|Grant Number:||5R01CA137178-05 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.
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.
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 Jul 15;null, p. null.
EPub date: 2014 Jul 15.
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.
A Review of the Application of Inflammatory Biomarkers in Epidemiologic Cancer Research.
Authors: Brenner DR, Scherer D, Muir K, Schildkraut J, Boffetta P, Spitz MR, Le Marchand L, Chan AT, Goode EL, Ulrich CM, Hung RJ
Source: Cancer Epidemiol Biomarkers Prev, 2014 Sep;23(9), p. 1729-1751.
EPub date: 2014 Jun 24.
Progress and opportunities in molecular pathological epidemiology of colorectal premalignant lesions.
Authors: Lochhead P, Chan AT, Giovannucci E, Fuchs CS, Wu K, Nishihara R, O'Brien M, Ogino S
Source: Am J Gastroenterol, 2014 Aug;109(8), p. 1205-14.
EPub date: 2014 Jun 17.
Etiologic field effect: reappraisal of the field effect concept in cancer predisposition and progression.
Authors: Lochhead P, Chan AT, Nishihara R, Fuchs CS, Beck AH, Giovannucci E, Ogino S
Source: Mod Pathol, 2014 Jun 13;null, p. null.
EPub date: 2014 Jun 13.
Predicted 25(OH)D score and colorectal cancer risk according to vitamin D receptor expression.
Authors: Jung S, Qian ZR, Yamauchi M, Bertrand KA, Fitzgerald KC, Inamura K, Kim SA, Mima K, Sukawa Y, Zhang X, Wang M, Smith-Warner SA, Wu K, Fuchs CS, Chan AT, Giovannucci EL, Ng K, Cho E, Ogino S, Nishihara R
Source: Cancer Epidemiol Biomarkers Prev, 2014 Aug;23(8), p. 1628-37.
EPub date: 2014 Jun 11.
Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: cohort study and literature review.
Authors: Imamura Y, Lochhead P, Yamauchi M, Kuchiba A, Qian ZR, Liao X, Nishihara R, Jung S, Wu K, Nosho K, Wang YE, Peng S, Bass AJ, Haigis KM, Meyerhardt JA, Chan AT, Fuchs CS, Ogino S
Source: Mol Cancer, 2014 May 31;13, p. 135.
EPub date: 2014 May 31.
Relating the metatranscriptome and metagenome of the human gut.
Authors: Franzosa EA, Morgan XC, Segata N, Waldron L, Reyes J, Earl AM, Giannoukos G, Boylan MR, Ciulla D, Gevers D, Izard J, Garrett WS, Chan AT, Huttenhower C
Source: Proc Natl Acad Sci U S A, 2014 Jun 3;111(22), p. E2329-38.
EPub date: 2014 May 19.
Urinary PGE-M levels are associated with risk of colorectal adenomas and chemopreventive response to anti-inflammatory drugs.
Authors: Bezawada N, Song M, Wu K, Mehta RS, Milne GL, Ogino S, Fuchs CS, Giovannucci EL, Chan AT
Source: Cancer Prev Res (Phila), 2014 Jul;7(7), p. 758-65.
EPub date: 2014 May 13.