As the first independent application led by a recipient of NCI K07 Award (""""""""Molecular Epidemiology of Colorectal Cancer""""""""), this proposal addresses hypotheses in epigenetics and epidemiology of colorectal cancer, in response to NIH Program Announcement PA- 09-234 (""""""""Diet, Epigenetic Events, and Cancer Prevention""""""""). Colorectal cancer is the second leading cause of cancer death in the United States. Abnormal DNA methylation patterns are a hallmark of most cancers including colorectal cancer. Furthermore, DNA methylation alterations (such as loss of imprinting) in non-cancerous cells may predispose to cancer development. Importantly, epigenetic changes, including DNA methylation alterations, are reversible and thus can be targets for therapy or chemoprevention. Accumulating evidence suggests that dietary factors (e.g., alcohol and one-carbon nutrients such as B vitamins) may affect cellular epigenetic status. Examining how dietary factors influence epigenetic alterations is important for better understanding of colorectal cancer development and progression, which can provide a scientific basis for dietary recommendations and help optimize preventive strategies. For that purpose, we will utilize the resources of two large prospective cohort studies, the Nurses'Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Both cohort studies provide dietary data over a 20-year period, DNA from blood cells, long-term survival data, and paraffin-embedded tissue of colorectal cancers. We anticipate over 4500 incident colorectal cancer cases up to 2012 in these cohorts, and among those, paraffin-embedded tissue materials will be available in over 3000 cases. We propose to examine the interrelationship between intake of dietary one-carbon nutrients and alcohol, colorectal cancer risk, cellular epigenetic changes, and clinical outcome. In addition, we will utilize data resulting from genome-wide expression profiling of 1000 colorectal cancers in the cohorts (which has been ongoing with separate funding supports) to discover genes potentially related to abnormal one-carbon metabolism as well as specific epigenomic aberrations in colorectal cancer. Thus, we are in a unique position to examine the relations between modifiable dietary factors, epigenetic and epigenomic aberrations, and genome-wide expression patterns in tumor cells. Through better understanding of epigenetic mechanisms of carcinogenesis, we can propose preventive measures for the incidence and mortality from colorectal cancer.

Public Health Relevance

Prevention of colorectal cancer occurrence and mortality is of great public interest, because approximately 140,000 Americans develop colorectal cancer and approximately 50,000 individuals die from the disease every year. We propose to examine the relations between modifiable dietary factors, colorectal cancer risk, cellular epigenetic changes, and patient survival. Through better understanding of epigenetic mechanisms of colorectal cancer development and progression, we can provide a scientific basis for dietary recommendations and help optimize preventive strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA151993-02
Application #
8101809
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Nelson, Stefanie A
Project Start
2010-07-01
Project End
2015-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
2
Fiscal Year
2011
Total Cost
$563,905
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Neumeyer, Sonja; Banbury, Barbara L; Arndt, Volker et al. (2018) Mendelian randomisation study of age at menarche and age at menopause and the risk of colorectal cancer. Br J Cancer 118:1639-1647
He, Xiaosheng; Wu, Kana; Ogino, Shuji et al. (2018) Association Between Risk Factors for Colorectal Cancer and Risk of Serrated Polyps and Conventional Adenomas. Gastroenterology 155:355-373.e18
Hu, Yang; Ding, Ming; Yuan, Chen et al. (2018) Association Between Coffee Intake After Diagnosis of Colorectal Cancer and Reduced Mortality. Gastroenterology 154:916-926.e9
Cao, Yin; Wu, Kana; Mehta, Raaj et al. (2018) Long-term use of antibiotics and risk of colorectal adenoma. Gut 67:672-678
Grasso, Catherine S; Giannakis, Marios; Wells, Daniel K et al. (2018) Genetic Mechanisms of Immune Evasion in Colorectal Cancer. Cancer Discov 8:730-749
Liu, Li; Nevo, Daniel; Nishihara, Reiko et al. (2018) Utility of inverse probability weighting in molecular pathological epidemiology. Eur J Epidemiol 33:381-392
Song, Mingyang; Wu, Kana; Meyerhardt, Jeffrey A et al. (2018) Fiber Intake and Survival After Colorectal Cancer Diagnosis. JAMA Oncol 4:71-79
Jeon, Jihyoun; Du, Mengmeng; Schoen, Robert E et al. (2018) Determining Risk of Colorectal Cancer and Starting Age of Screening Based on Lifestyle, Environmental, and Genetic Factors. Gastroenterology 154:2152-2164.e19
Wang, Xiaoliang; Chan, Andrew T; Slattery, Martha L et al. (2018) Influence of Smoking, Body Mass Index, and Other Factors on the Preventive Effect of Nonsteroidal Anti-Inflammatory Drugs on Colorectal Cancer Risk. Cancer Res 78:4790-4799
Hamada, Tsuyoshi; Zhang, Xuehong; Mima, Kosuke et al. (2018) Fusobacterium nucleatum in Colorectal Cancer Relates to Immune Response Differentially by Tumor Microsatellite Instability Status. Cancer Immunol Res 6:1327-1336

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