title: Whole-exome sequencing and targeted gene sequencing provide insights into the role of PALB2 as a male breast cancer susceptibility gene.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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. © 2016 American Cancer Society.
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Silvestri
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Zelli
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Virginia
authors.initials: V
authors.lastname: Valentini
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Piera
authors.initials: P
authors.lastname: Rizzolo
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Anna Sara
authors.initials: AS
authors.lastname: Navazio
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Coppa
authors.affiliation: Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV, Padua, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Agata
authors.affiliation: Oncology Unit, Local Health and Social Care Unit ULSS5 Ovest Vicentino, Montecchio Maggiore, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Oliani
authors.affiliation: Oncology Unit, Local Health and Social Care Unit ULSS5 Ovest Vicentino, Montecchio Maggiore, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Barana
authors.affiliation: Supercomputing Applications and Innovation Department, Interuniversity Consortium for Super Computing CINECA, Rome, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Castrignanò
authors.affiliation: Unit of Functional Onco-Genomics and Genetics, Aviano Oncology Reference Center CRO, National Cancer Institute, Aviano, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Viel
authors.affiliation: Section of Medical Oncology, Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Russo
authors.affiliation: Unit of Pathology, Circolo Hospital, Varese, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Tibiletti
authors.affiliation: Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute ISPO, Florence, Italy.
authors.forename: Ines
authors.initials: I
authors.lastname: Zanna
authors.affiliation: Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute ISPO, Florence, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Masala
authors.affiliation: Department of Oncology and Haematology, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Cortesi
authors.affiliation: Unit of Medical Genetics, Department of Preventive and Predictive Medicine, National Cancer Institute INT, Milan, Italy.
authors.forename: Siranoush
authors.initials: S
authors.lastname: Manoukian
authors.affiliation: Unit of Medical Genetics, Department of Preventive and Predictive Medicine, National Cancer Institute INT, Milan, Italy.
authors.forename: Jacopo
authors.initials: J
authors.lastname: Azzollini
authors.affiliation: Unit of Medical Genetics, Department of Preventive and Predictive Medicine, National Cancer Institute INT, Milan, Italy.
authors.forename: Bernard
authors.initials: B
authors.lastname: Peissel
authors.affiliation: Division of Cancer Prevention and Genetics, European Institute of Oncology IEO, Milan, Italy.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Bonanni
authors.affiliation: Italian Foundation for Cancer Research (FIRC) Institute of Molecular Oncology INT, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Peterlongo
authors.affiliation: Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, National Cancer Institute INT, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Radice
authors.affiliation: Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute ISPO, Florence, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Palli
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
authors.affiliation: Supercomputing Applications and Innovation Department, Interuniversity Consortium for Super Computing CINECA, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Chillemi
authors.affiliation: Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV, Padua, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Montagna
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Ottini
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics; D018567:Breast Neoplasms, Male / Q000235:genetics*; D016022:Case-Control Studies; D004252:DNA Mutational Analysis / Q000379:methods; D059472:Exome / Q000235:genetics*; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007558:Italy; D008297:Male; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins
keywords: N-acetyltransferase 1 (NAT1); genetic susceptibility; male breast cancer; partner and localizer of BRCA2 (PALB2); whole-exome sequencing