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Genes involved with folate uptake and distribution and their association with colorectal cancer risk

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Abstract

Folate status is an important predictor of colorectal cancer risk. Common genetic variants in genes involved in regulating cellular folate levels might also predict risk, but there are limited data on this issue. We conducted a family-based case–control association study of variants in four genes involved in folate uptake and distribution: FOLR1, FPGS, GGH and SLC19A1, using 1,750 population-based and 245 clinic-based cases of pathologically confirmed colorectal cancer and their unaffected relatives participating in the Colon Cancer Family Registries. Standardized questionnaires, administered to all participants, collected information on risk factors and diet. Standard molecular techniques were used to determine microsatellite instability (MSI) status on cases. tagSNPs (n = 29) were selected based on coverage as assessed by pairwise r 2. We found no evidence that tagSNPs in these genes were associated with risk of colorectal cancer. For the SLC19A1-rs1051266 (G80A, Arg27His) missense polymorphism, the A/A genotype was not associated with risk of colorectal cancer using population-based (OR = 1.00; 95% CI = 0.81–1.23) or clinic-based (OR = 0.75; 95% CI = 0.44–1.29) families compared to the G/A and G/G genotypes. We found no evidence that the association between any tagSNP and CRC risk was modified by multivitamin use, folic acid use and dietary folate intake and total folate intake. The odds ratios were similar, irrespective of MSI status, tumor subsite and family history of colorectal cancer. In conclusion, we found no significant evidence that genetic variants in FOLR1, GGH, FPGS and SLC19A1 are associated with the risk of colorectal cancer.

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Acknowledgments

We thank the following individuals for their support in data collection and management: Margreet Luchtenborg, Maj Earle, Barbara Saltzman, Kathy Kennedy, Darin Taverna, Chris Edlund, Matt Westlake, Paul Mosquin, Darshana Daftary, Michelle Cotterchio, Douglas Snazel, Allyson Templeton, Terry Teitsch, Helen Chen and Maggie Angelakos. We thank all the individuals who participated in the Colon CFR.

Funding

This work was supported by the National Cancer Institute, National Institutes of Health under RFA # CA-95-011 and through cooperative agreements with the Australasian Colorectal Cancer Family Registry (U01 CA097735), the USC Familial Colorectal Neoplasia Collaborative Group (U01 CA074799), the Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01 CA074800), the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783), the Seattle Colorectal Cancer Family Registry (U01 CA074794), and the University of Hawaii Colorectal Cancer Family Registry (U01 CA074806) as well as NCI T32 CA009142 (JNP), NCI R01 CA112237 (RWH), NCI PO1 CA41108 (MEM), CA23074 (MEM) and CA95060 (MEM). P. T. C. and J. C. F. were supported in part by National Cancer Institute of Canada post-PhD Fellowships (#18735 and #17602).

Disclosures

Paul Limburg is a consultant for Genomic Health, Inc.

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Authors and Affiliations

  1. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 1450 Biggy Street Room 1509J, Los Angeles, CA, 90033, USA

    Jane C. Figueiredo, A. Joan Levine, Won H. Lee, David V. Conti, Jenny N. Poynter, Juan Pablo Lewinger & Robert W. Haile

  2. Division of Pediatric Epidemiology and Clinical Research, University of Minnesota, Minneapolis, MN, USA

    Jenny N. Poynter

  3. Department of Epidemiology, American Cancer Society, Atlanta, GA, USA

    Peter T. Campbell

  4. Translational Genomics Research Institute, Phoenix, AZ, USA

    David Duggan

  5. Arizona Cancer Center, University of Arizona, Tucson, AZ, USA

    Maria Elena Martinez

  6. Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA

    Maria Elena Martinez

  7. Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Peter T. Campbell, Cornelia M. Ulrich, Polly Newcomb & John Potter

  8. Mayo Clinic, Rochester, MN, USA

    Paul J. Limburg

  9. Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Australia

    John Hopper & Mark A. Jenkins

  10. Cancer Research Center of Hawaii, University of Hawaii, Honolulu, HI, USA

    Loic Le Marchand

  11. Departments of Medicine and Community and Family Medicine, Dartmouth Medical School, Hanover, NH, USA

    John A. Baron

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  1. Jane C. Figueiredo
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  2. A. Joan Levine
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Correspondence to Jane C. Figueiredo.

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Figueiredo, J.C., Levine, A.J., Lee, W.H. et al. Genes involved with folate uptake and distribution and their association with colorectal cancer risk. Cancer Causes Control 21, 597–608 (2010). https://doi.org/10.1007/s10552-009-9489-6

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