Comprehensive evaluation of one-carbon metabolism pathway gene variants and renal cell cancer risk

Todd M. Gibson, Paul Brennan, Summer Han, Sara Karami, David Zaridze, Vladimir Janout, Helen Kollarova, Vladimir Bencko, Marie Navratilova, Neonila Szeszenia-Dabrowska, Dana Mates, Alena Slamova, Ruth M. Pfeiffer, Rachael Z. Stolzenberg-Solomon, Susan T. Mayne, Meredith Yeager, Stephen Chanock, Nat Rothman, Wong Ho Chow, Philip S. Rosenberg & 2 others Paolo Boffetta, Lee E. Moore

Research output: Contribution to journalArticle

Abstract

Introduction: Folate and one-carbon metabolism are linked to cancer risk through their integral role in DNA synthesis and methylation. Variation in one-carbon metabolism genes, particularly MTHFR, has been associated with risk of a number of cancers in epidemiologic studies, but little is known regarding renal cancer. Methods: Tag single nucleotide polymorphisms (SNPs) selected to produce high genomic coverage of 13 gene regions of one-carbon metabolism (ALDH1L1, BHMT, CBS, FOLR1, MTHFR, MTR, MTRR, SHMT1, SLC19A1, TYMS) and the closely associated glutathione synthesis pathway (CTH, GGH, GSS) were genotyped for 777 renal cell carcinoma (RCC) cases and 1,035 controls in the Central and Eastern European Renal Cancer case-control study. Associations of individual SNPs (n = 163) with RCC risk were calculated using unconditional logistic regression adjusted for age, sex and study center. Minimum p-value permutation (Min-P) tests were used to identify gene regions associated with risk, and haplotypes were evaluated within these genes. Results: The strongest associations with RCC risk were observed for SLC19A1 (P min-P = 0.03) and MTHFR (P min-P = 0.13). A haplotype consisting of four SNPs in SLC19A1 (rs12483553, rs2838950, rs2838951, and rs17004785) was associated with a 37% increased risk (p = 0.02), and exploratory stratified analysis suggested the association was only significant among those in the lowest tertile of vegetable intake. Conclusions: To our knowledge, this is the first study to comprehensively examine variation in one-carbon metabolism genes in relation to RCC risk. We identified a novel association with SLC19A1, which is important for transport of folate into cells. Replication in other populations is required to confirm these findings.

Original languageEnglish (US)
Article numbere26165
JournalPLoS One
Volume6
Issue number10
DOIs
StatePublished - 2011
Externally publishedYes

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kidney cells
Renal Cell Carcinoma
Metabolism
Carbon
Genes
neoplasms
metabolism
carbon
carcinoma
Polymorphism
kidney neoplasms
single nucleotide polymorphism
genes
Single Nucleotide Polymorphism
Nucleotides
Kidney Neoplasms
Folic Acid
folic acid
Haplotypes
haplotypes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Gibson, T. M., Brennan, P., Han, S., Karami, S., Zaridze, D., Janout, V., ... Moore, L. E. (2011). Comprehensive evaluation of one-carbon metabolism pathway gene variants and renal cell cancer risk. PLoS One, 6(10), [e26165]. https://doi.org/10.1371/journal.pone.0026165

Comprehensive evaluation of one-carbon metabolism pathway gene variants and renal cell cancer risk. / Gibson, Todd M.; Brennan, Paul; Han, Summer; Karami, Sara; Zaridze, David; Janout, Vladimir; Kollarova, Helen; Bencko, Vladimir; Navratilova, Marie; Szeszenia-Dabrowska, Neonila; Mates, Dana; Slamova, Alena; Pfeiffer, Ruth M.; Stolzenberg-Solomon, Rachael Z.; Mayne, Susan T.; Yeager, Meredith; Chanock, Stephen; Rothman, Nat; Chow, Wong Ho; Rosenberg, Philip S.; Boffetta, Paolo; Moore, Lee E.

In: PLoS One, Vol. 6, No. 10, e26165, 2011.

