title: BRCA1/BRCA2 founder mutations and cancer risks: impact in the western Danish population.
abstract: Mutations in the BRCA1 and BRCA2 genes significantly contribute to hereditary breast cancer and ovarian cancer, but the phenotypic effect from different mutations is insufficiently recognized. We used a western Danish clinic-based cohort of 299 BRCA families to study the female cancer risk in mutation carriers and their untested first-degree relatives. Founder mutations were characterized and the risk of cancer was assessed in relation to the specific mutations. In BRCA1, the cumulative cancer risk at age 70 was 35 % for breast cancer and 29 % for ovarian cancer. In BRCA2, the cumulative risk was 44 % for breast cancer and 15 % for ovarian cancer. We identified 47 distinct BRCA1 mutations and 48 distinct mutations in BRCA2. Among these, 8 founder mutations [BRCA1 c.81-?_4986+?del, c.3319G>T (p.Glu1107*), c.3874delT and c.5213G>A (p.Gly1738Glu) and BRCA2 c.6373delA, c.7008-1G>A, c.7617+1G>A and c.8474delC] were found to account for 23 % of the BRCA1 mutations and for 32 % of the BRCA2 mutations. The BRCA1 mutation c.3319G>T was, compared to other BRCA1 mutations, associated with a higher risk for ovarian cancer. In conclusion, founder mutations in BRCA1 and BRCA2 contribute to up to one-third of the families in western Denmark and among these the BRCA1 c.3319G>T mutation is potentially linked to an increased risk of ovarian cancer.
authors.affiliation: Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark.
authors.forename: Henriette Roed
authors.initials: HR
authors.lastname: Nielsen
authors.affiliation: HNPCC Register, Clinical Research Center, Copenhagen University Hospital, Hvidovre, Denmark.
authors.forename: Mef
authors.initials: M
authors.lastname: Nilbert
authors.affiliation: HNPCC Register, Clinical Research Center, Copenhagen University Hospital, Hvidovre, Denmark.|Section of Biostatistics, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Janne
authors.initials: J
authors.lastname: Petersen
authors.affiliation: HNPCC Register, Clinical Research Center, Copenhagen University Hospital, Hvidovre, Denmark.
authors.forename: Steen
authors.initials: S
authors.lastname: Ladelund
authors.affiliation: Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital, Odense, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Thomassen
authors.affiliation: Section of Molecular Diagnostics, Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Inge Søkilde
authors.initials: IS
authors.lastname: Pedersen
authors.affiliation: Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Thomas V O
authors.initials: TV
authors.lastname: Hansen
authors.affiliation: Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Anne-Bine
authors.initials: AB
authors.lastname: Skytte
authors.affiliation: Institute of Clinical Sciences, Department of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Borg
authors.affiliation: HNPCC Register, Clinical Research Center, Copenhagen University Hospital, Hvidovre, Denmark. 2xtherkild@gmail.com.
authors.forename: Christina
authors.initials: C
authors.lastname: Therkildsen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics; D015331:Cohort Studies; D003718:Denmark; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human
keywords: Cancer risk; Cumulative incidence; Founder mutation; Hereditary cancer
references.citation: Clin Genet. 2015 Mar;87(3):288-92
references.pmid: 24528374
references.citation: Breast Cancer Res Treat. 2010 Jan;119(2):409-14
references.pmid: 19885732
references.citation: J Natl Cancer Inst. 2002 Sep 18;94(18):1358-65
references.pmid: 12237281
references.citation: Am J Hum Genet. 1998 Mar;62(3):676-89
references.pmid: 9497246
references.citation: Nat Genet. 1997 Jan;15(1):103-5
references.pmid: 8988179
references.citation: Am J Hum Genet. 2001 Feb;68(2):410-9
references.pmid: 11170890
references.citation: Eur J Hum Genet. 2001 Oct;9(10):787-93
references.pmid: 11781691
references.citation: J Med Genet. 2014 Sep;51(9):573-80
references.pmid: 25053764
references.citation: Eur J Cancer. 2004 Dec;40(18):2788-93
references.pmid: 15571962
references.citation: Clin Genet. 2013 Jan;83(1):88-91
references.pmid: 22320316
references.citation: Nat Genet. 1996 May;13(1):117-9
references.pmid: 8673089
references.citation: Int J Oncol. 2001 Apr;18(4):831-5
references.pmid: 11251181
references.citation: Acta Oncol. 2008;47(4):772-7
references.pmid: 18465347
references.citation: Clin Cancer Res. 2002 Dec;8(12):3776-81
references.pmid: 12473589
references.citation: Cancer Genet Cytogenet. 2006 Jul 15;168(2):168-71
references.pmid: 16843109
references.citation: Cancer. 2012 Jan 15;118(2):493-9
references.pmid: 21598239
references.citation: Fam Cancer. 2004;3(1):1-10
references.pmid: 15131399
references.citation: J Clin Oncol. 2007 Apr 10;25(11):1329-33
references.pmid: 17416853
references.citation: Am J Hum Genet. 1997 Jul;61(1):120-8
references.pmid: 9245992
references.citation: J Clin Oncol. 2002 Mar 15;20(6):1480-90
references.pmid: 11896095
references.citation: Eur J Hum Genet. 2000 Oct;8(10):757-63
references.pmid: 11039575
references.citation: Cancer Epidemiol Biomarkers Prev. 2012 Jan;21(1):134-47
references.pmid: 22144499
references.citation: Science. 2003 Oct 24;302(5645):643-6
references.pmid: 14576434
references.citation: Cancer Res. 1996 Aug 15;56(16):3663-5
references.pmid: 8706004
references.citation: J Clin Oncol. 2015 Aug 10;33(23):2553-62
references.pmid: 26150446
references.citation: Nat Rev Cancer. 2004 Sep;4(9):665-76
references.pmid: 15343273
references.citation: Fam Cancer. 2005;4(2):89-96
references.pmid: 15951958
references.citation: Breast Cancer Res Treat. 2011 Jul;128(1):179-85
references.pmid: 21184276
references.citation: J Natl Cancer Inst. 2007 Jun 20;99(12):929-35
references.pmid: 17565157
references.citation: JAMA. 2015 Apr 7;313(13):1347-61
references.pmid: 25849179
references.citation: Breast Cancer Res Treat. 2009 May;115(2):315-23
references.pmid: 18546071
references.citation: Am J Hum Genet. 2003 May;72(5):1117-30
references.pmid: 12677558
references.citation: Lancet. 1994 Mar 19;343(8899):692-5
references.pmid: 7907678