Gene Dependent Cancer Risk and Optimal Cancer Prevention Strategies in Lynch Syndrome

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7. PROJECT SUMMARY/ABSTRACT Hereditary cancer syndromes are caused by a germline mutation in a cancer susceptibility gene and illustrate the potential of genomic information to tailor medical care. Lynch Syndrome is the most common hereditary gastrointestinal cancer syndrome affecting 1.2 million people in the United States. Its prevalence is similar to the more well-known Hereditary Breast and Ovar- ian Cancer Syndrome. Lynch Syndrome is caused by a mutation in one of four mismatch repair genes. Lifetime colorectal can- cer risk in Lynch Syndrome is dependent on causative gene and is highly variable, ranging between 10-80%, an 8-fold differ- ence. At present, colorectal cancer management strategies in Lynch Syndrome are uniform, consisting of a lifetime of annual to biennial invasive screening tests and prophylactic risk-reducing surgery. However, given the variability in gene-dependent cancer risk, the patient burden associated with noted intensive clinical management, and the potential for over/under-utiliza- tion, there is a critical need for evidence-based determination of gene-dependent colorectal cancer clinical management in Lynch Syndrome. The overall goal of this National Cancer Institute (NCI) K07 Career Development Award is to identify opti- mal gene-dependent colorectal cancer prevention and treatment strategies in Lynch Syndrome, using decision analysis, a meth- odologic pillar of health services research. Aims 1 and 2 generate pivotal inputs, gene-dependent colorectal cancer risk and utilization of recommended care, respectively, for the development of a Markov Model in Aim 3 that will determine optimal colorectal cancer clinical management in Lynch Syndrome by gene. Results from this study will help ensure the appropriate use of clinical care for those with Lynch Syndrome, moving the field closer to the promise of Precision Medicine and fulfilling the NCI's mandate to “take the genome to the clinic.” Dr. Sharaf is a gastroenterologist and budding health services researcher with a clinical focus on cancer genetics. His career goal is to become an independently-funded physician-scientist with exper- tise in cancer-related decision analysis. The proposed K07 Award will give him experience in the conduct of meta-analysis and large database analysis. These methodologies are fundamental for devising precise inputs for Markov models and for Markov model calibration and validation. He will also learn the conduct of Markov-modeling itself. In total, this health-services skill- set is versatile and can be applied to a variety of diseases. His long-term goal is to lead a cancer-focused Evidence-based Prac- tice Center. This NCI K07 Award will produce preliminary data for R01 applications that validate the Markov Model devel- oped in Aim 3 and expand it to explore gender-specific colorectal cancer risk and gene-specific management for endometrial and ovarian cancers (also Lynch-related), to ultimately set the stage for comparative modeling with the NCI's Cancer Interven- tion and Surveillance Modeling Network to enable national health policy recommendations for the gene-dependent clinical management of Lynch Syndrome.