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Grant Details

Grant Number: 5R01CA120523-05 Interpret this number
Primary Investigator: Ulrich, Cornelia
Organization: Fred Hutchinson Cancer Research Center
Project Title: A Prospective Study of Colorectal Cancer: One-Carbon Metabolism and Inflammation
Fiscal Year: 2012
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Abstract

DESCRIPTION (provided by applicant): The goal of the proposed study is to evaluate the role of genetic variability and biomarkers in two specific pathways - inflammation and folate-mediated one-carbon metabolism - in colorectal cancer etiology within a large cohort of women. Strong evidence from epidemiology and experimental studies implicates inflammation and one-carbon metabolism in colorectal cancer, and preliminary studies show that these two pathways may be interconnected. However, there are many remaining questions, particularly regarding the impact of genetic factors in these pathways in the presence of differences in nutritional status or NSAID use. To date, a comprehensive assessment of the impact of genetics and relevant biomarkers on colorectal cancer risk is lacking, and can best be achieved within a large prospective study. We propose to investigate these two interrelated pathways of demonstrated relevance to colorectal carcinogenesis within the Women's Health Initiative Observational Study, a prospective cohort of >93,000 postmenopausal women who will have been followed for an average of 10.2 years. We will evaluate whether 1) genetic variability and biomarkers relevant to one-carbon metabolism are associated with colorectal cancer risk, and whether associations differ by folic-acid fortification; 2) genetic variability and biomarkers relevant to prostaglandin synthesis and inflammation are associated with colorectal cancer risk; 3) whether genetic factors modify associations with nutrients or modify the response to NSAIDs; and 4) whether there are interconnections between the two pathways. A nested case-control study is proposed, which includes 1000 incident colorectal cancer cases and 1500 matched controls. Biomarker assays derived from blood obtained at the baseline visit include vitamin B12, holo-transcobalamin II, pyridoxalphosphate (vitamin B6), homocysteine, serum and RBC folate, and global lymphocyte DNA methylation. Biomarkers of inflammation include C-reactive protein and serum amyloid A. These will be measured at two time points, allowing us to evaluate whether a rise in these inflammatory markers is predictive of risk. Genotyping will focus both on candidate polymorphisms with strong evidence for functional impact and haplotype tagSNPs, for a comprehensive assessment of genetic variability. This interdisciplinary collaborative study will be both comprehensive and cost-effective, utilizing a high- quality data source. Results will: 1) further our understanding of the role of inflammation in colorectal carcinogenesis; 2) increase our knowledge about the mechanisms linking one-carbon metabolism to colorectal carcinogenesis, including about the influence of vitamins B6 and B12, and global DNA methylation and the impact of folic-acid fortification; and 3) provide valuable information regarding the possibility of developing targeted interventions involving one-carbon nutrients or NSAIDs among genetically defined groups. Colorectal cancer is the third most common cancer in the United States and the second most common cause of cancer death among both men and women. This study will investigate the role of diet and inflammation on women's risk of colorectal cancer. A person's nutrition, use of anti-inflammatory drugs, and inherited genetic factors can interact to determine an individual's risk of colorectal cancer. Through this research, we will learn more about how to prevent colorectal cancer and about possible public health recommendations based on genetic characteristics.

