Genetic susceptibility to breast cancer in French-Canadians: Role of carcinogen-metabolizing enzymes and gene-environment interactions

Breast cancer is the most frequent malignancy among women. Since genetic fa ctors such as BRCA1 and BRCA2 as well as reproductive history constitute on ly 30% of the cause, environmental exposure may play a significant role in the development of breast cancer. Likewise, the relevant enzymes involved i n the biotransformation of xenobiotics (from tobacco smoke, diet or other e nvironmental sources) might play a role in breast carcinogenesis. Since ind ividuals with modified ability to metabolize these carcinogens could have a different risk for breast cancer, we investigated the role of cytochromes P-450 (CYP1A1, CYP2D6) glutathione-S-transferases (CSTM1, GSTT1, GSTP1) and N-acetyltransferases (NAT1, NAT2) gene variants in breast carcinogenesis. A case-control study was conducted on 149 women with breast carcinoma and 2 07 healthy controls, both of French-Canadian origin. The CYP1A1*4 allele wa s found to be a significant risk determinant of breast carcinoma (OR = 3.3, 95% Cl 1.1-9.7), particularly among post-menopausal women (OR 4.0, 95% Cl 1.2-13.8). The frequency of NAT2 rapid acetylators was increased among smok ers (OW = 2.6, 95% Cl 0.8-8.2), while the NAT1*10 allele conferred a 4-fold increase in risk among women who consumed well-done meat (OR 4.4, 95% Cl 1 .0-18.9). These data suggest that CYP1A1*4 NAT1 and NAT2 variants are invol ved in the susceptibility to breast carcinoma by modifying the impact of ex ogenous and/or endogenous exposures. (C) 2001 Wiley-Liss, Inc.