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Grant Details

Grant Number: 5R01CA137178-04 Interpret this number
Primary Investigator: Chan, Andrew
Organization: Massachusetts General Hospital
Project Title: Inflammation and Colorectal Neoplasia
Fiscal Year: 2012
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Abstract

DESCRIPTION (provided by applicant): As the first independent application led by an NCI K career development award recipient, this proposal will address central hypotheses in inflammation, a NIH Major Roadmap Initiative for 2008. Considerable experimental, epidemiological, and clinical data strongly support a causative link between inflammation and colorectal cancer (CRC). A compelling proof of this principle is six randomized trials that demonstrate that anti- inflammatory drugs such as aspirin and cyclooxygenase-2 (COX-2) selective inhibitors reduce the risk of colorectal adenoma among patients with a prior history of colorectal neoplasia. The pro-inflammatory COX-2 enzyme appears to be a central mediator of this relationship. Recently, in two large prospective cohorts, the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), we observed that aspirin reduces risk of COX-2 positive CRC but not risk of COX-2 negative CRC. This work has raised "...important questions about the biological basis and clinical implications of discovering differences between colon cancers that express high or low levels of COX-2." This statement, especially considered within the context of uncertainty regarding the optimal use of aspirin and non-steroidal anti-inflammatory drugs in light of their associated toxicities, highlights the critical need to further elucidate 1) lifestyle, dietary, and biochemical markers of susceptibility to COX-2 positive CRCs; 2) underlying inflammatory and related prostaglandin pathways in aspirin-mediated inhibition of colorectal carcinogenesis. We will address these aims through studies which utilize the extensive questionnaire data, archived plasma and urine specimens, and tumor blocks already established for the NHS and HPFS cohorts and where needed, expand and collect more data to support our aims. Beyond our specific hypotheses, the resources generated in this proposal will allow for the rapid examination of future hypotheses as they emerge. As such, this application is a cost-efficient investment in improving our understanding of the key role of inflammation in colorectal neoplasia. Ultimately, the findings of this proposal may lead to improved risk stratification for tailoring preventative strategies utilizing lifestyle modification or chemopreventative agents that maximize efficacy but minimize toxicity. PUBLIC HEALTH RELEVANCE: Although aspirin can prevent colorectal cancer, a leading cause of death in the U.S., its optimal use in light of its toxicities remains uncertain. We will investigate the role of inflammation in colorectal carcinogenesis to define predictors of susceptibility for tailored preventative strategies.