Research output: Contribution to journalArticle

Gibson, TM, Brennan, P, Han, S, Karami, S, Zaridze, D, Janout, V, Kollarova, H, Bencko, V, Navratilova, M, Szeszenia-Dabrowska, N, Mates, D, Slamova, A, Pfeiffer, RM, Stolzenberg-Solomon, RZ, Mayne, ST, Yeager, M, Chanock, S, Rothman, N, Chow, WH, Rosenberg, PS, Boffetta, P & Moore, LE 2011, 'Comprehensive evaluation of one-carbon metabolism pathway gene variants and renal cell cancer risk', PLoS One, vol. 6, no. 10, e26165. https://doi.org/10.1371/journal.pone.0026165
Gibson, Todd M. ; Brennan, Paul ; Han, Summer ; Karami, Sara ; Zaridze, David ; Janout, Vladimir ; Kollarova, Helen ; Bencko, Vladimir ; Navratilova, Marie ; Szeszenia-Dabrowska, Neonila ; Mates, Dana ; Slamova, Alena ; Pfeiffer, Ruth M. ; Stolzenberg-Solomon, Rachael Z. ; Mayne, Susan T. ; Yeager, Meredith ; Chanock, Stephen ; Rothman, Nat ; Chow, Wong Ho ; Rosenberg, Philip S. ; Boffetta, Paolo ; Moore, Lee E. / Comprehensive evaluation of one-carbon metabolism pathway gene variants and renal cell cancer risk. In: PLoS One. 2011 ; Vol. 6, No. 10.
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abstract = "Introduction: Folate and one-carbon metabolism are linked to cancer risk through their integral role in DNA synthesis and methylation. Variation in one-carbon metabolism genes, particularly MTHFR, has been associated with risk of a number of cancers in epidemiologic studies, but little is known regarding renal cancer. Methods: Tag single nucleotide polymorphisms (SNPs) selected to produce high genomic coverage of 13 gene regions of one-carbon metabolism (ALDH1L1, BHMT, CBS, FOLR1, MTHFR, MTR, MTRR, SHMT1, SLC19A1, TYMS) and the closely associated glutathione synthesis pathway (CTH, GGH, GSS) were genotyped for 777 renal cell carcinoma (RCC) cases and 1,035 controls in the Central and Eastern European Renal Cancer case-control study. Associations of individual SNPs (n = 163) with RCC risk were calculated using unconditional logistic regression adjusted for age, sex and study center. Minimum p-value permutation (Min-P) tests were used to identify gene regions associated with risk, and haplotypes were evaluated within these genes. Results: The strongest associations with RCC risk were observed for SLC19A1 (P min-P = 0.03) and MTHFR (P min-P = 0.13). A haplotype consisting of four SNPs in SLC19A1 (rs12483553, rs2838950, rs2838951, and rs17004785) was associated with a 37{\%} increased risk (p = 0.02), and exploratory stratified analysis suggested the association was only significant among those in the lowest tertile of vegetable intake. Conclusions: To our knowledge, this is the first study to comprehensively examine variation in one-carbon metabolism genes in relation to RCC risk. We identified a novel association with SLC19A1, which is important for transport of folate into cells. Replication in other populations is required to confirm these findings.",
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AU - Brennan, Paul

AU - Han, Summer

AU - Karami, Sara

AU - Zaridze, David

AU - Janout, Vladimir

AU - Kollarova, Helen

AU - Bencko, Vladimir

AU - Navratilova, Marie

AU - Szeszenia-Dabrowska, Neonila

AU - Mates, Dana

AU - Slamova, Alena

AU - Pfeiffer, Ruth M.

AU - Stolzenberg-Solomon, Rachael Z.

AU - Mayne, Susan T.

AU - Yeager, Meredith

AU - Chanock, Stephen

AU - Rothman, Nat

AU - Chow, Wong Ho

AU - Rosenberg, Philip S.

AU - Boffetta, Paolo

AU - Moore, Lee E.

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