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

Amanda B Spurdle,Xiaoqing Chen,David M Purdie,David L Duffy,Beth Newman,Georgia Chenevix-Trench,Douglas F Easton,Gillian S Dite,Livia Kelemen,Graham G Giles,Antonis C Antoniou,Carmel Apicella,Nirmala Pandeya,Paula L Smith,Margaret R Cook,Melissa C Southey,Susan Peock,John L Hopper

doi:10.1186/bcr971

Abstract

IntroductionThe androgen receptor (AR) gene exon 1 CAG repeat polymorphism encodes a string of 9–32 glutamines. Women with germline BRCA1 mutations who carry at least one AR allele with 28 or more repeats have been reported to have an earlier age at onset of breast cancer.MethodsA 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.ResultsThere 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.ConclusionThe AR exon 1 CAG repeat polymorphism does not appear to have an effect on breast cancer risk in BRCA1 or BRCA2 mutation carriers.

Highlights

The androgen receptor (AR) gene exon 1 CAG repeat polymorphism encodes a string of 9–32 glutamines
We evaluated the power of detecting the effects reported by Rebbeck and coworkers [7] in our samples of BRCA1 and BRCA2 mutation carriers using simulations
There was little power to assess potential confounding or risk associated with the cut-point ≥ 30 CAG repeats, because only 11 BRCA1 and 11 BRCA2 carriers had at least one allele of this size

Summary

Introduction

The androgen receptor (AR) gene exon 1 CAG repeat polymorphism encodes a string of 9–32 glutamines. Women with germline BRCA1 mutations who carry at least one AR allele with 28 or more repeats have been reported to have an earlier age at onset of breast cancer. 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]. 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]).

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Discussion

Conclusion