Associations between family history of cancer and genes coding for metabolizing enzymes (United States)

Objective: Family history of cancer has been a useful tool to identify high ly penetrant genes. However, the association between family history and low -penetrance genes that are prevalent in the population is less well underst ood. While epidemiologists have studied low-penetrance genes in association studies at the population level, geneticists have often favored family stu dies to identify low-penetrance genes in the same manner that these familie s have been used to identify high-penetrance genes. In this study, we evalu ated the association between family history of cancer and molecular variant s of three genes: N-acetyltransferases (NAT2), glutathione-S-transferases ( GSTM-1), and methylenetetrahydrofolate reductase (MTHFR). These genes were examined because of their plausible functional significance and their assoc iation with cancer risk in some studies. Methods: In a large multi-centered study of colon cancer, reported family h istory of cancer in first-degree relatives was used to classify cases and c ontrols separately as having a family history of colorectal cancer, hormone -related cancers, smoking-related cancers, prostate cancer, and any cancer. Results: With three weak exceptions, we did not observe significant associa tions between any of these genes and family history of cancer. The ability of family history to positively predict the presence of variants of low-pen etrance genes that may carry an elevated risk ranged from 41% to 60%; low-p enetrance variants accurately predicted a family history of cancer 9 to 17% of the time. Assessment of the likelihood of having a family history of ca ncer given the combination of genetic and environmental factors, showed tha t those who smoked 20 or more cigarettes per day were more likely to have a family history of a smoking-related cancer irrespective of genotype. Conclusions: People with a family history of cancer are not more likely to have a variant of low-penetrance genes than those without a family history of cancer. Family studies may not be efficient methods to study low-penetra nce genes.