Genetic variation in the one-carbon transfer pathway and ovarian cancer risk

Linda E. Kelemen, Thomas A. Sellers, Joellen M. Schildkraut, Julie M Cunningham, Robert A. Vierkant, V. Shane Pankratz, Zachary S. Fredericksen, Madhura K. Gadre, David N. Rider, Mark Liebow, Ellen L Goode

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Abstract

Dysfunction in enzymes involved in one-carbon (1-C) metabolism can lead to increased chromosomal strand breaking and abnormal methylation patterns, which are both associated with cancer risk. Availability of 1-C units may modify risk. We investigated the association of single-nucleotide polymorphisms (SNP) in 21 genes in the 1-C transfer pathway among 829 Caucasian cases with primary epithelial ovarian cancer and 941 frequency-matched unaffected controls enrolled at Mayo Clinic (Rochester, MN) and Duke University (Durham, NC) and examined risk modification by multivitamin supplement use. Multivariable-adjusted SNP-specific logistic regression and haplotype analyses were done for 180 SNPs and false positive report probabilities (FPRP) were calculated. Each copy of the minor allele in SHMT1 intron 5 A>G (rs9909104) was associated with epithelial ovarian cancer [odds ratio (OR), 1.2; 95% confidence interval (95% CI), 1.0-1.4; P trend = 0.02; FPRP = 0.16] and a 5-SNP SHMT1 haplotype was associated with decreased risk (P = 0.01; FPRP = 0.09). Three SNPs in DNMT3A were associated with risk among multivitamin supplement users: 3′ untranslated region (UTR) C>G (rs13420827: OR, 0.8; 95% CI, 0.6-1.0; P interaction = 0.006; FPRP = 0.54), intron 6 G>A (rs11887120: OR, 0.8; 95% CI, 0.7-1.0; P interaction = 0.007; FPRP = 0.57), and intron 22 A>T (rs11695471: OR, 1.2; 95% CI, 1.0-1.5; P interaction = 0.01; FPRP = 0.66). These data extend previous findings from other cancers of a role for SHMT1 in ovarian cancer, and provide evidence that SNPs in methylation and DNA synthesis reactions are associated with risk of ovarian cancer. Interventions with modifiable factors such as multivitamin intake may reduce risk.

Original languageEnglish (US)
Pages (from-to)2498-2506
Number of pages9
JournalCancer Research
Volume68
Issue number7
DOIs
StatePublished - Apr 1 2008

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Ovarian Neoplasms
Carbon
Single Nucleotide Polymorphism
Odds Ratio
Confidence Intervals
Introns
Haplotypes
3' Untranslated Regions
DNA Methylation
Methylation
Neoplasms
Logistic Models
Alleles
Regression Analysis
Enzymes
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Genetic variation in the one-carbon transfer pathway and ovarian cancer risk. / Kelemen, Linda E.; Sellers, Thomas A.; Schildkraut, Joellen M.; Cunningham, Julie M; Vierkant, Robert A.; Pankratz, V. Shane; Fredericksen, Zachary S.; Gadre, Madhura K.; Rider, David N.; Liebow, Mark; Goode, Ellen L.

In: Cancer Research, Vol. 68, No. 7, 01.04.2008, p. 2498-2506.

Research output: Contribution to journalArticle

Kelemen, LE, Sellers, TA, Schildkraut, JM, Cunningham, JM, Vierkant, RA, Pankratz, VS, Fredericksen, ZS, Gadre, MK, Rider, DN, Liebow, M & Goode, EL 2008, 'Genetic variation in the one-carbon transfer pathway and ovarian cancer risk', Cancer Research, vol. 68, no. 7, pp. 2498-2506. https://doi.org/10.1158/0008-5472.CAN-07-5165
Kelemen LE, Sellers TA, Schildkraut JM, Cunningham JM, Vierkant RA, Pankratz VS et al. Genetic variation in the one-carbon transfer pathway and ovarian cancer risk. Cancer Research. 2008 Apr 1;68(7):2498-2506. https://doi.org/10.1158/0008-5472.CAN-07-5165
Kelemen, Linda E. ; Sellers, Thomas A. ; Schildkraut, Joellen M. ; Cunningham, Julie M ; Vierkant, Robert A. ; Pankratz, V. Shane ; Fredericksen, Zachary S. ; Gadre, Madhura K. ; Rider, David N. ; Liebow, Mark ; Goode, Ellen L. / Genetic variation in the one-carbon transfer pathway and ovarian cancer risk. In: Cancer Research. 2008 ; Vol. 68, No. 7. pp. 2498-2506.
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