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Publications

Plasma Choline Metabolites and Colorectal Cancer Risk in the Women's Health Initiative Observational Study.
Authors: Bae S, Ulrich CM, Neuhouser ML, Malysheva O, Bailey LB, Xiao L, Brown EC, Cushing-Haugen KL, Zheng Y, Cheng TY, Miller JW, Green R, Lane DS, Beresford SA, Caudill MA
Source: Cancer Res, 2014 Dec 15;74(24), p. 7442-52.
EPub date: 2014 Oct 21.
PMID: 25336191
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Biomarkers of one-carbon metabolism are associated with biomarkers of inflammation in women.
Authors: Abbenhardt C, Miller JW, Song X, Brown EC, Cheng TY, Wener MH, Zheng Y, Toriola AT, Neuhouser ML, Beresford SA, Makar KW, Bailey LB, Maneval DR, Green R, Manson JE, Van Horn L, Ulrich CM
Source: J Nutr, 2014 May;144(5), p. 714-21.
EPub date: 2014 Mar 19.
PMID: 24647390
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Impact of folic acid fortification on global DNA methylation and one-carbon biomarkers in the Women's Health Initiative Observational Study cohort.
Authors: Bae S, Ulrich CM, Bailey LB, Malysheva O, Brown EC, Maneval DR, Neuhouser ML, Cheng TY, Miller JW, Zheng Y, Xiao L, Hou L, Song X, Buck K, Beresford SA, Caudill MA
Source: Epigenetics, 2014 Mar;9(3), p. 396-403.
EPub date: 2013 Dec 3.
PMID: 24300587
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Review of mass spectrometry-based metabolomics in cancer research.
Authors: Liesenfeld DB, Habermann N, Owen RW, Scalbert A, Ulrich CM
Source: Cancer Epidemiol Biomarkers Prev, 2013 Dec;22(12), p. 2182-201.
EPub date: 2013 Oct 4.
PMID: 24096148
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COX-1 (PTGS1) and COX-2 (PTGS2) polymorphisms, NSAID interactions, and risk of colon and rectal cancers in two independent populations.
Authors: Makar KW, Poole EM, Resler AJ, Seufert B, Curtin K, Kleinstein SE, Duggan D, Kulmacz RJ, Hsu L, Whitton J, Carlson CS, Rimorin CF, Caan BJ, Baron JA, Potter JD, Slattery ML, Ulrich CM
Source: Cancer Causes Control, 2013 Dec;24(12), p. 2059-75.
PMID: 24022467
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Homocysteine, cysteine, and risk of incident colorectal cancer in the Women's Health Initiative observational cohort.
Authors: Miller JW, Beresford SA, Neuhouser ML, Cheng TY, Song X, Brown EC, Zheng Y, Rodriguez B, Green R, Ulrich CM
Source: Am J Clin Nutr, 2013 Apr;97(4), p. 827-34.
EPub date: 2013 Feb 20.
PMID: 23426034
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B vitamin intakes and incidence of colorectal cancer: results from the Women's Health Initiative Observational Study cohort.
Authors: Zschäbitz S, Cheng TY, Neuhouser ML, Zheng Y, Ray RM, Miller JW, Song X, Maneval DR, Beresford SA, Lane D, Shikany JM, Ulrich CM
Source: Am J Clin Nutr, 2013 Feb;97(2), p. 332-43.
EPub date: 2012 Dec 19.
PMID: 23255571
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Biomarkers of inflammation are associated with colorectal cancer risk in women but are not suitable as early detection markers.
Authors: Toriola AT, Cheng TY, Neuhouser ML, Wener MH, Zheng Y, Brown E, Miller JW, Song X, Beresford SA, Gunter MJ, Caudill MA, Ulrich CM
Source: Int J Cancer, 2013 Jun 1;132(11), p. 2648-58.
EPub date: 2012 Dec 5.
PMID: 23161620
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Gene-diet-interactions in folate-mediated one-carbon metabolism modify colon cancer risk.
Authors: Liu AY, Scherer D, Poole E, Potter JD, Curtin K, Makar K, Slattery ML, Caan BJ, Ulrich CM
Source: Mol Nutr Food Res, 2013 Apr;57(4), p. 721-34.
EPub date: 2012 Sep 7.
PMID: 22961839
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Linking epidemiology to epigenomics--where are we today?
Authors: Ulrich CM, Grady WM
Source: Cancer Prev Res (Phila), 2010 Dec;3(12), p. 1505-8.
PMID: 21149325
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Use of folic acid-containing supplements after a diagnosis of colorectal cancer in the Colon Cancer Family Registry.
Authors: Holmes RS, Zheng Y, Baron JA, Li L, McKeown-Eyssen G, Newcomb PA, Stern MC, Haile RW, Grady WM, Potter JD, Le Marchand L, Campbell PT, Figueiredo JC, Limburg PJ, Jenkins MA, Hopper JL, Ulrich CM, Colon Cancer Family Registry
Source: Cancer Epidemiol Biomarkers Prev, 2010 Aug;19(8), p. 2023-34.
PMID: 20696661
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MRI predictors of cognitive change in a diverse and carefully characterized elderly population.
Authors: Carmichael O, Mungas D, Beckett L, Harvey D, Tomaszewski Farias S, Reed B, Olichney J, Miller J, Decarli C
Source: Neurobiol Aging, 2012 Jan;33(1), p. 83-95.
EPub date: 2010 Apr 1.
PMID: 20359776
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Vitamin D and cognitive function in older adults: are we concerned about vitamin D-mentia?
Authors: Miller JW
Source: Neurology, 2010 Jan 5;74(1), p. 13-5.
EPub date: 2009 Nov 25.
PMID: 19940269
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Mathematical modeling of folate metabolism: predicted effects of genetic polymorphisms on mechanisms and biomarkers relevant to carcinogenesis.
Authors: Ulrich CM, Neuhouser M, Liu AY, Boynton A, Gregory JF 3rd, Shane B, James SJ, Reed MC, Nijhout HF
Source: Cancer Epidemiol Biomarkers Prev, 2008 Jul;17(7), p. 1822-31.
PMID: 18628437
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