Clinicopathology of IGF2 loss of imprinting in colon neoplasia

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DESCRIPTION (provided by applicant): Dr. Cruz-Correa is currently an Associate Professor of Medicine at the University of Puerto Rico Comprehensive Cancer Center (UPRCCC) and visiting Assistant Professor of Medicine at Johns Hopkins University (JHU). She completed a gastroenterology fellowship at JHU and finished a doctorate degree in Clinical Investigation at the Johns Hopkins Bloomberg School of Public Health, while completing her current K07 NCI Mentored Award. Her immediate career goals are to transition into an independent investigator having the financial and time resources to complete her current hypothesis in a timely fashion. Her long-term objectives are to become a leader in the field of gastrointestinal oncology with emphasis in epigenetics, clinical outcomes and prevention. Specifically, Dr. Cruz-Correa envisions a translational gastrointestinal research institute integrated by: (1) a basic laboratory unit, and (2) a clinical research unit, working together evaluating multiple hypotheses to sequentially elucidate mechanisms of gastrointestinal carcinogenesis. The UPRCCC is fully committed to the development of Dr. Cruz-Correa's career, and will provide all the needed personnel, laboratory, clinical resources as well as the protected time required for successful completion of this investigation. This award will enable her to continue to develop the necessary skills for a successful independent career in clinical research with the support of her current mentors and co-investigators, Dr. Francis Giardiello, Dr. Andrew Feinberg (Johns Hopkins University), Dr. Steven Wexner (Cleveland Clinic Florida), and Dr. Reynold Lopez (UPRCCC). This project will test the hypothesis that abnormal imprinting of the IGF2 gene is a biomarker for colorectal cancer (CRC) predisposition, with a diffuse tissue distribution, which exerts its increased risk via the IGF axis, resulting in specific pathological and molecular characteristics and a unique CRC phenotype. Loss of imprinting (LOI) of IGF2 is an independent risk factor for CRC, but the underlying carcinogenic mechanisms remain unclear. LOI of IGF2 is present in the peripheral blood lymphocytes (PBL) of patients with CRC and is not associated with common environmental exposures. This investigation will determine the clinicopathological impact of LOI of IGF2 and delineate the underlying molecular mechanisms of the IGF2 system in CRC patients using a feasible cross-sectional and matched case-control design. Specifically, it will evaluate the association of LOI of IGF2 with the IGF2 peptide, proliferation index, apoptosis index and micro-vascular density in CRC patients. It will also examine the association between LOI and rectal cancer recurrence. LOI of IGF2 has potential as a new biomarker for colorectal cancer predisposition, and may change our current risk-stratification, screening, and surveillance colorectal cancer paradigms.