Pancreaticobiliary cancers with deficient methylenetetrahydrofolate reductase genotypes

Hiroyuki Matsubayashi, Halcyon G. Skinner, Christine Iacobuzio-Donahue, Tadayoshi Abe, Norihiro Sato, Taylor Sohn Riall, Charles J. Yeo, Scott E. Kern, Michael Goggins

Research output: Contribution to journalArticle

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Abstract

Background & Aims: Methyl group deficiency might promote carcinogenesis by inducing DNA breaks and DNA hypomethylation. We hypothesized that deficient methylenetetrahydrofolate reductase (MTHFR) genotypes could promote pancreatic cancer development. Methods: First, we performed a case-control study of germline MTHFR polymorphisms (C677T, A1298C) in 303 patients with pancreatic cancer and 305 matched control subjects. Pancreatic neoplasms frequently lose an MTHFR allele during tumorigenesis; we hypothesized that such loss could promote carcinogenesis. We therefore evaluated the cancer MTHFR genotypes of 82 patients with pancreaticobiliary cancers and correlated them to genome-wide measures of chromosomal deletion by using 386 microsatellite markers. Finally, MTHFR genotypes were correlated with global DNA methylation in 68 cancer cell lines. Results: Germline MTHFR polymorphisms were not associated with an increased likelihood of having pancreatic cancer. Fractional allelic loss (a measure of chromosomal loss) trended higher in cancers with 677T genotypes than in cancers with other genotypes (P = .055). Among cancers with loss of an MTHFR allele, cancers with 677T MTHFR alleles had more deletions at folate-sensitive fragile sites (36.9%) and at tumor suppressor gene loci (68.5%) than 677C cancers (28.7% and 47.8%, P = .079 and .014, respectively). LINE1 methylation was lower in cancers with less functional 677T/TT genotypes (24.4%) than in those with 677CT (26.0%) and CC/C genotypes (32.5%) (P = .014). Conclusion: Cancers with defective MTHFR genotypes have more DNA hypomethylation and more chromosomal losses. Deficient MTHFR function due to loss of an MTHFR allele by an evolving neoplasm might, by promoting chromosomal losses, accelerate cancer development.

Original languageEnglish (US)
Pages (from-to)752-760
Number of pages9
JournalClinical Gastroenterology and Hepatology
Volume3
Issue number8
DOIs
StatePublished - Aug 2005
Externally publishedYes

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Methylenetetrahydrofolate Reductase (NADPH2)
Genotype
Neoplasms
Pancreatic Neoplasms
Alleles
Carcinogenesis
DNA Breaks
Loss of Heterozygosity
DNA
DNA Methylation
Tumor Suppressor Genes
Folic Acid
Microsatellite Repeats
Methylation
Case-Control Studies

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Matsubayashi, H., Skinner, H. G., Iacobuzio-Donahue, C., Abe, T., Sato, N., Riall, T. S., ... Goggins, M. (2005). Pancreaticobiliary cancers with deficient methylenetetrahydrofolate reductase genotypes. Clinical Gastroenterology and Hepatology, 3(8), 752-760. https://doi.org/10.1016/S1542-3565(05)00359-9

Pancreaticobiliary cancers with deficient methylenetetrahydrofolate reductase genotypes. / Matsubayashi, Hiroyuki; Skinner, Halcyon G.; Iacobuzio-Donahue, Christine; Abe, Tadayoshi; Sato, Norihiro; Riall, Taylor Sohn; Yeo, Charles J.; Kern, Scott E.; Goggins, Michael.

In: Clinical Gastroenterology and Hepatology, Vol. 3, No. 8, 08.2005, p. 752-760.

Research output: Contribution to journalArticle

Matsubayashi, H, Skinner, HG, Iacobuzio-Donahue, C, Abe, T, Sato, N, Riall, TS, Yeo, CJ, Kern, SE & Goggins, M 2005, 'Pancreaticobiliary cancers with deficient methylenetetrahydrofolate reductase genotypes', Clinical Gastroenterology and Hepatology, vol. 3, no. 8, pp. 752-760. https://doi.org/10.1016/S1542-3565(05)00359-9
Matsubayashi, Hiroyuki ; Skinner, Halcyon G. ; Iacobuzio-Donahue, Christine ; Abe, Tadayoshi ; Sato, Norihiro ; Riall, Taylor Sohn ; Yeo, Charles J. ; Kern, Scott E. ; Goggins, Michael. / Pancreaticobiliary cancers with deficient methylenetetrahydrofolate reductase genotypes. In: Clinical Gastroenterology and Hepatology. 2005 ; Vol. 3, No. 8. pp. 752-760.
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abstract = "Background & Aims: Methyl group deficiency might promote carcinogenesis by inducing DNA breaks and DNA hypomethylation. We hypothesized that deficient methylenetetrahydrofolate reductase (MTHFR) genotypes could promote pancreatic cancer development. Methods: First, we performed a case-control study of germline MTHFR polymorphisms (C677T, A1298C) in 303 patients with pancreatic cancer and 305 matched control subjects. Pancreatic neoplasms frequently lose an MTHFR allele during tumorigenesis; we hypothesized that such loss could promote carcinogenesis. We therefore evaluated the cancer MTHFR genotypes of 82 patients with pancreaticobiliary cancers and correlated them to genome-wide measures of chromosomal deletion by using 386 microsatellite markers. Finally, MTHFR genotypes were correlated with global DNA methylation in 68 cancer cell lines. Results: Germline MTHFR polymorphisms were not associated with an increased likelihood of having pancreatic cancer. Fractional allelic loss (a measure of chromosomal loss) trended higher in cancers with 677T genotypes than in cancers with other genotypes (P = .055). Among cancers with loss of an MTHFR allele, cancers with 677T MTHFR alleles had more deletions at folate-sensitive fragile sites (36.9{\%}) and at tumor suppressor gene loci (68.5{\%}) than 677C cancers (28.7{\%} and 47.8{\%}, P = .079 and .014, respectively). LINE1 methylation was lower in cancers with less functional 677T/TT genotypes (24.4{\%}) than in those with 677CT (26.0{\%}) and CC/C genotypes (32.5{\%}) (P = .014). Conclusion: Cancers with defective MTHFR genotypes have more DNA hypomethylation and more chromosomal losses. Deficient MTHFR function due to loss of an MTHFR allele by an evolving neoplasm might, by promoting chromosomal losses, accelerate cancer development.",
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AU - Matsubayashi, Hiroyuki

