Polyglutamine repeat length in the AIB1 gene modifies breast cancer susceptibility in BRCA1 carriers.

Variation in the penetrance estimates for BRCA1 and BRCA2 mutation carriers suggests that other factors may modify cancer risk from specific mutations. One possible mechanism is an epigenetic effect of polymorphisms in other genes. Genes involved in hormonal signal transduction are possible candidates. The AIB1 gene, an estrogen receptor (ER) coactivator, is frequently amplified in breast and ovarian tumors. Variation of a CAG repeat length has been reported within this gene that encodes a polyglutamine repeat in the C-terminus of the protein. Three hundred eleven BRCA1/2 mutation carriers (257 were of Ashkenazi origin) were genotyped for the AIB1 polyglutamine repeat. Relative risks (RR) were estimated using a maximum likelihood approach. The estimated breast cancer (BC) RR per average repeat length adjusted for population type (Ashkenazi vs. non-Ashkenazi) was 1.15 (95% CI = 1.02-1.30; p = 0.01) for BRCA1/2 carriers, and 1.25 (95% CI = 1.09-1.42; p = 0.001) when analysis was restricted to BRCA1 carriers. RR of BC was 1.17 (95% CI = 0.91-1.74), for individuals with 2 alleles >/=29 polyglutamine repeats and 0.78 (95% CI = 0.50-1.16) for those with at least 1 allele of </=26 repeats, compared to individuals with the common genotypes 28;28, 28;29 or 28;30. The corresponding BC RR in BRCA1 mutation carriers was 0.55 (95% CI = 0.34-0.90) and 1.29 (95% CI = 0.85-1.96) in those with </=26 and >/=29 repeats respectively (p = 0.025). These results indicate significant association of the risk for BC in carriers of BRCA1 mutations with the polyglutamine chain of the AIB1 gene. Longer repeat length correlates with elevated risk, whereas in carriers of a shorter AIB1 allele BC risk was reduced. The AIB1 polyglutamine length did not affect BC risk among BRCA2 mutation carriers.

Kadouri L ，Kote-Jarai Z ，Easton DF ，Hubert A ，Hamoudi R ，Glaser B ，Abeliovich D ，Peretz T ，Eeles RA ... -  《INTERNATIONAL JOURNAL OF CANCER》

CAG and GGC repeat polymorphisms in the androgen receptor gene and breast cancer susceptibility in BRCA1/2 carriers and non-carriers.

Variation in the penetrance estimates for BRCA1 and BRCA2 mutations carriers suggests that other genetic polymorphisms may modify the cancer risk in carriers. A previous study has suggested that BRCA1 carriers with longer lengths of the CAG repeat in the androgen receptor (AR) gene are at increased risk of breast cancer (BC). We genotyped 188 BRCA1/2 carriers (122 affected and 66 unaffected with breast cancer), 158 of them of Ashkenazi origin, 166 BC cases without BRCA1/2 mutations and 156 Ashkenazi control individuals aged over 56 for the AR CAG and GGC repeats. In carriers, risk analyses were conducted using a variant of the log-rank test, assuming two sets of risk estimates in carriers: penetrance estimates based on the Breast Cancer Linkage Consortium (BCLC) studies of multiple case families, and lower estimates as suggested by population-based studies. We found no association of the CAG and GGC repeats with BC risk in either BRCA1/2 carriers or in the general population. Assuming BRCA1/2 penetrance estimates appropriate to the Ashkenazi population, the estimated RR per repeat adjusted for ethnic group (Ashkenazi and non-Ashkenazi) was 1.05 (95%CI 0.97-1.17) for BC and 1.00 (95%CI 0.83-1.20) for ovarian cancer (OC) for CAG repeats and 0.96 (95%CI 0.80-1.15) and 0.90 (95%CI 0.60-1.22) respectively for GGC repeats. The corresponding RR estimates for the unselected case-control series were 1.00 (95%CI 0.91-1.10) for the CAG and 1.05 (95%CI 0.90-1.22) for the GGC repeats. The estimated relative risk of BC in carriers associated with > or =28 CAG repeats was 1.08 (95%CI 0.45-2.61). Furthermore, no significant association was found if attention was restricted to the Ashkenazi carriers, or only to BRCA1 or BRCA2 carriers. We conclude that, in contrast to previous observations, if there is any effect of the AR repeat length on BRCA1 penetrance, it is likely to be weak.

