Common Variant in ALDH2 Modifies the Risk of Breast Cancer Among Carriers of the p.K3326* Variant in BRCA2.

Abstract

The <i>BRCA2</i> p.K3326* variant is considered a low-penetrance variant for breast cancer. Aldehydes that accumulate in cells under insufficient aldehyde oxidation were most recently shown to trigger carcinogenesis by promoting depletion of BRCA2 protein. Allele T of the common variant rs10744777 in the <i>ALDH2</i> gene was associated with reduced expression of aldehyde dehydrogenase, the main enzyme in aldehyde oxidation. We hypothesized that this allele could modify breast cancer risk in women with the <i>BRCA2</i> p.K3326* low-penetrance variant through reduced function of ALDH2, increased accumulation of cellular aldehydes, and depletion of BRCA2 protein. We genotyped 11,873 Polish women diagnosed with breast cancer and 7,615 ethnically matched controls for these two variants. Next, we extended our analysis of rs10744777 to 231 carriers of pathogenic <i>BRCA2</i> mutations. <i>BRCA2</i> p.K3326* variant was associated with significant increase in breast cancer risk only in those who were homozygous for the T allele of the <i>ALDH2</i> rs10744777 variant (odds ratio = 1.72; 95% CI, 1.19 to 2.48; <i>P</i> = .003). The <i>BRCA2</i> p.K3326* variant did not increase the risk of breast cancer among those who were heterozygous or homozygous for the C allele of the <i>ALDH2</i> rs10744777 variant (odds ratio = 1.05; 95% CI, 0.73 to 1.51; <i>P</i> = .81). In the carriers of high-risk <i>BRCA2</i> mutations, the TT genotype of rs10744777 conferred a modest (18%) and not significant increase in breast cancer risk. Our results suggest that <i>BRCA2</i> p.K3326* variant, which is low-penetrance by itself, confers increased breast cancer risk on the background of the TT genotype of the <i>ALDH2</i> rs10744777 variant in the Polish population.