Project Summary/Abstract Colorectal cancer (CRC) is the third most common cancer in both men and women. The role of inflammation and metabolic disturbance in the pathogenesis of CRC is well-established. However, the biological mechanisms underlying these pathways and how they may mediate the diet-CRC link are poorly understood. In this application, we propose to derive metabolomic signatures that characterize inflammation and metabolic health in three large cohorts: the Nurses’ Health Study I and II and Health Professionals Follow-up Study. We will use reduced rank regression, a novel statistical method that combines the data-driven approach of principal components analysis with prior knowledge of intermediate factors, to identify patterns of metabolites describing maximal variation in biomarkers and lifestyle factors that characterize 1) inflammation (TNF receptor superfamily member 1B, interleukin 6, C-reactive protein, and adiponectin) and 2) metabolic health (body mass index, waist circumference, C-peptide, physical activity, and adiponectin). We will then use elastic net regression to select the most important metabolites contributing to the two factors derived using reduced rank regression and test the association between these metabolomic signatures and CRC risk, independently and as a mediator of processed meat consumption. The goal of this project is to elucidate the biological mechanisms relating inflammation and metabolic health to CRC and, in the long-term, to generate strategies to optimize dietary and lifestyle interventions for CRC prevention. Ms. Bever (PI) will conduct this research under the mentorship of Dr. Meir Stampfer, Professor of Epidemiology and Nutrition at Harvard T.H. Chan School of Public Health (HSPH); Dr. Mingyang Song, Assistant Professor of Clinical Epidemiology and Nutrition at HSPH; Dr. Jeffrey Meyerhardt, a practicing gastrointestinal oncologist and researcher at the Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School (HMS); Dr. Liming Liang, Associate Professor of Statistical Genetics at HSPH; Dr. Edward Giovannucci, Professor of Epidemiology and Nutrition at HSPH; Dr. Andrew Chan, a practicing gastrointestinal oncologist and Director of Cancer Epidemiology at Massachusetts General Hospital; and Dr. Wei Zheng, Professor of Medicine and Associate Director for Population Sciences Research at Vanderbilt University Medical Center. Ms. Bever is a rising fourth-year student in the Harvard/MIT MD-PhD Program, about to begin her second year of the Population Health Sciences PhD program at HSPH. Her training plan includes coursework in advanced biostatistics and epidemiologic methods, local seminars and national conferences, and weekly meetings with mentors. The training plan has been designed to support Ms. Bever’s long-term goal of becoming a physician-epidemiologist with expertise in risk factors for cancer. The plan includes integration of clinical activities during Ms. Bever’s pre-doctoral training and continued opportunities for research during her last two years of medical school.

Project Narrative Despite advances in screening and identification of modifiable risk factors, the incidence and mortality of colorectal cancer (CRC) remains high, as does the incidence of obesity, which is a well-established risk factor for CRC. Lack of understanding of the biological pathways linking obesity and associated risk factors to CRC is a major limiting factor in the development of new strategies for CRC prevention. If successful, our project will identify novel pathways for CRC prevention and will establish methods for integrating metabolomic and other biomarker data and dimension-reduction approaches to identify pathways underlying risk factors for cancer and other chronic diseases.