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The androgen receptor CAG repeat polymorphism and modification of breast cancer risk in BRCA1 and BRCA2 mutation carriers

DOI: 10.1186/bcr971

Keywords: AR, BRCA1, BRCA2, modifier

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A total of 604 living female Australian and British BRCA1 and/or BRCA2 mutation carriers from 376 families were genotyped for the AR CAG repeat polymorphism. The association between AR genotype and disease risk was assessed using Cox regression. AR genotype was analyzed as a dichotomous covariate using cut-points previously reported to be associated with increased risk among BRCA1 mutation carriers, and as a continuous variable considering smaller allele, larger allele and average allele size.There was no evidence that the AR CAG repeat polymorphism modified disease risk in the 376 BRCA1 or 219 BRCA2 mutation carriers screened successfully. The rate ratio associated with possession of at least one allele with 28 or more CAG repeats was 0.74 (95% confidence interval 0.42–1.29; P = 0.3) for BRCA1 carriers, and 1.12 (95% confidence interval 0.55–2.25; P = 0.8) for BRCA2 carriers.The AR exon 1 CAG repeat polymorphism does not appear to have an effect on breast cancer risk in BRCA1 or BRCA2 mutation carriers.A CAG length polymorphism within exon 1 of the androgen receptor (AR) gene encodes a string of 9–32 glutamines. Even within this normal range, CAG repeat number is inversely associated with AR-mediated transcriptional activation in vitro [1,2]. Involvement of the AR in breast tumourigenesis is suggested by the existence of inactivating germline mutations in the hormone-binding domain in male breast cancer patients [3,4], and by splice variants that disrupt the transactivation domain in female breast tumours and tumour cell lines [5].There is evidence that suggests an association between longer AR CAG repeat length – representative of less active AR – and breast cancer risk at the population level (for review, see Lillie and coworkers [6]). Using slightly variable definitions of shorter and longer allele size across studies, one study reported a significant twofold increased risk for breast cancer, another three studies reported a slightly increased risk for breast ca


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