The Molecular Epidemiology of Colorectal Cancer (MECC) is a population-based case-control study that examines the contribution of genetic sequence variation and environmental factors to the development of colorectal cancer (CRC). CRC is the second leading cause of cancer death in the United States and is the most common cause of cancer in Israel. The majority of CRC is diagnosed in individuals without identifiable risk factors other than age. Major susceptibility genes are likely to account for less than 25% of all CRC, but new evidence supports the existence of low penetrance susceptibility alleles which may play an important role in the population dynamics of this complex disease. A novel cancer susceptibility allele, APC I1307K, has been identified in 6% of individuals of Ashkenazi Jewish descent and appears to double the risk of CRC. The broad objective of the MECC study is to examine how environmental factors may modify genetic risk. This collaborative study between the University of Michigan and the National Center for Cancer Control of Kupat Holim Clalit (Israel's largest health provider) will identify 2100 cases of incident CRC and 2100 age-, sex-, and geographically-matched controls in Northern Israel. Interviews and food frequency questionnaires will assess epidemiologic risk factors, and histopathologic and molecular studies will provide data for understanding the genetic basis of CRC. The advantage of studying CRC in Israel is that this population is one of the few in the world where a known cancer susceptibility allele occurs at a high enough frequency to study how inherited risk may be modified. The specific aims of the MECC study are to: 1) Measure thee risks of developing cancer associated with the APC I1307K Allele, 2) Identify and measure potential effect modification of genetic and environmental risks in the pathogenesis of CRC, 3) Analyze CRC tumor specimens to characterize the somatic mutational fingerprint in a defined region of the APC tumor suppressor gene to understand what influences the transformational of normal colonic epithelium to CRC, 4) Establish a resource for further epidemiologic studies and genome screening to map novel, low-penetrance colorectal cancer genes.