Low-Penetrance Genotypes and Gene-Environment Interactions

The glutathione-S-transferases are involved in the detoxification of carcinogens. Several related genes exist; the most studied are the µ, t, and p classes. The homozygous deletion in GSTµ is common, occurring in 50% of whites. No association with breast cancer was seen in studies of 212 cases, 245 cases, 232 cases, and 361 cases. In a study of 110 cases, an increased risk for the GSTµ null genotype was observed (odds ratio, 2.1; 95% confidence interval, 1.2 to 3.6), along with nonsignificant elevations in risk for the homozygous deletion in GSTt and for an isoleucine-valine substitution polymorphism in GSTp. No interactions with cigarette smoking were seen for these genotypes in studies that reported data on this issue.

Hormone-Metabolizing Genes
Because steroid hormones, particularly estrogens and progesterone, are so strongly implicated in breast carcinogenesis, genes involved in the steroidogenic pathway are natural candidates in the search for polymorphic variants that influence breast cancer risk. This pathway includes many enzymes, and many of them are large and have complex tissue-specific patterns of gene expression and alternate coding and splicing forms; much work needs to be done to define potential polymorphic variants with definite functional significance.

The CYP17 gene encodes the rate-limiting step in androgen production in the ovary and adrenal glands. A polymorphism in the 5’ untranslated region designated the A2 allele was initially associated with a nonsignificant elevation in breast cancer risk and a significant increase in risk ofadvanced breast cancer (odds ratio, 2.5; 95% confidence interval, 1.1 to 5.9). Subsequent larger studies have not observed any increase in risk overall, or among cases of more advanced breast cancer.

The catechol-O-methyltransferase (COMT) enzyme inactivates catechol estrogens and is polymorphic, with approximately 25% of whites being homozygous for the low activity allele of the enzyme (LL). In a study including 112 cases, the LL genotype was associated with increased breast cancer risk among postmenopausal women (odds ratio, 2.2; 95% confidence interval, 0.9 to 5.1). In another study, this risk was inversely associated with risk among postmenopausal women (odds ratio, 0.3; 95% confidence interval, 0.1 to 0.7) but was positively associated with risk among premenopausal women (odds ratio, 2.1; 95% confidence interval, 1.4 to 4.3).

The aromatase coded by the CYP19 gene is responsible for the conversion of C19 steroids to estrogens and plays a major role in the production of estrogens in postmenopausal women. A polymorphic tetranucleotide (TTTA) repeat in intron 5 was studied among 182 sporadic and 185 familial breast cancer cases in Scandinavia. A relatively rare allele containing the longest repeat (12 TTTA repeats) was found significantly more frequently in women with breast cancer than in controls (odds ratio, 2.4; 95% confidence interval, 1.0 to 5.8).

Page 2 of 31 2 3 Next »

Provided by ArmMed Media