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Germ-Line Variants in Methyl-Group Metabolism Genes and Susceptibility to DNA Methylation in Normal Tissues and Human Primary Tumors¹

Cancer Epigenetics Laboratory, Molecular Pathology Program, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain [M. F. P., S. A., M. F. F., M. S-C., M. E.]; Cancer Epidemiology Unit, National Center for Epidemiology, Carlos III Institute of Health, 28029 Madrid, Spain [M. P.]; Institut de Recerca Oncologica-Institut Catala d’Oncologia, 08907 Barcelona, Catalonia, Spain [G. C., M. A. P.]; and The Johns Hopkins Oncology Center, Baltimore, Maryland 21231 [J. G. H.]

Aberrant DNA methylation is recognized as being a common feature of human neoplasia.CpG island hypermethylation and global genomic hypomethylationoccur simultaneously in the cancer cell. However, very little is known about the interindividual inherited susceptibility to these epigenetic processes. To address this matter, we have genotyped in 233 cancer patients (with colorectal, breast, or lung tumors), four germ-line variants in three key genes involved in the metabolism of the methyl group, methylene-tetrahydrofolate reductase, methionine synthase, and cystathionine ß-synthase, and analyzed their association with DNA methylation parameters. The epigenetic features analyzed were the 5-methylcytosine content in the genome of the tumors and their normal counterparts, and the presence of CpG island hypermethylation of tumor suppressor genes (p16^INK4a, p14^ARF, hMLH1, MGMT, APC, LKB1, DAPK, GSTP1, BRCA1, RARß2, CDH1, and RASSF1). Two positive associations were found. First, carriers of genotypes containing the methylene-tetrahydrofolate reductase 677T allele show constitutive low levels of 5-methylcytosine in their genomes (P = 0.002), and tumors in these patients do not achieve severe degrees of global hypomethylation (P = 0.047). Second, tumors occurring in homozygous carriers of the methionine synthase 2756G allele show a lower number of hypermethylated CpG islands of tumor suppressor genes (P = 0.029). The existence of these associations may provide another example of the interplay between genetic and epigenetic factors in the cancer cell.

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