Gene-Environment Interactions In Hereditary Colorectal Cancer Risk

Cancer economic impact is enormous and depending on the stage in which a colon cancer\ud is detected, five-year survival rates for colon cancer may be as high as 74%, or as low as\ud 6% (American Cancer Society, 2012). Thus early prevention of colon cancer is crucial to\ud maximize the chances of survival and total remission, and also to save billions of dollars\ud spent on treatment. This project will provide an experimentally tested basis for\ud identification of individuals at increased risk, and allow for targeted treatments to reduce\ud such risk such as increased screening and/or pharmacological interventions.\ud Combinations of genetic and environmental factors determine an individual’s\ud susceptibility to cancer. Exposure to carcinogens, including the ubiquitous polycyclic\ud aromatic hydrocarbons (PAHs), and mutations in DNA repair pathways, such as DNA\ud mismatch repair (MMR), or nucleotide excision repair (NER) are associated with\ud increased cancer risk. We hypothesized that partial deficiencies in multiple DNA repair\ud pathways can interact synergistically to increase the carcinogenic effects of\ud environmental exposure. We plan to create an experimental system to model the\ud individuals who have multiple, partially deficient DNA repair pathways, specifically in\ud the MMR and NER pathways. The goal was to use siRNA to create isogenic cell cultures\ud with reduced gene expression for several different genes: MLH1 and MSH2 that are\ud important for MMR, and XPA, which is an essential NER gene. We anticipated to use the\ud created cell cultures to measure mutation induced by PAH exposure. Preliminary data\ud suggested successful reduction in the accumulation of MLH1 and MSH2, in particular, at\ud 48 and 72-hour post-transfection with siRNA. Unfortunately, the project did not progress\ud to targeting XPA siRNA’s gene or the creation of multi-deficient cell cultures