title: Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.
abstract: OBJECTIVE
  Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.
  
  
  OBJECTIVE
  To identify mutation-specific cancer risks for carriers of BRCA1/2.
  
  
  METHODS
  Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.
  
  
  METHODS
  Mutations of BRCA1 or BRCA2.
  
  
  METHODS
  Breast and ovarian cancer risks.
  
  
  RESULTS
  Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers.
  
  
  CONCLUSIONS
  Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.
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authors: Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
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authors: Katarzyna
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authors: Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
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authors: Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
authors: Aleksandra
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authors: Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
authors: Elżbieta
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authors: Department of Surgical Gynecology and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland.
authors: Janusz
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authors: Department of Pathology, Landspitali University Hospital, Reykjavík, Iceland147BMC, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
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authors: Rosa B
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authors: Elisa
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authors: Department of Genetics, Portuguese Oncology Institute, Porto, Portugal153Biomedical Sciences Institute (ICBAS), University of Porto, Portugal.
authors: Manuel R
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authors: Department of Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia.
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authors: Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
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authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota159Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
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authors: Andreas
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authors: Amanda Ewart
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authors: Leigha
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authors: Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark.
authors: Anders
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authors: Section of Molecular Diagnostics, Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark.
authors: Inge Sokilde
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authors: Pedersen
authors: Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark.
authors: Anne-Bine
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authors: Skytte
authors: Department of Clinical Genetics, Aarhus University Hospital, Aarhus N, Denmark.
authors: Lone
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authors: Sunde
authors: Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark.
authors: Mads
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authors: Thomassen
authors: Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark.
authors: Sanne Traasdahl
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authors: Moeller
authors: Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark.
authors: Torben A
authors: TA
authors: Kruse
authors: Department of Clinical Genetics, Aarhus University Hospital, Aarhus N, Denmark.
authors: Uffe Birk
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authors: Jensen
authors: Section of Genetic Oncology, Department of Oncology, University of Pisa and University Hospital of Pisa, Pisa, Italy.
authors: Maria Adelaide
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authors: Caligo
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authors: Paolo
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authors: Aretini
authors: Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia176Department of Surgery, Faculty of Medicine, University Malaya Cancer Research Institute, University Malaya, Kuala Lumpur, Malaysia.
authors: Soo-Hwang
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authors: Teo
authors: NorthShore University HealthSystem, Department of Medicine, Evanston, Illinois.
authors: Christina G
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authors: Selkirk
authors: NorthShore University HealthSystem, Department of Medicine, Evanston, Illinois.
authors: Peter J
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authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada.
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mesh_terms: D000328:Adult; D017668:Age of Onset; D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009711:Nucleotides; D010051:Ovarian Neoplasms / Q000235:genetics*; D012307:Risk Factors
chemical_list: D009711:Nucleotides