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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

Association of aspirin and NSAID use with risk of colorectal cancer according to genetic variants.
Authors: Nan H, Hutter CM, Lin Y, Jacobs EJ, Ulrich CM, White E, Baron JA, Berndt SI, Brenner H, Butterbach K, Caan BJ, Campbell PT, Carlson CS, Casey G, Chang-Claude J, Chanock SJ, Cotterchio M, Duggan D, Figueiredo JC, Fuchs CS, Giovannucci EL, Gong J, Haile RW, Harrison TA, Hayes RB, Hoffmeister M, Hopper JL, Hudson TJ, Jenkins MA, Jiao S, Lindor NM, Lemire M, Le Marchand L, Newcomb PA, Ogino S, Pflugeisen BM, Potter JD, Qu C, Rosse SA, Rudolph A, Schoen RE, Schumacher FR, Seminara D, Slattery ML, Thibodeau SN, Thomas F, Thornquist M, Warnick GS, Zanke BW, Gauderman WJ, Peters U, Hsu L, Chan AT, CCFR, GECCO
Source: JAMA, 2015 Mar 17;313(11), p. 1133-42.
PMID: 25781442
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Plasma 25-hydroxyvitamin D and colorectal cancer risk according to tumour immunity status.
Authors: Song M, Nishihara R, Wang M, Chan AT, Qian ZR, Inamura K, Zhang X, Ng K, Kim SA, Mima K, Sukawa Y, Nosho K, Fuchs CS, Giovannucci EL, Wu K, Ogino S
Source: Gut, 2015 Jan 15;null, p. null.
EPub date: 2015 Jan 15.
PMID: 25591978
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Television watching and risk of colorectal adenoma.
Authors: Cao Y, Keum NN, Chan AT, Fuchs CS, Wu K, Giovannucci EL
Source: Br J Cancer, 2015 Mar 3;112(5), p. 934-42.
EPub date: 2015 Jan 15.
PMID: 25590667
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Measures of obesity and risk of Crohn's disease and ulcerative colitis.
Authors: Khalili H, Ananthakrishnan AN, Konijeti GG, Higuchi LM, Fuchs CS, Richter JM, Chan AT
Source: Inflamm Bowel Dis, 2015 Feb;21(2), p. 361-8.
PMID: 25563694
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Toll-like receptor signaling in colorectal cancer: carcinogenesis to cancer therapy.
Authors: Li TT, Ogino S, Qian ZR
Source: World J Gastroenterol, 2014 Dec 21;20(47), p. 17699-708.
PMID: 25548469
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Molecular pathways: aspirin and wnt signaling-a molecularly targeted approach to cancer prevention and treatment.
Authors: Gala MK, Chan AT
Source: Clin Cancer Res, 2015 Apr 1;21(7), p. 1543-8.
EPub date: 2014 Dec 11.
PMID: 25501125
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Genetic variants of adiponectin and risk of colorectal cancer.
Authors: Song M, Gong J, Giovannucci EL, Berndt SI, Brenner H, Chang-Claude J, Curtis KR, Harrison TA, Hoffmeister M, Hsu L, Jiao S, Le Marchand L, Potter JD, Schoen RE, Seminara D, Slattery ML, White E, Wu K, Ogino S, Fuchs CS, Hunter DJ, Tworoger SS, Hu FB, Rimm E, Jensen M, Peters U, Chan AT
Source: Int J Cancer, 2015 Jul 1;137(1), p. 154-64.
EPub date: 2014 Dec 8.
PMID: 25431318
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Alcohol, one-carbon nutrient intake, and risk of colorectal cancer according to tumor methylation level of IGF2 differentially methylated region.
Authors: Nishihara R, Wang M, Qian ZR, Baba Y, Yamauchi M, Mima K, Sukawa Y, Kim SA, Inamura K, Zhang X, Wu K, Giovannucci EL, Chan AT, Fuchs CS, Ogino S, Schernhammer ES
Source: Am J Clin Nutr, 2014 Dec;100(6), p. 1479-88.
EPub date: 2014 Oct 8.
PMID: 25411283
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Genome-wide association study of selenium concentrations.
Authors: Cornelis MC, Fornage M, Foy M, Xun P, Gladyshev VN, Morris S, Chasman DI, Hu FB, Rimm EB, Kraft P, Jordan JM, Mozaffarian D, He K
Source: Hum Mol Genet, 2015 Mar 1;24(5), p. 1469-77.
EPub date: 2014 Oct 24.
PMID: 25343990
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Red meat intake, NAT2, and risk of colorectal cancer: a pooled analysis of 11 studies.
