Thesis

Application of whole-exome sequencing to mine for novel genes associated with Lynch Syndrome

Lynch syndrome is a highly heterogeneous cancer predisposition syndrome characterized by an increased risk for colorectal and endometrial tumors exhibiting microsatellite instability due to a deficiency in the DNA mismatch repair (MMR) system. Most individuals with Lynch syndrome have germline mutations in one of the four main MMR genes, however there is a group of Lynch syndrome patients who display all of the hallmarks of the disease, but lack identifiable MMR gene mutations. We used exome sequencing as a tool to mine for novel genetic causes of Lynch syndrome in a cohort of 32 individuals, 31 of which clinical Lynch syndrome and are MMR mutation negative by Sanger sequencing. The method of variant filtering used for this study excluded variants in all genes except for 809 genes previously identified to have a role in carcinogenesis, and only variants that are predicted damaging by in silico models were included. Exome sequencing did not identify new mutations in the four main MMR genes associated with Lynch syndrome in this cohort of 32 individuals, confirming the original Sanger sequencing results. Variants in seven known cancer susceptibility genes were identified, as well as variants in 103 other genes. This study did not produce any definitive link between a novel gene and LS, however the FOXO3, JAG2, and MTUS1 genes were identified as possible candidates based on their molecular role in cancer. Future research will focus on alternative methods of variant filtering in this same data set.

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