cases. METHODS: Germ-line DNA of 1 male and 2 female BRCA1/2 mutation-negative breast cancer (BC) cases from a pedigree showing a first-degree family history of MBC was analyzed with WES. Targeted gene sequencing for the validation of WES results was performed for 48 high-risk, BRCA1/2 mutation-negative MBC cases from an Italian multicenter study of MBC. A case-control series of 433 BRCA1/2 mutation-negative MBC and female breast cancer (FBC) cases and 849 male and female controls was included in the study. RESULTS: WES in the family identified the partner and localizer of BRCA2 (PALB2) c.419delA truncating mutation carried by the proband, her father, and her paternal uncle (all affected with BC) and the N-acetyltransferase 1 (NAT1) c.97C>T nonsense mutation carried by the proband's maternal aunt. Targeted PALB2 sequencing detected the c.1984A>T nonsense mutation in 1 of the 48 BRCA1/2 mutation-negative MBC cases. NAT1 c.97C>T was not found in the case-control series. CONCLUSIONS: These results add strength to the evidence showing that PALB2 is involved in BC risk for both sexes and indicate that consideration should be given to clinical testing of PALB2 for BRCA1/2 mutation-negative families with multiple MBC and FBC cases. Cancer 2017;123:210-218.
BACKGROUND:Male breast cancer (MBC) is a rare disease whose etiology appears to be largely associated with genetic factors. BRCA1 and BRCA2 mutations account for about 10% of all MBC cases. Thus, a fraction of MBC cases are expected to be due to genetic factors not yet identified. To further explain the genetic susceptibility for MBC, whole-exome sequencing (WES) and targeted gene sequencing were applied to high-risk, BRCA1/2 mutation-negative MBC cases. METHODS: Germ-line DNA of 1 male and 2 female BRCA1/2 mutation-negative breast cancer (BC) cases from a pedigree showing a first-degree family history of MBC was analyzed with WES. Targeted gene sequencing for the validation of WES results was performed for 48 high-risk, BRCA1/2 mutation-negative MBC cases from an Italian multicenter study of MBC. A case-control series of 433 BRCA1/2 mutation-negative MBC and female breast cancer (FBC) cases and 849 male and female controls was included in the study. RESULTS: WES in the family identified the partner and localizer of BRCA2 (PALB2) c.419delA truncating mutation carried by the proband, her father, and her paternal uncle (all affected with BC) and the N-acetyltransferase 1 (NAT1) c.97C>T nonsense mutation carried by the proband's maternal aunt. Targeted PALB2 sequencing detected the c.1984A>T nonsense mutation in 1 of the 48 BRCA1/2 mutation-negative MBC cases. NAT1 c.97C>T was not found in the case-control series. CONCLUSIONS: These results add strength to the evidence showing that PALB2 is involved in BC risk for both sexes and indicate that consideration should be given to clinical testing of PALB2 for BRCA1/2 mutation-negative families with multiple MBC and FBC cases. Cancer 2017;123:210-218.
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