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Comparing the frequency of common genetic variants and haplotypes between carriers and non-carriers of BRCA1 and BRCA2deleterious mutations in Australian women diagnosed with breast cancer before 40 years of age

Authors: Turkovic, L; Gurrin, LC; Bahlo, M; Dite, GS; Southey, MC; Hopper, JL;

Comparing the frequency of common genetic variants and haplotypes between carriers and non-carriers of BRCA1 and BRCA2deleterious mutations in Australian women diagnosed with breast cancer before 40 years of age

Abstract

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.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.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.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.

Country
Australia
Keywords

Adult, Cancer Research, Adolescent, 610, Breast Neoplasms, Young Adult, Risk Factors, 616, Genetics, Humans, Genetic Predisposition to Disease, RC254-282, Germ-Line Mutation, Neoplasm Staging, BRCA2 Protein, Polymorphism, Genetic, BRCA1 Protein, Australia, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Middle Aged, Prognosis, Founder Effect, Survival Rate, Oncology, Haplotypes, Case-Control Studies, Female, Research Article

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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
9
Average
Average
Average
Green
gold