DESCRIPTION: (Applicant's Description) Considerable progress has been made in our understanding of the inherited susceptibility to cancer. Even among sporadic malignancies that are not part of a defined genetic syndrome, a family history of a specific cancer has become an accepted risk factor for the development of-that cancer. For instance, a family history of colorectal cancer has been associated with up to an eight-fold increased risk of developing colorectal cancer. However, as a result of the retrospective design of most previous studies and their failure to adequately control for environmental risk factors, uncertainty remains regarding the strength of these associations, particularly as they are influenced by the characteristics and habits of the individual at risk and the family member(s) who were diagnosed with the specific cancer. The goal of this proposed research is to define the contribution of inherited susceptibility to the risk of common malignancies and determine what factors may influence the effect of this inherited susceptibility. The Nurse's Health Study(NHS) and the Health Professionals Follow-up Study (HPFS) provide large, prospectively followed cohorts where data regarding a family history of several common cancers was obtained prior to any diagnosis of cancer. In addition, participants in these studies provided extensive exposure data on risk factors for various cancers, including repeated measures of dietary consumption. Using this data, I propose the following specific aims: 1) To determine prospectively, the contribution of family history to the risk of common cancers after adjusting for other known or suspected risk factors, and to determine the influence of the characteristics of the individual at risk and the family members upon the risk associated with a family history; 2) To identify potential interactions between the risk associated with a family history and known or suspected risk factors, including non-dietary and dietary predictors of these cancers, and 3) To determine the prevalence of Hereditary Nonpolyposis Colorectal Cancer families in these unselected populations and to determine the nature and frequency of germline mutations among the affected kindred. Information generated from this proposal will improve clinical decision making by allowing for more effective methods of primary prevention and early detection, will generate important hypotheses for the mechanisms by which inherited susceptibilities for common cancers are conferred, and will allow a more knowledgeable and systematic application of a new potential genetic test for inherited malignancy.