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Publications

Aspirin use, 8q24 single nucleotide polymorphism rs6983267, and colorectal cancer according to CTNNB1 alterations.
Authors: Nan H, Morikawa T, Suuriniemi M, Imamura Y, Werner L, Kuchiba A, Yamauchi M, Hunter DJ, Kraft P, Giovannucci EL, Fuchs CS, Ogino S, Freedman ML, Chan AT
Source: J Natl Cancer Inst, 2013 Dec 18;105(24), p. 1852-61.
EPub date: 2013 Dec 7.
PMID: 24317174
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Physical activity and risk of inflammatory bowel disease: prospective study from the Nurses' Health Study cohorts.
Authors: Khalili H, Ananthakrishnan AN, Konijeti GG, Liao X, Higuchi LM, Fuchs CS, Spiegelman D, Richter JM, Korzenik JR, Chan AT
Source: BMJ, 2013 Nov 14;347, p. f6633.
EPub date: 2013 Nov 14.
PMID: 24231178
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Long-term colorectal-cancer incidence and mortality after lower endoscopy.
Authors: Nishihara R, Wu K, Lochhead P, Morikawa T, Liao X, Qian ZR, Inamura K, Kim SA, Kuchiba A, Yamauchi M, Imamura Y, Willett WC, Rosner BA, Fuchs CS, Giovannucci E, Ogino S, Chan AT
Source: N Engl J Med, 2013 Sep 19;369(12), p. 1095-105.
PMID: 24047059
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Genetic predictors of circulating 25-hydroxyvitamin d and risk of colorectal cancer.
Authors: Hiraki LT, Qu C, Hutter CM, Baron JA, Berndt SI, Bézieau S, Brenner H, Caan BJ, Casey G, Chang-Claude J, Chanock SJ, Conti DV, Duggan D, Fuchs CS, Gallinger S, Giovannucci EL, Harrison TA, Hayes RB, Hazra A, Henderson B, Hoffmeister M, Hopper JL, Hudson TJ, Jenkins MA, Küry S, Le Marchand L, Lemire M, Ma J, Manson JE, Nan H, Newcomb PA, Ng K, Potter JD, Schoen RE, Schumacher FR, Seminara D, Slattery ML, Wactawski-Wende J, White E, Wu K, Zanke BW, Kraft P, Peters U, Chan AT
Source: Cancer Epidemiol Biomarkers Prev, 2013 Nov;22(11), p. 2037-46.
EPub date: 2013 Aug 27.
PMID: 23983240
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No association between germline variation in catechol-O-methyltransferase and colorectal cancer survival in postmenopausal women.
Authors: Passarelli MN, Newcomb PA, Makar KW, Burnett-Hartman AN, Phipps AI, David SP, Hsu L, Harrison TA, Hutter CM, Duggan DJ, White E, Chan AT, Peters U
Source: Menopause, 2014 Apr;21(4), p. 415-20.
PMID: 23880798
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Plasma adiponectin and soluble leptin receptor and risk of colorectal cancer: a prospective study.
Authors: Song M, Zhang X, Wu K, Ogino S, Fuchs CS, Giovannucci EL, Chan AT
Source: Cancer Prev Res (Phila), 2013 Sep;6(9), p. 875-85.
EPub date: 2013 Jul 19.
PMID: 23872505
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Aspirin use and risk of colorectal cancer according to BRAF mutation status.
Authors: Nishihara R, Lochhead P, Kuchiba A, Jung S, Yamauchi M, Liao X, Imamura Y, Qian ZR, Morikawa T, Wang M, Spiegelman D, Cho E, Giovannucci E, Fuchs CS, Chan AT, Ogino S
Source: JAMA, 2013 Jun 26;309(24), p. 2563-71.
PMID: 23800934
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Discovery of colorectal cancer PIK3CA mutation as potential predictive biomarker: power and promise of molecular pathological epidemiology.
Authors: Ogino S, Lochhead P, Giovannucci E, Meyerhardt JA, Fuchs CS, Chan AT
Source: Oncogene, 2013 Jun 24;null, p. null.
EPub date: 2013 Jun 24.
PMID: 23792451
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A prospective study of duration of smoking cessation and colorectal cancer risk by epigenetics-related tumor classification.
Authors: Nishihara R, Morikawa T, Kuchiba A, Lochhead P, Yamauchi M, Liao X, Imamura Y, Nosho K, Shima K, Kawachi I, Qian ZR, Fuchs CS, Chan AT, Giovannucci E, Ogino S
Source: Am J Epidemiol, 2013 Jul 1;178(1), p. 84-100.
EPub date: 2013 Jun 20.
PMID: 23788674
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Physical activity, tumor PTGS2 expression, and survival in patients with colorectal cancer.
Authors: Yamauchi M, Lochhead P, Imamura Y, Kuchiba A, Liao X, Qian ZR, Nishihara R, Morikawa T, Shima K, Wu K, Giovannucci E, Meyerhardt JA, Fuchs CS, Chan AT, Ogino S
Source: Cancer Epidemiol Biomarkers Prev, 2013 Jun;22(6), p. 1142-52.
EPub date: 2013 Apr 29.
PMID: 23629521
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A prospective study of plasma inflammatory markers and risk of colorectal cancer in men.
Authors: Song M, Wu K, Ogino S, Fuchs CS, Giovannucci EL, Chan AT
Source: Br J Cancer, 2013 May 14;108(9), p. 1891-8.
EPub date: 2013 Apr 16.
PMID: 23591192
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Prospective cohort studies of bowel movement frequency and laxative use and colorectal cancer incidence in US women and men.
Authors: Zhang X, Wu K, Cho E, Ma J, Chan AT, Gao X, Willett WC, Fuchs CS, Giovannucci EL
Source: Cancer Causes Control, 2013 May;24(5), p. 1015-24.
EPub date: 2013 Mar 2.
PMID: 23456271
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Prospective analysis of body mass index, physical activity, and colorectal cancer risk associated with ?-catenin (CTNNB1) status.
Authors: Morikawa T, Kuchiba A, Lochhead P, Nishihara R, Yamauchi M, Imamura Y, Liao X, Qian ZR, Ng K, Chan AT, Meyerhardt JA, Giovannucci E, Fuchs CS, Ogino S
Source: Cancer Res, 2013 Mar 1;73(5), p. 1600-10.
EPub date: 2013 Feb 26.
PMID: 23442321
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Early life factors and risk of inflammatory bowel disease in adulthood.
Authors: Khalili H, Ananthakrishnan AN, Higuchi LM, Richter JM, Fuchs CS, Chan AT
Source: Inflamm Bowel Dis, 2013 Mar;19(3), p. 542-7.
PMID: 23429446
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Molecular pathological epidemiology of epigenetics: emerging integrative science to analyze environment, host, and disease.
Authors: Ogino S, Lochhead P, Chan AT, Nishihara R, Cho E, Wolpin BM, Meyerhardt JA, Meissner A, Schernhammer ES, Fuchs CS, Giovannucci E
Source: Mod Pathol, 2013 Apr;26(4), p. 465-84.
EPub date: 2013 Jan 11.
PMID: 23307060
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