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Int J Mol Epidemiol Genet 2011;2(1):1-8
Original Article
Candidate pathway polymorphisms in one-carbon metabolism and risk of
rectal tumor mutations
Karen Curtin, Cornelia M. Ulrich, Wade S. Samowitz, Roger K. Wolff, David J. Duggan, Karen W. Makar, Bette J. Caan, Martha L.
Slattery
Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah, USA; Cancer Prevention
Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; National Center for Tumor Diseases and
German Cancer Research Center, Heidelberg, Germany; Department of Pathology, University of Utah Health Sciences Center,
Salt Lake City, Utah, USA; Translational Genomics Research Institute, Phoenix, Arizona, USA; Divsion of Research, Kaiser
Permanente Medical Care Program, Oakland, California, USA.
Received September 22, 2010; accepted November 1, 2010; Epub November 5, 2010; published January 1, 2010
Abstract: We examined candidate polymorphisms in genes involved in the folate-mediated, one-carbon metabolism pathway,
DNMT1 I311V, MTHFD1 R134K and R653Q, MTHFR R594Q, MTR D919G, MTRR H595Y and I22M, SHMT1 L474F, SLC19A1
H27R, and TDG G199S, and associations with rectal tumor characteristics. We hypothesized that these candidate genes
would influence CpG Island Methylator Phenotype and potentially KRAS2 or TP53 tumors. Data from a population-based study
of 747 rectal cases (593 with tumor markers) and 956 controls were evaluated using generalized estimating equations. We
observed an increased risk of TP53 tumor mutations in homozygous carriers of the MTHFD1 134K allele (OR=2.0, 95%CI
1.2-3.1, P trend=0.02). In the presence of low folate intake, the R134K variant was associated with increased risk of CIMP+
tumors (OR 2.8, 95%CI 1.04-7.7). The MTRR I22M variant genotype, was associated with a modest increased risk of TP53
mutations (OR=1.7, 95%CI 1.2-2.5, P trend=0.001). Our findings offer limited support that polymorphisms in one-carbon
metabolism genes influence rectal tumor phenotype, and that folate may interact with MTHFD1 to alter CIMP+ risk.
(IJMEG1009003).
Key words: Folate-mediated one-carbon metabolism (FOCM), single nucleotide polymorphism, CpG island methylator
phenotype (CIMP), TP53, KRAS2, rectal cancer
Full Text PDF
Address all correspondence to:
Karen Curtin, PhD
Department of Internal Medicine
University of Utah Health Sciences Center
391 Chipeta Way Suite D2
Salt Lake City, Utah, USA 84108
Telephone number: (+1) 801-581-4006
Fax number: (+1) 801-581-6052
E-mail: karen.curtin@hsc.utah.edu
Original Article
Candidate pathway polymorphisms in one-carbon metabolism and risk of
rectal tumor mutations
Karen Curtin, Cornelia M. Ulrich, Wade S. Samowitz, Roger K. Wolff, David J. Duggan, Karen W. Makar, Bette J. Caan, Martha L.
Slattery
Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah, USA; Cancer Prevention
Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; National Center for Tumor Diseases and
German Cancer Research Center, Heidelberg, Germany; Department of Pathology, University of Utah Health Sciences Center,
Salt Lake City, Utah, USA; Translational Genomics Research Institute, Phoenix, Arizona, USA; Divsion of Research, Kaiser
Permanente Medical Care Program, Oakland, California, USA.
Received September 22, 2010; accepted November 1, 2010; Epub November 5, 2010; published January 1, 2010
Abstract: We examined candidate polymorphisms in genes involved in the folate-mediated, one-carbon metabolism pathway,
DNMT1 I311V, MTHFD1 R134K and R653Q, MTHFR R594Q, MTR D919G, MTRR H595Y and I22M, SHMT1 L474F, SLC19A1
H27R, and TDG G199S, and associations with rectal tumor characteristics. We hypothesized that these candidate genes
would influence CpG Island Methylator Phenotype and potentially KRAS2 or TP53 tumors. Data from a population-based study
of 747 rectal cases (593 with tumor markers) and 956 controls were evaluated using generalized estimating equations. We
observed an increased risk of TP53 tumor mutations in homozygous carriers of the MTHFD1 134K allele (OR=2.0, 95%CI
1.2-3.1, P trend=0.02). In the presence of low folate intake, the R134K variant was associated with increased risk of CIMP+
tumors (OR 2.8, 95%CI 1.04-7.7). The MTRR I22M variant genotype, was associated with a modest increased risk of TP53
mutations (OR=1.7, 95%CI 1.2-2.5, P trend=0.001). Our findings offer limited support that polymorphisms in one-carbon
metabolism genes influence rectal tumor phenotype, and that folate may interact with MTHFD1 to alter CIMP+ risk.
(IJMEG1009003).
Key words: Folate-mediated one-carbon metabolism (FOCM), single nucleotide polymorphism, CpG island methylator
phenotype (CIMP), TP53, KRAS2, rectal cancer
Full Text PDF
Address all correspondence to:
Karen Curtin, PhD
Department of Internal Medicine
University of Utah Health Sciences Center
391 Chipeta Way Suite D2
Salt Lake City, Utah, USA 84108
Telephone number: (+1) 801-581-4006
Fax number: (+1) 801-581-6052
E-mail: karen.curtin@hsc.utah.edu
