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 #
5R01CA151993-04
Application #
8466939
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
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$510,451
Indirect Cost
$162,488
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Ananthakrishnan, Ashwin N; Du, Mengmeng; Berndt, Sonja I et al. (2015) Red meat intake, NAT2, and risk of colorectal cancer: a pooled analysis of 11 studies. Cancer Epidemiol Biomarkers Prev 24:198-205
Lochhead, Paul; Chan, Andrew T; Nishihara, Reiko et al. (2015) Etiologic field effect: reappraisal of the field effect concept in cancer predisposition and progression. Mod Pathol 28:14-29
Inamura, Kentaro; Yamauchi, Mai; Nishihara, Reiko et al. (2015) Prognostic significance and molecular features of signet-ring cell and mucinous components in colorectal carcinoma. Ann Surg Oncol 22:1226-35
Giannakis, Marios; Hodis, Eran; Jasmine Mu, Xinmeng et al. (2014) RNF43 is frequently mutated in colorectal and endometrial cancers. Nat Genet 46:1264-6
Lochhead, Paul; Chan, Andrew T; Giovannucci, Edward et al. (2014) Progress and opportunities in molecular pathological epidemiology of colorectal premalignant lesions. Am J Gastroenterol 109:1205-14
Epplein, Meira; Bostick, Roberd M; Mu, Lina et al. (2014) Challenges and opportunities in international molecular cancer prevention research: An ASPO Molecular Epidemiology and the Environment and International Cancer Prevention Interest Groups Report. Cancer Epidemiol Biomarkers Prev 23:2613-7
Fink, Stephen P; Yamauchi, Mai; Nishihara, Reiko et al. (2014) Aspirin and the risk of colorectal cancer in relation to the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD). Sci Transl Med 6:233re2
Imamura, Yu; Lochhead, Paul; Yamauchi, Mai et al. (2014) Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: cohort study and literature review. Mol Cancer 13:135
Ogino, S; Lochhead, P; Giovannucci, E et al. (2014) Discovery of colorectal cancer PIK3CA mutation as potential predictive biomarker: power and promise of molecular pathological epidemiology. Oncogene 33:2949-55
Mehta, Raaj S; Song, Mingyang; Bezawada, Navya et al. (2014) A prospective study of macrophage inhibitory cytokine-1 (MIC-1/GDF15) and risk of colorectal cancer. J Natl Cancer Inst 106:dju016

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