AU - Skinner, Halcyon G.

AU - Iacobuzio-Donahue, Christine

AU - Abe, Tadayoshi

AU - Sato, Norihiro

AU - Riall, Taylor Sohn

AU - Yeo, Charles J.

AU - Kern, Scott E.

AU - Goggins, Michael

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N2 - Background & Aims: Methyl group deficiency might promote carcinogenesis by inducing DNA breaks and DNA hypomethylation. We hypothesized that deficient methylenetetrahydrofolate reductase (MTHFR) genotypes could promote pancreatic cancer development. Methods: First, we performed a case-control study of germline MTHFR polymorphisms (C677T, A1298C) in 303 patients with pancreatic cancer and 305 matched control subjects. Pancreatic neoplasms frequently lose an MTHFR allele during tumorigenesis; we hypothesized that such loss could promote carcinogenesis. We therefore evaluated the cancer MTHFR genotypes of 82 patients with pancreaticobiliary cancers and correlated them to genome-wide measures of chromosomal deletion by using 386 microsatellite markers. Finally, MTHFR genotypes were correlated with global DNA methylation in 68 cancer cell lines. Results: Germline MTHFR polymorphisms were not associated with an increased likelihood of having pancreatic cancer. Fractional allelic loss (a measure of chromosomal loss) trended higher in cancers with 677T genotypes than in cancers with other genotypes (P = .055). Among cancers with loss of an MTHFR allele, cancers with 677T MTHFR alleles had more deletions at folate-sensitive fragile sites (36.9%) and at tumor suppressor gene loci (68.5%) than 677C cancers (28.7% and 47.8%, P = .079 and .014, respectively). LINE1 methylation was lower in cancers with less functional 677T/TT genotypes (24.4%) than in those with 677CT (26.0%) and CC/C genotypes (32.5%) (P = .014). Conclusion: Cancers with defective MTHFR genotypes have more DNA hypomethylation and more chromosomal losses. Deficient MTHFR function due to loss of an MTHFR allele by an evolving neoplasm might, by promoting chromosomal losses, accelerate cancer development.

AB - Background & Aims: Methyl group deficiency might promote carcinogenesis by inducing DNA breaks and DNA hypomethylation. We hypothesized that deficient methylenetetrahydrofolate reductase (MTHFR) genotypes could promote pancreatic cancer development. Methods: First, we performed a case-control study of germline MTHFR polymorphisms (C677T, A1298C) in 303 patients with pancreatic cancer and 305 matched control subjects. Pancreatic neoplasms frequently lose an MTHFR allele during tumorigenesis; we hypothesized that such loss could promote carcinogenesis. We therefore evaluated the cancer MTHFR genotypes of 82 patients with pancreaticobiliary cancers and correlated them to genome-wide measures of chromosomal deletion by using 386 microsatellite markers. Finally, MTHFR genotypes were correlated with global DNA methylation in 68 cancer cell lines. Results: Germline MTHFR polymorphisms were not associated with an increased likelihood of having pancreatic cancer. Fractional allelic loss (a measure of chromosomal loss) trended higher in cancers with 677T genotypes than in cancers with other genotypes (P = .055). Among cancers with loss of an MTHFR allele, cancers with 677T MTHFR alleles had more deletions at folate-sensitive fragile sites (36.9%) and at tumor suppressor gene loci (68.5%) than 677C cancers (28.7% and 47.8%, P = .079 and .014, respectively). LINE1 methylation was lower in cancers with less functional 677T/TT genotypes (24.4%) than in those with 677CT (26.0%) and CC/C genotypes (32.5%) (P = .014). Conclusion: Cancers with defective MTHFR genotypes have more DNA hypomethylation and more chromosomal losses. Deficient MTHFR function due to loss of an MTHFR allele by an evolving neoplasm might, by promoting chromosomal losses, accelerate cancer development.

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