|Grant Number:||5R01CA137178-04 Interpret this number|
|Primary Investigator:||Chan, Andrew|
|Organization:||Massachusetts General Hospital|
|Project Title:||Inflammation and Colorectal Neoplasia|
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.
Association Between Plasma Levels of Macrophage Inhibitory Cytokine-1 Before Diagnosis of Colorectal Cancer and Mortality.
Authors: Mehta RS, Chong DQ, Song M, Meyerhardt JA, Ng K, Nishihara R, Qian Z, Morikawa T, Wu K, Giovannucci EL, Fuchs CS, Ogino S, Chan AT
Source: Gastroenterology, 2015 Sep;149(3), p. 614-22.
EPub date: 2015 May 27.
Mendelian randomization study of height and risk of colorectal cancer.
Authors: Thrift AP, Gong J, Peters U, Chang-Claude J, Rudolph A, Slattery ML, Chan AT, Esko T, Wood AR, Yang J, Vedantam S, Gustafsson S, Pers TH, GIANT Consortium, Baron JA, Bezieau S, Küry S, Ogino S, Berndt SI, Casey G, Haile RW, Du M, Harrison TA, Thornquist M, Duggan DJ, Le Marchand L, Lemire M, Lindor NM, Seminara D, Song M, Thibodeau SN, Cotterchio M, Win AK, Jenkins MA, Hopper JL, Ulrich CM, Potter JD, Newcomb PA, Schoen RE, Hoffmeister M, Brenner H, White E, Hsu L, Campbell PT
Source: Int J Epidemiol, 2015 Apr;44(2), p. 662-72.
EPub date: 2015 May 20.
Mendelian Randomization Study of Body Mass Index and Colorectal Cancer Risk.
Authors: Thrift AP, Gong J, Peters U, Chang-Claude J, Rudolph A, Slattery ML, Chan AT, Locke AE, Kahali B, Justice AE, Pers TH, Gallinger S, Hayes RB, Baron JA, Caan BJ, Ogino S, Berndt SI, Chanock SJ, Casey G, Haile RW, Du M, Harrison TA, Thornquist M, Duggan DJ, Le Marchand L, Lindor NM, Seminara D, Song M, Wu K, Thibodeau SN, Cotterchio M, Win AK, Jenkins MA, Hopper JL, Ulrich CM, Potter JD, Newcomb PA, Hoffmeister M, Brenner H, White E, Hsu L, Campbell PT
Source: Cancer Epidemiol Biomarkers Prev, 2015 Jul;24(7), p. 1024-31.
EPub date: 2015 May 14.
Proceedings of the second international molecular pathological epidemiology (MPE) meeting.
Authors: Ogino S, Campbell PT, Nishihara R, Phipps AI, Beck AH, Sherman ME, Chan AT, Troester MA, Bass AJ, Fitzgerald KC, Irizarry RA, Kelsey KT, Nan H, Peters U, Poole EM, Qian ZR, Tamimi RM, Tchetgen Tchetgen EJ, Tworoger SS, Zhang X, Giovannucci EL, van den Brandt PA, Rosner BA, Wang M, Chatterjee N, Begg CB
Source: Cancer Causes Control, 2015 Jul;26(7), p. 959-72.
EPub date: 2015 May 9.
TFF2-CXCR4 Axis Is Associated with BRAF V600E Colon Cancer.
Authors: Gala MK, Austin T, Ogino S, Chan AT
Source: Cancer Prev Res (Phila), 2015 Jul;8(7), p. 614-9.
EPub date: 2015 Apr 21.
Analyses of 7,635 Patients with Colorectal Cancer Using Independent Training and Validation Cohorts Show That rs9929218 in CDH1 Is a Prognostic Marker of Survival.
Authors: Smith CG, Fisher D, Harris R, Maughan TS, Phipps AI, Richman S, Seymour M, Tomlinson I, Rosmarin D, Kerr D, Chan AT, Peters U, Newcomb PA, Idziaszczyk S, West H, Meade A, Kaplan R, Cheadle JP
Source: Clin Cancer Res, 2015 Aug 1;21(15), p. 3453-61.
EPub date: 2015 Apr 14.
Endogenous levels of circulating androgens and risk of Crohn's disease and ulcerative colitis among women: a nested case-control study from the nurses' health study cohorts.
Authors: Khalili H, Ananthakrishnan AN, Konijeti GG, Higuchi LM, Fuchs CS, Richter JM, Tworoger SS, Hankinson SE, Chan AT
Source: Inflamm Bowel Dis, 2015 Jun;21(6), p. 1378-85.
Marine ?-3 polyunsaturated fatty acids and risk of colorectal cancer according to microsatellite instability.
Authors: Song M, Nishihara R, Wu K, Qian ZR, Kim SA, Sukawa Y, Mima K, Inamura K, Masuda A, Yang J, Fuchs CS, Giovannucci EL, Ogino S, Chan AT
Source: J Natl Cancer Inst, 2015 Apr;107(4), p. null.
EPub date: 2015 Mar 25.
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.
A model to determine colorectal cancer risk using common genetic susceptibility loci.
Authors: Hsu L, Jeon J, Brenner H, Gruber SB, Schoen RE, Berndt SI, Chan AT, Chang-Claude J, Du M, Gong J, Harrison TA, Hayes RB, Hoffmeister M, Hutter CM, Lin Y, Nishihara R, Ogino S, Prentice RL, Schumacher FR, Seminara D, Slattery ML, Thomas DC, Thornquist M, Newcomb PA, Potter JD, Zheng Y, White E, Peters U, Colorectal Transdisciplinary (CORECT) Study, Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO)
Source: Gastroenterology, 2015 Jun;148(7), p. 1330-9.e14.
EPub date: 2015 Feb 13.
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.
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.
Nutrients, foods, and colorectal cancer prevention.
Authors: Song M, Garrett WS, Chan AT
Source: Gastroenterology, 2015 May;148(6), p. 1244-60.e16.
EPub date: 2015 Jan 6.
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.