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Grant Details

Grant Number: 5R01CA176272-05 Interpret this number
Primary Investigator: Newcomb, Polly
Organization: Fred Hutchinson Cancer Research Center
Project Title: Molecular Correlates of Outcomes in Clinical Trials of Colon Cancer
Fiscal Year: 2017


Abstract

DESCRIPTION (provided by applicant): Despite advances in early detection and treatment, colon cancer remains a leading cause of cancer death in the United States. Traditional clinical and pathological features of colon cancer are inadequate in predicting survival. Patient characteristics, such as germline genetic variation, may provide additional prognostic information. To date, only a few studies have used candidate gene and pathway approaches to identify germline genetic factors related to cancer outcomes, and no comprehensive genome-wide studies have been conducted to assess broader genetic variation in relation to outcomes after colon cancer diagnosis. Randomized clinical trials (RCTs) provide a powerful setting in which to address this gap in knowledge, because the patient populations are well-characterized, treatment is standardized, and follow-up is uniform. The overarching goal of the proposed study is to identify genetic factors associated with colon cancer clinical outcomes and to assess whether incorporation of genetic variants improves existing prognostic models. To achieve this goal, we will leverage the resources of three NCI-sponsored phase III RCTs of colon cancer and a recently approved collaboration with the Center for Inherited Disease Research. We propose to use a discovery-based search of host genome-wide single nucleotide polymorphism data in over 6,500 stage II-III colon cancer patients participating in three RCTs, all of whom received 5-fluorouracil / leucovorin / oxaliplatin (FOLFOX) chemotherapy with or without adjuvant therapy, to examine associations with clinical outcomes. Specifically, we will evaluate associations between common genetic variation and disease-free and overall survival among patients with stage II-III colon cancer (Aim 1). We will also evaluate germline genetic variation in relation to treatment-associated serious adverse events (Aim 2). Finally, we will evaluate the impact of adding genetic data into existing web-based, publicly available prognostic models to determine if germline genetic loci can be used, in combination with patient characteristics and clinical factors, to more accurately predict colon cancer outcomes (Aim 3). These prognostic models will be validated in an independent sample of 1,000 stage II-III colon cancer patients from the three RCTs. Data yielded by these investigations will be among the first describing genome-wide germline genetic factors associated with colon cancer prognosis. These results have high translational potential for informing prognosis, augmenting both current strategies that rely on traditional clinical factors and emerging strategies that incorporate information on somatic molecular alterations. Moreover, identifying loci associated with clinical outcomes after colon cancer diagnosis may provide mechanistic insight into cancer progression and metastasis, potentially illuminating new therapeutic targets that can be exploited for clinical translation.