Authors: Ananthakrishnan AN, Du M, Berndt SI, Brenner H, Caan BJ, Casey G, Chang-Claude J, Duggan D, Fuchs CS, Gallinger S, Giovannucci EL, Harrison TA, Hayes RB, Hoffmeister M, Hopper JL, Hou L, Hsu L, Jenkins MA, Kraft P, Ma J, Nan H, Newcomb PA, Ogino S, Potter JD, Seminara D, Slattery ML, Thornquist M, White E, Wu K, Peters U, Chan AT
Source: Cancer Epidemiol Biomarkers Prev, 2015 Jan;24(1), p. 198-205.
EPub date: 2014 Oct 23.
PMID: 25342387
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No evidence of gene-calcium interactions from genome-wide analysis of colorectal cancer risk.
Authors: Du M, Zhang X, Hoffmeister M, Schoen RE, Baron JA, Berndt SI, Brenner H, Carlson CS, Casey G, Chan AT, Curtis KR, Duggan D, Gauderman WJ, Giovannucci EL, Gong J, Harrison TA, Hayes RB, Henderson BE, Hopper JL, Hsu L, Hudson TJ, Hutter CM, Jenkins MA, Jiao S, Kocarnik JM, Kolonel LN, Le Marchand L, Lin Y, Newcomb PA, Rudolph A, Seminara D, Thornquist MD, Ulrich CM, White E, Wu K, Zanke BW, Campbell PT, Slattery ML, Peters U, Chang-Claude J, Potter JD, Colon Cancer Family Registry and Genetics and Epidemiology of Colorectal Cancer Consortium
Source: Cancer Epidemiol Biomarkers Prev, 2014 Dec;23(12), p. 2971-6.
EPub date: 2014 Sep 5.
PMID: 25192705
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Tumor LINE-1 methylation level and microsatellite instability in relation to colorectal cancer prognosis.
Authors: Inamura K, Yamauchi M, Nishihara R, Lochhead P, Qian ZR, Kuchiba A, Kim SA, Mima K, Sukawa Y, Jung S, Zhang X, Wu K, Cho E, Chan AT, Meyerhardt JA, Harris CC, Fuchs CS, Ogino S
Source: J Natl Cancer Inst, 2014 Sep;106(9), p. null.
EPub date: 2014 Sep 4.
PMID: 25190725
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Trans-ethnic genome-wide association study of colorectal cancer identifies a new susceptibility locus in VTI1A.
Authors: Wang H, Burnett T, Kono S, Haiman CA, Iwasaki M, Wilkens LR, Loo LW, Van Den Berg D, Kolonel LN, Henderson BE, Keku TO, Sandler RS, Signorello LB, Blot WJ, Newcomb PA, Pande M, Amos CI, West DW, Bézieau S, Berndt SI, Zanke BW, Hsu L, Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Lindor NM, Haile RW, Hopper JL, Jenkins MA, Gallinger S, Casey G, Colon Cancer Family Registry (CCFR), Stenzel SL, Schumacher FR, Peters U, Gruber SB, Colorectal Transdisciplinary Study (CORECT), Tsugane S, Stram DO, Le Marchand L
Source: Nat Commun, 2014 Aug 8;5, p. 4613.
EPub date: 2014 Aug 8.
PMID: 25105248
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SMO expression in colorectal cancer: associations with clinical, pathological, and molecular features.
Authors: Li T, Liao X, Lochhead P, Morikawa T, Yamauchi M, Nishihara R, Inamura K, Kim SA, Mima K, Sukawa Y, Kuchiba A, Imamura Y, Baba Y, Shima K, Meyerhardt JA, Chan AT, Fuchs CS, Ogino S, Qian ZR
Source: Ann Surg Oncol, 2014 Dec;21(13), p. 4164-73.
EPub date: 2014 Jul 15.
PMID: 25023548
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Gene-environment interaction involving recently identified colorectal cancer susceptibility Loci.
Authors: Kantor ED, Hutter CM, Minnier J, Berndt SI, Brenner H, Caan BJ, Campbell PT, Carlson CS, Casey G, Chan AT, Chang-Claude J, Chanock SJ, Cotterchio M, Du M, Duggan D, Fuchs CS, Giovannucci EL, Gong J, Harrison TA, Hayes RB, Henderson BE, Hoffmeister M, Hopper JL, Jenkins MA, Jiao S, Kolonel LN, Le Marchand L, Lemire M, Ma J, Newcomb PA, Ochs-Balcom HM, Pflugeisen BM, Potter JD, Rudolph A, Schoen RE, Seminara D, Slattery ML, Stelling DL, Thomas F, Thornquist M, Ulrich CM, Warnick GS, Zanke BW, Peters U, Hsu L, White E
Source: Cancer Epidemiol Biomarkers Prev, 2014 Sep;23(9), p. 1824-33.
EPub date: 2014 Jul 3.
PMID: 24994789
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