Pancreaticobiliary cancers with deficient methylenetetrahydrofolate reductase genotypes.
OBJECTIVE
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).


CONCLUSIONS
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.
Matsubayashi
Hiroyuki
H
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205-2196, USA.
Skinner
Halcyon G
HG
Iacobuzio-Donahue
Christine
C
Abe
Tadayoshi
T
Sato
Norihiro
N
Riall
Taylor Sohn
TS
Yeo
Charles J
CJ
Kern
Scott E
SE
Goggins
Michael
M
D000230:Adenocarcinoma / Q000235:genetics*; D001661:Biliary Tract Neoplasms / Q000235:genetics*; D044383:Black People / Q000235:genetics; D016022:Case-Control Studies; D002872:Chromosome Deletion; D019175:DNA Methylation; D048909:Diabetes Complications; D005260:Female; D005838:Genotype; D006801:Humans; D016013:Likelihood Functions; D020084:Long Interspersed Nucleotide Elements; D019656:Loss of Heterozygosity; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D018895:Microsatellite Repeats; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics*; D011110:Polymorphism, Genetic; D012907:Smoking / Q000009:adverse effects; D016019:Survival Analysis; D044465:White People / Q000235:genetics
D042965:Methylenetetrahydrofolate Reductase (NADPH2)