Genetic variants of methyl metabolizing enzymes and epigenetic regulators: associations with promoter CpG island hypermethylation in colorectal cancer.
Aberrant DNA methylation affects carcinogenesis of colorectal cancer. Folate metabolizing enzymes may influence the bioavailability of methyl groups, whereas DNA and histone methyltransferases are involved in epigenetic regulation of gene expression. We studied associations of genetic variants of folate metabolizing enzymes (MTHFR, MTR, and MTRR), DNA methyltransferase DNMT3b, and histone methyltransferases (EHMT1, EHMT2, and PRDM2), with colorectal cancers, with or without the CpG island methylator phenotype (CIMP), MLH1 hypermethylation, or microsatellite instability. Incidence rate ratios were calculated in case-cohort analyses, with common homozygotes as reference, among 659 cases and 1,736 subcohort members of the Netherlands Cohort Study on diet and cancer (n = 120,852). Men with the MTHFR 677TT genotype were at decreased colorectal cancer risk (incidence rate ratio, 0.49; P = 0.01), but the T allele was associated with increased risk in women (incidence rate ratio, 1.39; P = 0.02). The MTR 2756GG genotype was associated with increased colorectal cancer risk (incidence rate ratio, 1.58; P = 0.04), and inverse associations were observed among women carrying DNMT3b C-->T (rs406193; incidence rate ratio, 0.72; P = 0.04) or EHMT2 G-->A (rs535586; incidence rate ratio, 0.76; P = 0.05) polymorphisms. Although significantly correlated (P < 0.001), only 41.5% and 33.3% of CIMP tumors harbored MLH1 hypermethylation or microsatellite instability, respectively. We observed inverse associations between MTR A2756G and CIMP among men (incidence rate ratio, 0.58; P = 0.04), and between MTRR A66G and MLH1 hypermethylation among women (incidence rate ratio, 0.55; P = 0.02). In conclusion, MTHFR, MTR, DNMT3b, and EHMT2 polymorphisms are associated with colorectal cancer, and rare variants of MTR and MTRR may reduce promoter hypermethylation. The incomplete overlap between CIMP, MLH1 hypermethylation, and microsatellite instability indicates that these related "methylation phenotypes" may not be similar and should be investigated separately.
Departments of Epidemiology, GROW-School for Oncology and Developmental Biology, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
Stefan
S
de Vogel
Kim A D
KA
Wouters
Ralph W H
RW
Gottschalk
Frederik J
FJ
van Schooten
Anton F P M
AF
de Goeij
Adriaan P
AP
de Bruïne
Royle A
RA
Goldbohm
Piet A
PA
van den Brandt
Matty P
MP
Weijenberg
Manon
M
van Engeland
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005838:Genotype; D006649:Histocompatibility Antigens / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics*; D009367:Neoplasm Staging; D009426:Netherlands; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011446:Prospective Studies; D012307:Risk Factors; D050053:TRPM Cation Channels / Q000235:genetics; D000097584:DNA Methyltransferase 3B
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D004248:DNA (Cytosine-5-)-Methyltransferases; D006649:Histocompatibility Antigens; D011495:Histone-Lysine N-Methyltransferase; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D050053:TRPM Cation Channels; D000097584:DNA Methyltransferase 3B; C501486:MLH1 protein, human; C404409:TRPM5 protein, human; C445405:EHMT2 protein, human