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

Project: A - Government Institutionb - National Science and Technology Council

Project Details


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. Molecular and genetic testing has emerged as an essential strategy for the diagnosis of Lynch syndrome comprising a careful family history evaluation, microsatellite instability (MSI), immunohistochemistry (IHC) and mutation analysis of 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 and CRC risk in Lynch syndrome families have largely focused on Caucasian populations and the results have not been consistent. This inconsistency might be due to the limited sample size or heterogeneous populations used in previous studies. This project will conduct a mutation detection study for establishing the spectrum and frequencies of mutations in four MMR genes among Taiwanese Lynch syndrome families. Then a genetic epidemiology study will be used to explore the association between genetic polymorphisms and susceptibility or clinical outcomes of CRC in MMR mutation carriers. The specific aims are to: 1. determine the spectrum and frequency of mutations in MMR genes including MSH2, MLH1, MSH6, and PMS2; 2. estimate the risk of developing cancers in Lynch syndrome families; 3. examine the association between genetic polymorphisms and CRC risk in MMR mutation carriers; 4. investigate the gene-environment interaction on CRC risk in MMR mutation carriers. To our best knowledge, this proposal will be the largest study to describe the clinical features of the Lynch syndrome which will help to identify patients with a high probability of carrying a MMR-gene mutation. 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.
Effective start/end date8/1/127/31/13


  • Lynch syndrome
  • Colorectal cancer
  • Mismatch repair
  • Microsatellite instability
  • Immunohistochemistry
  • Mutation analysis
  • Genetic polymorphisms
  • Gene-environment interaction


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