Publications

Molecular and pathology features of colorectal tumors and patient outcomes are associated with Fusobacterium nucleatum and its subspecies animalis.
Authors: Borozan I. , Zaidi S.H. , Harrison T.A. , Phipps A.I. , Zheng J. , Lee S. , Trinh Q.M. , Steinfelder R.S. , Adams J. , Banbury B.L. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2021-11-04; , .
EPub date: 2021-11-04.
PMID: 34737207
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Genetically Predicted Circulating C-Reactive Protein Concentration and Colorectal Cancer Survival: A Mendelian Randomization Consortium Study.
Authors: Hua X. , Dai J.Y. , Lindström S. , Harrison T.A. , Lin Y. , Alberts S.R. , Alwers E. , Berndt S.I. , Brenner H. , Buchanan D.D. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2021 07; 30(7), p. 1349-1358.
EPub date: 2021-05-10.
PMID: 33972368
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Genetic Predictors of Severe Skin Toxicity in Patients with Stage III Colon Cancer Treated with Cetuximab: NCCTG N0147 (Alliance).
Authors: Labadie J.D. , Hua X. , Harrison T.A. , Banbury B.L. , Huyghe J.R. , Sun W. , Shi Q. , Yothers G. , Alberts S.R. , Sinicrope F.A. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2021 02; 30(2), p. 404-411.
EPub date: 2020-11-17.
PMID: 33203692
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Genetic Variants in the Regulatory T cell-Related Pathway and Colorectal Cancer Prognosis.
Authors: Neumeyer S. , Hua X. , Seibold P. , Jansen L. , Benner A. , Burwinkel B. , Halama N. , Berndt S.I. , Phipps A.I. , Sakoda L.C. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2020 12; 29(12), p. 2719-2728.
EPub date: 2020-10-02.
PMID: 33008876
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Genetic Variant Associated With Survival of Patients With Stage II-III Colon Cancer.
Authors: Penney K.L. , Banbury B.L. , Bien S. , Harrison T.A. , Hua X. , Phipps A.I. , Sun W. , Song M. , Joshi A.D. , Alberts S.R. , et al. .
Source: Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 2020 11; 18(12), p. 2717-2723.e3.
EPub date: 2019-12-04.
PMID: 31811950
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Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival.
Authors: Zaidi S.H. , Harrison T.A. , Phipps A.I. , Steinfelder R. , Trinh Q.M. , Qu C. , Banbury B.L. , Georgeson P. , Grasso C.S. , Giannakis M. , et al. .
Source: Nature communications, 2020-07-20; 11(1), p. 3644.
EPub date: 2020-07-20.
PMID: 32686686
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Genetic Predictors of Circulating 25-Hydroxyvitamin D and Prognosis after Colorectal Cancer.
Authors: Neumeyer S. , Butterbach K. , Banbury B.L. , Berndt S.I. , Campbell P.T. , Chlebowski R.T. , Chan A.T. , Giovannucci E.L. , Joshi A.D. , Ogino S. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2020 06; 29(6), p. 1128-1134.
EPub date: 2020-03-18.
PMID: 32188599
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Association Between Molecular Subtypes of Colorectal Tumors and Patient Survival, Based on Pooled Analysis of 7 International Studies.
Authors: Phipps A.I. , Alwers E. , Harrison T. , Banbury B. , Brenner H. , Campbell P.T. , Chang-Claude J. , Buchanan D. , Chan A.T. , Farris A.B. , et al. .
Source: Gastroenterology, 2020 06; 158(8), p. 2158-2168.e4.
EPub date: 2020-02-20.
PMID: 32088204
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Long-term Risk of Colorectal Cancer After Removal of Conventional Adenomas and Serrated Polyps.
Authors: He X. , Hang D. , Wu K. , Nayor J. , Drew D.A. , Giovannucci E.L. , Ogino S. , Chan A.T. , Song M. .
Source: Gastroenterology, 2020 03; 158(4), p. 852-861.e4.
EPub date: 2019-07-11.
PMID: 31302144
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Association Between Intake of Red and Processed Meat and Survival in Patients With Colorectal Cancer in a Pooled Analysis.
Authors: Carr P.R. , Banbury B.L. , Berndt S.I. , Campbell P.T. , Chang-Claude J. , Hayes R.B. , Howard B.V. , Jansen L. , Jacobs E.J. , Lane D.S. , et al. .
Source: Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 2019 07; 17(8), p. 1561-1570.e3.
EPub date: 2018-11-23.
PMID: 30476588
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Low-Carbohydrate Diet Score and Macronutrient Intake in Relation to Survival After Colorectal Cancer Diagnosis.
Authors: Song M. , Wu K. , Meyerhardt J.A. , Yilmaz O. , Wang M. , Ogino S. , Fuchs C.S. , Giovannucci E.L. , Chan A.T. .
Source: JNCI cancer spectrum, 2018 Nov; 2(4), p. pky077.
EPub date: 2019-01-28.
PMID: 30734025
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Association of family history and survival in patients with colorectal cancer: a pooled analysis of eight epidemiologic studies.
Authors: Chong D.Q. , Banbury B.L. , Phipps A.I. , Hua X. , Kocarnik J. , Peters U. , Berndt S.I. , Huang W.Y. , Potter J.D. , Slattery M.L. , et al. .
Source: Cancer medicine, 2018 05; 7(5), p. 2192-2199.
EPub date: 2018-03-26.
PMID: 29582567
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Family History of Cancer and Risk of Biliary Tract Cancers: Results from the Biliary Tract Cancers Pooling Project.
Authors: Van Dyke A.L. , Langhamer M.S. , Zhu B. , Pfeiffer R.M. , Albanes D. , Andreotti G. , Beane Freeman L.E. , Chan A.T. , Freedman N.D. , Gapstur S.M. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2018 03; 27(3), p. 348-351.
EPub date: 2018-01-16.
PMID: 29339358
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Fiber Intake and Survival After Colorectal Cancer Diagnosis.
Authors: Song M. , Wu K. , Meyerhardt J.A. , Ogino S. , Wang M. , Fuchs C.S. , Giovannucci E.L. , Chan A.T. .
Source: JAMA oncology, 2018-01-01; 4(1), p. 71-79.
PMID: 29098294
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Relationship of prediagnostic body mass index with survival after colorectal cancer: Stage-specific associations.
Authors: Kocarnik J.M. , Chan A.T. , Slattery M.L. , Potter J.D. , Meyerhardt J. , Phipps A. , Nan H. , Harrison T. , Rohan T.E. , Qi L. , et al. .
Source: International journal of cancer, 2016-09-01; 139(5), p. 1065-72.
EPub date: 2016-05-14.
PMID: 27121247
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Common genetic variation and survival after colorectal cancer diagnosis: a genome-wide analysis.
Authors: Phipps A.I. , Passarelli M.N. , Chan A.T. , Harrison T.A. , Jeon J. , Hutter C.M. , Berndt S.I. , Brenner H. , Caan B.J. , Campbell P.T. , et al. .
Source: Carcinogenesis, 2016 Jan; 37(1), p. 87-95.
EPub date: 2015-11-19.
PMID: 26586795
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Postdiagnostic intake of one-carbon nutrients and alcohol in relation to colorectal cancer survival.
Authors: Lochhead P. , Nishihara R. , Qian Z.R. , Mima K. , Cao Y. , Sukawa Y. , Kim S.A. , Inamura K. , Zhang X. , Wu K. , et al. .
Source: The American journal of clinical nutrition, 2015 Nov; 102(5), p. 1134-41.
EPub date: 2015-09-30.
PMID: 26423386
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TFF2-CXCR4 Axis Is Associated with BRAF V600E Colon Cancer.
Authors: Gala M.K. , Austin T. , Ogino S. , Chan A.T. .
Source: Cancer prevention research (Philadelphia, Pa.), 2015 Jul; 8(7), p. 614-9.
EPub date: 2015-04-21.
PMID: 25899003
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Molecular pathways: aspirin and Wnt signaling-a molecularly targeted approach to cancer prevention and treatment.
Authors: Gala M.K. , Chan A.T. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2015-04-01; 21(7), p. 1543-8.
EPub date: 2014-12-11.
PMID: 25501125
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