A candidate gene study of folate-associated one carbon metabolism genes and colorectal cancer risk

A. Joan Levine, Jane C. Figueiredo, Won Lee, David V. Conti, Kathleen Kennedy, David J. Duggan, Jenny N. Poynter, Peter T. Campbell, Polly Newcomb, Maria Elena Martinez, John L. Hopper, Loic Le Marchand, John A. Baron, Paul John Limburg, Cornelia M. Ulrich, Robert W. Haile

Research output: Contribution to journalArticle

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Abstract

Background: Folate-associated one-carbon metabolism (FOCM) may play an important role in colorectal carcinogenesis. Variation in FOCM genes may explain some of the underlying risk of colorectal cancer. Methods: This study utilized data from 1,805 population-based colorectal cancer cases and 2,878 matched sibling controls from the Colon Cancer Family Registry. We used a comprehensive haplotype tagging single nucleotide polymorphism (tagSNP) approach to select 395 tagSNPs in 15 genes involved in folate and vitamin B12 metabolism. Genotyping was done using the Illumina GoldenGate or Sequenom platforms. Risk factor and dietary data were collected using self-completed questionnaires. Microsatellite instability (MSI) status was determined using standard techniques, and tumor subsite was obtained from pathology reports. The association between SNPs and colorectal cancer was assessed using conditional logistic regression with sibships as the matching factor and assuming a log additive or codominant model. Results: In the log additive model, two linked (r2 = 0.99) tagSNPs in the DHFR gene (rs1677693 and rs1643659) were associated with a significant decrease in colorectal cancer risk after correction for multiple testing (odds ratio, 0.87; 95% confidence interval, 0.71-0.94; P = 0.029; and odds ratio, 0.87; 95% confidence interval, 0.71-0.95; P = 0.034 for rs1677693 and rs1643659, respectively). These two linked (r 2 = 0.99) tagSNPs and one tagSNP in the MTR gene (rs4659744) were significantly associated with reduced colorectal cancer risk only among individuals not using multivitamin supplements. Conclusions: Overall, we found only moderate evidence that genetic variation in 15 folate pathway genes may affect colorectal cancer risk except in non-multivitamin users. Impact: This study suggests that multivitamin supplement use may modify the association between folate pathway genes and colorectal cancer risk in a post-folic-acid-supplemented population.

Original languageEnglish (US)
Pages (from-to)1812-1821
Number of pages10
JournalCancer Epidemiology Biomarkers and Prevention
Volume19
Issue number7
DOIs
StatePublished - Jul 2010

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Folic Acid
Colorectal Neoplasms
Carbon
Genes
Single Nucleotide Polymorphism
Odds Ratio
Confidence Intervals
Microsatellite Instability
Vitamin B 12
Colonic Neoplasms
Haplotypes
Population
Registries
Carcinogenesis
Logistic Models
Pathology
Neoplasms

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

Cite this

Levine, A. J., Figueiredo, J. C., Lee, W., Conti, D. V., Kennedy, K., Duggan, D. J., ... Haile, R. W. (2010). A candidate gene study of folate-associated one carbon metabolism genes and colorectal cancer risk. Cancer Epidemiology Biomarkers and Prevention, 19(7), 1812-1821. https://doi.org/10.1158/1055-9965.EPI-10-0151

A candidate gene study of folate-associated one carbon metabolism genes and colorectal cancer risk. / Levine, A. Joan; Figueiredo, Jane C.; Lee, Won; Conti, David V.; Kennedy, Kathleen; Duggan, David J.; Poynter, Jenny N.; Campbell, Peter T.; Newcomb, Polly; Martinez, Maria Elena; Hopper, John L.; Le Marchand, Loic; Baron, John A.; Limburg, Paul John; Ulrich, Cornelia M.; Haile, Robert W.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 19, No. 7, 07.2010, p. 1812-1821.

Research output: Contribution to journalArticle

Levine, AJ, Figueiredo, JC, Lee, W, Conti, DV, Kennedy, K, Duggan, DJ, Poynter, JN, Campbell, PT, Newcomb, P, Martinez, ME, Hopper, JL, Le Marchand, L, Baron, JA, Limburg, PJ, Ulrich, CM & Haile, RW 2010, 'A candidate gene study of folate-associated one carbon metabolism genes and colorectal cancer risk', Cancer Epidemiology Biomarkers and Prevention, vol. 19, no. 7, pp. 1812-1821. https://doi.org/10.1158/1055-9965.EPI-10-0151
Levine, A. Joan ; Figueiredo, Jane C. ; Lee, Won ; Conti, David V. ; Kennedy, Kathleen ; Duggan, David J. ; Poynter, Jenny N. ; Campbell, Peter T. ; Newcomb, Polly ; Martinez, Maria Elena ; Hopper, John L. ; Le Marchand, Loic ; Baron, John A. ; Limburg, Paul John ; Ulrich, Cornelia M. ; Haile, Robert W. / A candidate gene study of folate-associated one carbon metabolism genes and colorectal cancer risk. In: Cancer Epidemiology Biomarkers and Prevention. 2010 ; Vol. 19, No. 7. pp. 1812-1821.
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abstract = "Background: Folate-associated one-carbon metabolism (FOCM) may play an important role in colorectal carcinogenesis. Variation in FOCM genes may explain some of the underlying risk of colorectal cancer. Methods: This study utilized data from 1,805 population-based colorectal cancer cases and 2,878 matched sibling controls from the Colon Cancer Family Registry. We used a comprehensive haplotype tagging single nucleotide polymorphism (tagSNP) approach to select 395 tagSNPs in 15 genes involved in folate and vitamin B12 metabolism. Genotyping was done using the Illumina GoldenGate or Sequenom platforms. Risk factor and dietary data were collected using self-completed questionnaires. Microsatellite instability (MSI) status was determined using standard techniques, and tumor subsite was obtained from pathology reports. The association between SNPs and colorectal cancer was assessed using conditional logistic regression with sibships as the matching factor and assuming a log additive or codominant model. Results: In the log additive model, two linked (r2 = 0.99) tagSNPs in the DHFR gene (rs1677693 and rs1643659) were associated with a significant decrease in colorectal cancer risk after correction for multiple testing (odds ratio, 0.87; 95{\%} confidence interval, 0.71-0.94; P = 0.029; and odds ratio, 0.87; 95{\%} confidence interval, 0.71-0.95; P = 0.034 for rs1677693 and rs1643659, respectively). These two linked (r 2 = 0.99) tagSNPs and one tagSNP in the MTR gene (rs4659744) were significantly associated with reduced colorectal cancer risk only among individuals not using multivitamin supplements. Conclusions: Overall, we found only moderate evidence that genetic variation in 15 folate pathway genes may affect colorectal cancer risk except in non-multivitamin users. Impact: This study suggests that multivitamin supplement use may modify the association between folate pathway genes and colorectal cancer risk in a post-folic-acid-supplemented population.",
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AU - Figueiredo, Jane C.

AU - Lee, Won

AU - Conti, David V.

AU - Kennedy, Kathleen

AU - Duggan, David J.

AU - Poynter, Jenny N.

AU - Campbell, Peter T.

AU - Newcomb, Polly

AU - Martinez, Maria Elena

AU - Hopper, John L.

AU - Le Marchand, Loic

AU - Baron, John A.

AU - Limburg, Paul John

AU - Ulrich, Cornelia M.

AU - Haile, Robert W.

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