Metabolomic signatures of inflammation and metabolic health in relation to colorectal cancer risk

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.

Grant Number: 5F30CA265012-04
NIH Institute/Center: NIH
Principal Investigator: Alaina Bever