The Roles of Genetic Polymorphisms for Susceptibility and Clinical Outcomes of Colorectal Cancer in Taiwanese Lynch Syndrome Families

Lynch syndrome, or hereditary nonpolyposis colorectal cancer (HNPCC), is the most common hereditary colorectal cancer (CRC) syndrome, accounting for approximately 2-5% of all newly diagnosed cases of CRC. Patients with Lynch syndrome have an increased lifetime risk of colorectal, endometrial and other cancers. This syndrome is caused by germline mutations in one of several DNA mismatch repair (MMR) genes. Despite the presence of a germline mutation in a MMR gene being a strong predictor of disease, there is considerable variation in the phenotypic expression in Lynch syndrome patients, in particular the age of CRC onset. This appears to be largely independent of the type or location of MMR mutation, suggesting that genetic or environmental modifying effects influence the age of disease onset. Most studies investigating the association between genetic polymorphisms/environmental factors and CRC risk in Lynch syndrome families have largely focused on Caucasian populations and the results have not been consistent. The associations detected so far may not therefore be applicable to other populations such as Chinese population and further studies are needed. This project will conduct a cancer risk assessment to estimate the lifetime cancer risk in 135 Taiwanese Lynch syndrome families including 1014 family members in the first year. Then a genetic epidemiology analysis will be used to explore if genetic polymorphisms associate with susceptibility or clinical outcomes of CRC in MMR gene mutation carriers in the second year. The specific aims are to: 1. estimate the lifetime cancer risks in Lynch syndrome families. 2. determine the association between genetic polymorphisms and CRC risk in MMR gene mutation carriers. 3. investigate the effects of gene-gene and gene-environment interactions on CRC risk in MMR gene mutation carriers. To our best knowledge, our study cohort is the largest Lynch syndrome cohort in Chinese population. This proposal investigates the lifetime cancer risks in Lynch syndrome. In addition, this is the first study combining the knowledge of multiple genetic modifiers along with environmental factors that influence CRC risk in MMR mutation carriers. Such knowledge can help to provide more efficient cancer screening, surveillance and management strategies for Lynch syndrome.