The investigators are currently undertaking two NCI-funded case-control studies of colon cancer (2400 cases and 24 control) and adenomatous polyps of the large bowel (600 cases and 1800 controls), investigating the role of diet, physical activity, reproduction, and family history. The two studies were designed to answer similar questions using similar instruments. It is increasingly clear that, in addition to the environmental factors, genetic susceptibility is important in the etiology of these disorders. Since the original submission of CA48998, much progress has been made in Utah and elsewhere in identifying genes associated with colon cancer. The FAP gene is located on 5q21 and the search for it has now been narrowed to a small region, less than 400 kilobases. It is expected that this gene (whether or not it is the recently identified MCC gene) will be cloned and sequenced before the completion of data collection, allowing genotyping of the case-control study subjects. Further, it is appropriate to consider at least one other marker for restriction fragment length polymorphism (RFLP) analysis, namely fast-acetylator genotype, for which there is evidence, albeit inconsistent, of an association with colon cancer. Three polymorphisms have now been identified. Southern Blot analysis allows direct determination of acetylator-genotype. Other candidate markers will be identified over the next few years.
The specific aims of this proposal are: 1. To collect blood from participants in the 2 population-based studies of colon cancer (R01 CA48998) and adenomatous polyps (P01 CA50305; 2. To analyze DNA from all participants to explore the role of acetylator status and the FAP gene in the etiology of colon neoplasia; and 3. To explore the evidence for confounding and interaction between the genotypes and diet, particularly intake of meat, fat, protein, but also of total calories, calcium, micronutrients, and fiber, and physical activity, reproduction, and family history, in the etiology of colon neoplasia. 4. To store white blood cells and DNA for future analysis of specific genes as they become available from the work at Utah or elsewhere. The combined environment/diet/gene dataset will provide the first and perhaps the most comprehensive opportunity to determine the way in which genes and environment interact in the etiology of colon cancer and its precursor lesion.
| Bigler, J; Chen, C; Potter, J D (1997) Determination of human NAT2 acetylator genotype by oligonucleotide ligation assay. Biotechniques 22:682-4, 686, 688 passim |
