Glutathione-S-transferase M1, T1 and P1 polymorphisms, and breast cancer risk, in BRCA1/2 mutation carriers

Abstract

5The Royal Marsden NHS Foundation Trust, Sutton, UK Variation in penetrance estimates for BRCA1/2 carriers suggests that other environmental and genetic factors may modify cancer risk in carriers. The GSTM1, T1 and P1 isoenzymes are involved in metabolism of environmental carcinogens. The GSTM1 and GSTT1 gene is absent in a substantial proportion of the population. In GSTP1, a single-nucleotide polymorphism that translates to Ile112Val was associated with lower activity. We studied the effect of these polymorphisms on breast cancer (BC) risk in BRCA1/2 carriers. A population of 320 BRCA1/2 carriers were genotyped; of them 262 were carriers of one of the three Ashkenazi founder mutations. Two hundred and eleven were affected with BC (20 also with ovarian cancer (OC)) and 109 were unaffected with BC (39 of them had OC). Risk analyses were conducted using Cox proportional hazard models adjusted for origin (Ashkenazi vs non-Ashkenazi). We found an estimated BC HR of 0.89 (95% CI 0.65 -1.12, P ¼ 0.25) and 1.11 (95% CI 0.81 -1.52, P ¼ 0.53) for the null alleles of GSTM1 and GSTT1, respectively. For GSTP1, HR for BC was 1.36 (95% CI 1.02 -1.81, P ¼ 0.04) for individuals with Ile/Val, and 2.00 (95% CI 1.18 -3.38) for carriers of the Val/Val genotype (P ¼ 0.01). An HR of 3.20 (95% CI 1.26 -8.09, P ¼ 0.01), and younger age at BC onset (P ¼ 0.2), were found among Val/Val, BRCA2 carriers, but not among BRCA1 carriers. In conclusion, our results indicate significantly elevated risk for BC in carriers of BRCA2 mutations with GSTP1-Val allele with dosage effect, as implicated by higher risk in homozygous Val carriers. The GSTM1-and GSTT1-null allele did not seem to have a major effect.

Pooled analysis indicates that the GSTT1 deletion, GSTM1 deletion, and GSTP1 Ile105Val polymorphisms do not modify breast cancer risk in BRCA1 and BRCA2 mutation carriers

“…Notably, the GSTP1 105Val variant, which was previously reported to be associated with increased risk of breast cancer in a small study of 90 BRCA2 carriers [20], was associated with non-significant reduced risk for BRCA2 carriers in our larger sample of 245 women with BRCA2 mutations. Although the sample size of this study is still relatively small, there is a statistically significant difference ( P = 0.02) between the HR for BRCA2 in this study and that reported by Kadouri et al [20]. These results support the need for replication studies to confirm or refute hypothesis-generating studies, including analyses that use existing unpublished data collated by consortia.…”

“…However, their effects on breast cancer risk in carriers of BRCA1 or BRCA2 mutations have been reported in only a single study [20]. Their analysis of 320 BRCA1/2 carriers showed no evidence for altered risk of breast cancer for individuals with the GSTT1 and GSTM1 deletion variants, but did report that the GSTP1 Ile105Val variant was associated with increased breast cancer risk (HR 1.36 ( p = 0.04) for heterozygotes, and HR 2.00 ( P = 0.01) for homozygotes).…”

Worldwide population distribution of the common LCE3C-LCE3B deletion associated with psoriasis and other autoimmune disorders

“…For example, CFHR3 and CFHR1 are associated with age-related macular degeneration [43-45] and systemic lupus erythematous [46]. GSTT1 has been linked to breast cancer [47], NAFLD to non-alcoholic fatty liver disease [48], and HLA-DRB5 and HLA-DQA1 to autoimmune diseases [49,50]. Due to their functional characteristics, most of these genes are very appealing from both biomedical and evolutionary perspectives, supporting the idea that the variable prevalence of some diseases among ethnic groups is in part linked to environmental conditions.…”

Association between GSTP1 Genotypes and Hormone Receptor Phenotype in Invasive Ductal Carcinomas of Breast

“…Several studies reported that the GSTP1 polymorphism is associated with a higher risk of breast cancer especially Ile/Val and Val/Val allele carriers in different population such as Americans (Kadouri et al, 2008), Indians (Samson et al, 2007;Saxena et al, 2009), Chinese in North china (Ge et al, 2013) and Chinese in Southeast China (Lee et al, 2008). On the other hand, studies of the Finnish (Mitrunen et al, 2001) and Koreans (Kim et al, 2004) revealed that the variant allele of GSTP1 was connected with a reduced breast cancer risk.…”