Mutations in Non-MMR genes modifying or mimicking lynch syndrome phenotype

Lynch syndrome is an inherited cancer predisposition syndrome associated with an increased risk of colorectal, endometrial and many other cancers, typically with an earlier age of cancer onset. The underlying cause of Lynch syndrome is a defect in DNA mismatch repair (MMR) due to mutations in one of the DNA MMR genes: MLH1, MSH2, MSH6 or PMS2. It has been observed that cancer risk and cancer age of onset vary significantly among MMR gene mutation carriers suggesting that other non-MMR genes may modify the Lynch syndrome phenotype. Studies examining the association of genetic variation in non-MMR genes and colorectal cancer (CRC) risk in MMR mutation carriers have found an increased risk or an earlier age of cancer onset for polymorphisms in genes in pathways such as cell cycle, DNA repair and methylation, carcinogen metabolism, and others. Some common genetic variants associated with sporadic CRC risk in genome wide association studies have also been implicated in modifying CRC risk in Lynch syndrome suggesting a global role of these variants in influencing CRC risk. The Lynch syndrome cancer phenotype is also manifested indirectly through epimutations outside the MMR genes that influence expression of these genes. For example, deletions in the EPCAM gene upstream of the MSH2 promoter region lead to hypermethylation of the MSH2 promoter, resulting in loss of MSH2 expression and predisposing people with EPCAM deletions to a cancer spectrum that mimics Lynch syndrome. The chapter provides a review of mutations in non-MMR genes that modify or mimic the Lynch syndrome phenotype.