title: Comparing the frequency of common genetic variants and haplotypes between carriers and non-carriers of BRCA1 and BRCA2 deleterious mutations in Australian women diagnosed with breast cancer before 40 years of age.
abstract: BACKGROUND
  BRCA1 and BRCA2 mutations are found in a proportion of families with multiple early-onset breast cancers. There are a large number of different deleterious mutations in both genes, none of which would be detectable using standard genetic association studies. Single common variants and haplotypes of common variants may capture groups of deleterious mutations since some low prevalence haplotypes of common variants occur more frequently among chromosomes that carry rare, deleterious mutations than chromosomes that do not.
  
  
  METHODS
  DNA sequence data for BRCA1 and BRCA2 was obtained from 571 participants from the Australian Breast Cancer Family Study. Genetic variants were classified as either deleterious mutations or common genetic variants. Variants tagging common polymorphisms were selected and haplotypes resolved using Haploview. Their frequency was compared to those with and without deleterious mutations using a permutation test.
  
  
  RESULTS
  A common genetic variant in BRCA1 (3232A > G) was found to be over-represented in deleterious mutation carriers (p = 0.05), whereas a common genetic variant in BRCA2 (1342A > C) occurred less frequently in deleterious mutation carriers (p = 0.04). All four of the common BRCA1 variants used to form haplotypes occurred more frequently in the deleterious mutation carriers when compared to the non-carriers, but there was no evidence of a difference in the distributions between the two groups (p = 0.34). In BRCA2, all four common variants were found to occur less frequently in the deleterious mutation carriers when compared to non-carriers, but the evidence for difference in the distribution between the two groups was weak (p = 0.16). Several less common haplotypes of common BRCA1 variants were found to be over-represented among deleterious mutation carriers but there was no evidence for this at the population level. In BRCA2, only the most common haplotype was found to occur more frequently in deleterious mutation carriers, with again no evidence at the population level.
  
  
  CONCLUSIONS
  We observed differences in the frequency of common genetic variants of the BRCA1 and BRCA2 and their haplotypes between early-onset breast cancer cases who did and did not carry deleterious mutations in these genes. Although our data provide only weak evidence for a difference in frequencies at the population level, the number of deleterious mutation carriers was low and the results may yet be substantiated in a larger study using pooled data.
authors.affiliation: Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, The University of Melbourne, Victoria 3010, Australia. lidija78@yahoo.com
authors.forename: Lidija
authors.initials: L
authors.lastname: Turkovic
authors.forename: Lyle C
authors.initials: LC
authors.lastname: Gurrin
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
authors.forename: Gillian S
authors.initials: GS
authors.lastname: Dite
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
mesh_terms: D000293:Adolescent; D000328:Adult; D001315:Australia; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D012307:Risk Factors; D015996:Survival Rate; D055815:Young Adult
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human
references.citation: Am J Hum Genet. 2002 Feb;70(2):425-34
references.pmid: 11791212
references.citation: Genome Res. 2001 Jan;11(1):143-51
references.pmid: 11156623
references.citation: Genetics. 1964 Jan;49(1):49-67
references.pmid: 17248194
references.citation: Am J Hum Genet. 2004 Jul;75(1):35-43
references.pmid: 15148658
references.citation: J Natl Cancer Inst. 2003 Mar 19;95(6):448-57
references.pmid: 12644538
references.citation: Breast Cancer Res Treat. 2009 Jul;116(2):379-86
references.pmid: 18704680
references.citation: Eur J Hum Genet. 2003 Jun;11(6):489-92
references.pmid: 12774043
references.citation: Am J Hum Genet. 2003 Nov;73(5):1162-9
references.pmid: 14574645
references.citation: Breast Cancer Res. 2005;7(2):R171-5
references.pmid: 15743496
references.citation: Am J Hum Genet. 2001 Apr;68(4):978-89
references.pmid: 11254454
references.citation: Am J Hum Genet. 2004 Jan;74(1):106-20
references.pmid: 14681826
references.citation: Hum Mol Genet. 1997 Feb;6(2):285-9
references.pmid: 9063749
references.citation: Hum Mutat. 2002 Jul;20(1):65-73
references.pmid: 12112659
references.citation: Bioinformatics. 2005 Jan 15;21(2):263-5
references.pmid: 15297300
references.citation: J Natl Cancer Inst. 1998 Apr 1;90(7):532-6
references.pmid: 9539249
references.citation: Hum Mol Genet. 2004 Oct 15;13(20):2431-41
references.pmid: 15317758
references.citation: Cancer Res. 2005 Aug 15;65(16):7516-22
references.pmid: 16103107