Kadouri L ，Easton DF ，Edwards S ，Hubert A ，Kote-Jarai Z ，Glaser B ，Durocher F ，Abeliovich D ，Peretz T ，Eeles RA ... -  《-》

Breast cancer risk in BRCA1 and BRCA2 mutation carriers and polyglutamine repeat length in the AIB1 gene.

Hughes DJ ，Ginolhac SM ，Coupier I ，Barjhoux L ，Gaborieau V ，Bressac-de-Paillerets B ，Chompret A ，Bignon YJ ，Uhrhammer N ，Lasset C ，Giraud S ，Sobol H ，Hardouin A ，Berthet P ，Peyrat JP ，Fournier J ，Nogues C ，Lidereau R ，Muller D ，Fricker JP ，Longy M ，Toulas C ，Guimbaud R ，Yannoukakos D ，Mazoyer S ，Lynch HT ，Lenoir GM ，Goldgar DE ，Stoppa-Lyonnet D ，Sinilnikova OM ... -  《INTERNATIONAL JOURNAL OF CANCER》

The AIB1 polyglutamine repeat does not modify breast cancer risk in BRCA1 and BRCA2 mutation carriers.

This is by far the largest study of its kind to date, and further suggests that AIB1 does not play a substantial role in modifying the phenotype of BRCA1 and BRCA2 carriers. The AIB1 gene encodes the AIB1/SRC-3 steroid hormone receptor coactivator, and amplification of the gene and/or protein occurs in breast and ovarian tumors. A CAG/CAA repeat length polymorphism encodes a stretch of 17 to 29 glutamines in the HR-interacting carboxyl-terminal region of the protein which is somatically unstable in tumor tissues and cell lines. There is conflicting evidence regarding the role of this polymorphism as a modifier of breast cancer risk in BRCA1 and BRCA2 carriers. To further evaluate the evidence for an association between AIB1 glutamine repeat length and breast cancer risk in BRCA1 and BRCA2 mutation carriers, we have genotyped this polymorphism in 1,090 BRCA1 and 661 BRCA2 mutation carriers from Australia, Europe, and North America. There was no evidence for an increased risk associated with AIB1 glutamine repeat length. Given the large sample size, with more than adequate power to detect previously reported effects, we conclude that the AIB1 glutamine repeat does not substantially modify risk of breast cancer in BRCA1 and BRCA2 mutation carriers.

Spurdle AB ，Antoniou AC ，Kelemen L ，Holland H ，Peock S ，Cook MR ，Smith PL ，Greene MH ，Simard J ，Plourde M ，Southey MC ，Godwin AK ，Beck J ，Miron A ，Daly MB ，Santella RM ，Hopper JL ，John EM ，Andrulis IL ，Durocher F ，Struewing JP ，Easton DF ，Chenevix-Trench G ，Australian Breast Cancer Family Study ，Australian Jewish Breast Cancer Study ，Breast Cancer Family Registry ，Interdisciplinary Health Research International Team on Breast Cancer Susceptibility ，Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer ，Epidemiological Study of Familial Breast Cancer Study Collaborators ... -  《CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION》

Polymorphic repeat length in the AIB1 gene and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a meta-analysis of observational studies.

Bianco A ，Quaresima B ，Pileggi C ，Faniello MC ，De Lorenzo C ，Costanzo F ，Pavia M ... -  《PLoS One》