title: Serum Trimethylamine N-oxide, Carnitine, Choline, and Betaine in Relation to Colorectal Cancer Risk in the Alpha Tocopherol, Beta Carotene Cancer Prevention Study.
abstract: Background:Trimethylamine N-oxide (TMAO), a choline-derived metabolite produced by gut microbiota, and its biomarker precursors have not been adequately evaluated in relation to colorectal cancer risk.Methods:We investigated the relationship between serum concentrations of TMAO and its biomarker precursors (choline, carnitine, and betaine) and incident colorectal cancer risk in a nested case-control study of male smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. We measured biomarker concentrations in baseline fasting serum samples from 644 incident colorectal cancer cases and 644 controls using LC/MS-MS. Logistic regression models estimated the ORs and 95% confidence interval (CI) for colorectal cancer by quartile (Q) of serum TMAO, choline, carnitine, and betaine concentrations.Results:Men with higher serum choline at ATBC baseline had approximately 3-fold greater risk of developing colorectal cancer over the ensuing (median ± IQR) 14 ± 10 years (in fully adjusted models, Q4 vs. Q1, OR, 3.22; 95% CI, 2.24-4.61;Ptrend< 0.0001). The prognostic value of serum choline for prediction of incident colorectal cancer was similarly robust for proximal, distal, and rectal colon cancers (allP< 0.0001). The association between serum TMAO, carnitine, or betaine and colorectal cancer risk was not statistically significant (P= 0.25, 0.71, and 0.61, respectively).Conclusions:Higher serum choline concentration (but not TMAO, carnitine, or betaine) was associated with increased risk of colorectal cancer.Impact:Serum choline levels showed strong prognostic value for prediction of incident colorectal cancer risk across all anatomical subsites, suggesting a role of altered choline metabolism in colorectal cancer pathogenesis.Cancer Epidemiol Biomarkers Prev; 26(6); 945-52. ©2017 AACR.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland. kguertin@virginia.edu.|Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, Virginia.
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Guertin
authors.affiliation: Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Xinmin S
authors.initials: XS
authors.lastname: Li
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Barry I
authors.initials: BI
authors.lastname: Graubard
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Demetrius
authors.initials: D
authors.lastname: Albanes
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Weinstein
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: James J
authors.initials: JJ
authors.lastname: Goedert
authors.affiliation: Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.|Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Sinha
mesh_terms: D001622:Betaine / Q000378:metabolism*; D002331:Carnitine / Q000378:metabolism*; D016022:Case-Control Studies; D002794:Choline / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000517:prevention & control*; D005260:Female; D006801:Humans; D008297:Male; D008744:Methylamines / Q000378:metabolism*; D008875:Middle Aged; D011379:Prognosis; D012307:Risk Factors; D024502:alpha-Tocopherol / Q000378:metabolism*; D019207:beta Carotene / Q000378:metabolism*
chemical_list: D008744:Methylamines; D019207:beta Carotene; D001622:Betaine; C005855:trimethyloxamine; D024502:alpha-Tocopherol; D002794:Choline; D002331:Carnitine