A major achievement during the past funding cycle of the Center was to be selected as one of six participants in the NCI-sponsored Collaborative Family Registry for Colorectal Cancer Studies (CFRCCS), which is an international registry of families at high risk of colorectal cancer. Data collected from these families will include pedigrees, risk factor questionnaires, blood samples, and tumor blocks on cases. There will be over 4,000 families (including over 1,000 with three or more cases of colorectal cancer) in this Registry. The goal is to facilitate research on the causes and prevention of colorectal cancer. Several NIEHS Center members (R. Haile, D. Thomas, J. Gauderman, and K. Sigmund) are participating in this activity.

Dr. Haile is a member of a national clinical trials consortium, that conducts clinical trials in the prevention of colorectal adenomas, accepted precursors of colorectal cancer. The most significant achievement this past year is a recently completed trial strongly suggesting that calcium (3,000 mg of calcium carbonate per day) reduces the risk of adenomas by nearly 20%. We have now been funded to conduct additional laboratory and statistical analyses to elucidate the mechanism whereby calcium reduces risk. We are also involved in an ongoing trial of aspirin and folic acid in the prevention of colorectal adenomas. We have also recently been funded to add a study of DNA methylation to this trial. DNA methylation is the topic of one of our newly formed research focus groups.

We have completed a study of risk factors for an initial adenoma. The study includes about 900 cases and 900 controls. To date there have been 18 publications from this study. Two results obtained in the past year are described here to illustrate the type of research findings emerging from this study. In a recent issue of Cancer Epidemiology, Biomarkers, and Prevention, we had the lead article, with an accompanying editorial, that reported evidence of an interaction between GSTM1 and the protective effect of cruciferous vegetables, broccoli in particular. This was taken as some of the first convincing evidence of a gene x environment interaction in the etiology of colorectal adenomas. The results suggest that isothiocyanates, which can inhibit selected phase 1 enzymes and induce certain phase 2 enzymes, may be responsible for all or at least some of the protective effect of cruciferous vegetables. A second significant finding in the past year is a set of preliminary results suggesting that heterocyclic aromatic amines (HAA's) may be responsible for part of the increased risk associated with consumption of red meat. We only observe strong effects when we take fast acetylators (defined by the upper end of a phenotype distribution for NAT1, NAT2, and cyp1A2) and cross it with consumption of well done red meat. These results not only suggest the HAA's may increase risk but that one may need to take into account both the genotype/phenotype data and the environmental sources of exposure to detect an important effect.

Several Center members (R. Ross, A. Wu) are involved in a study designed to determine the population prevalence of colon cancers that are positive for microsatellite instability (MSI+), a genetic change identified to be a hallmark of hereditary nonpolyposis colorectal cancer (HNPCC). We have completed the laboratory work to determine MSI status, and have shown that the overall prevalence even in families selected for a high likelihood of HNPCC is quite low. To continue this investigation, we have just received funding to determine the prevalence of germline mutations of DNA mismatch repair genes among colon cancers that are MSI+. We are in the process of determining whether certain lifestyle risk factors (smoking, alcohol, diet) might be involved in MSI+ colon cancer.