Growing Pains for the Environmental Genetics of Breast Cancer: Observations on a Study of the Glutathione S-Transferases

Extract

Researchers now pursue two distinct avenues of investigation in the search to understand breast cancer susceptibility; one is aimed at highly penetrant genes that confer large absolute cancer risks, while the other focuses on common gene polymorphisms associated with modest individual risk. Among the second group are genes that govern a woman's defense against environmental exposures. In this context, environment is broadly defined and includes exogenous as well as endogenous agents. The first approach has received the greatest attention and has yielded dramatic results (e.g., BRCA1 and BRCA2), while the second avenue is less traveled and has yet to produce markers with definite clinical or public health utility.

Illustrating this situation is a report appearing in this issue of the Journal by Helzlsouer et al. (1), who describe an association between genetic deficiency in isoforms of the detoxification enzyme glutathione S-transferase (GST), principally GST class mu (GSTM1), and breast cancer. In this rather small prospective study, the significant association of the GSTM1 null genotype with breast cancer is driven by women who were postmenopausal at diagnosis. These investigators also observed a nonsignificant elevated risk for breast cancer in GSTT1 (GST class theta) null individuals and women who had the variant genotype for the GSTP1 (GST class pi) enzyme. When the variant genotypes were combined, a statistically significant, almost fourfold increase in risk was observed for individuals with two or three putative high-risk genotypes.