title: Mutational profiling of familial male breast cancers reveals similarities with luminal A female breast cancer with rare TP53 mutations.
abstract: BACKGROUND
  Male breast cancer (MBC) is still poorly understood with a large proportion arising in families with a history of breast cancer. Genomic studies have focused on germline determinants of MBC risk, with minimal knowledge of somatic changes in these cancers.
  
  
  METHODS
  Using a TruSeq amplicon cancer panel, this study evaluated 48 familial MBCs (3 BRCA1 germline mutant, 17 BRCA2 germline mutant and 28 BRCAX) for hotspot somatic mutations and copy number changes in 48 common cancer genes.
  
  
  RESULTS
  Twelve missense mutations included nine PIK3CA mutations (seven in BRCAX patients), two TP53 mutations (both in BRCA2 patients) and one PTEN mutation. Common gains were seen in GNAS (34.1%) and losses were seen in GNAQ (36.4%), ABL1 (47.7%) and ATM (34.1%). Gains of HRAS (37.5% vs 3%, P=0.006), STK11 (25.0% vs 0%, P=0.01) and SMARCB1 (18.8% vs 0%, P=0.04) and the loss of RB1 (43.8% vs 13%, P=0.03) were specific to BRCA2 tumours.
  
  
  CONCLUSIONS
  This study is the first to perform high-throughput somatic sequencing on familial MBCs. Overall, PIK3CA mutations are most commonly seen, with fewer TP53 and PTEN mutations, similar to the profile seen in luminal A female breast cancers. Differences in mutation profiles and patterns of gene gains/losses are seen between BRCA2 (associated with TP53/PTEN mutations, loss of RB1 and gain of HRAS, STK11 and SMARCB1) and BRCAX (associated with PIK3CA mutations) tumours, suggesting that BRCA2 and BRCAX MBCs may be distinct and arise from different tumour pathways. This has implications on potential therapies, depending on the BRCA status of MBC patients.
authors.affiliation: 1] Department of Molecular Pathology, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia [2] Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia [3] Department of Pathology, University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Deb
authors.affiliation: Department of Molecular Pathology, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia.
authors.forename: S Q
authors.initials: SQ
authors.lastname: Wong
authors.affiliation: Department of Bioinformatics, Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Translational Genomics and Epigenomics Laboratory, Ludwig Institute for Cancer Research, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, VIC 3084, Australia.
authors.forename: H
authors.initials: H
authors.lastname: Do
authors.affiliation: Translational Genomics and Epigenomics Laboratory, Ludwig Institute for Cancer Research, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, VIC 3084, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Weiss
authors.affiliation: Department of Molecular Pathology, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Byrne
authors.affiliation: Metastasis Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Chakrabarti
authors.affiliation: Molecular Diagnostics, Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Bosma
authors.affiliation: Molecular Diagnostics, Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Fellowes
authors.affiliation: 1] Department of Molecular Pathology, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia [2] Translational Genomics and Epigenomics Laboratory, Ludwig Institute for Cancer Research, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, VIC 3084, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Dobrovic
authors.affiliation: 1] Department of Molecular Pathology, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia [2] Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia [3] Department of Pathology, University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: S B
authors.initials: SB
authors.lastname: Fox
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D018567:Breast Neoplasms, Male / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human