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

ABSTRACT Aberrant DNA methylation is recognized as being a common feature ofhuman neoplasia. CpG island hypermethylation and global genomic hy-pomethylation occur simultaneously in the cancer cell. However, verylittle is known about the interindividual inherited susceptibility to theseepigenetic processes. To address this matter, we have genotyped in 233cancer patients (with colorectal, breast, or lung tumors), four germ-linevariants in three key genes involved in the metabolism of the methylgroup, methylene-tetrahydrofolate reductase, methionine synthase, andcystathionine -synthase, and analyzed their association with DNA meth-ylation parameters. The epigenetic features analyzed were the 5-methyl-cytosine content in the genome of the tumors and their normal counter-parts, and the presence of CpG island hypermethylation of tumorsuppressor genes (p16 INK4a , p14 ARF , hMLH1, MGMT, APC, LKB1, DAPK,GSTP1, BRCA1, RAR 2, CDH1, and RASSF1). Two positive associationswere found. First, carriers of genotypes containing the methylene-tetrahy-drofolate reductase 677T allele show constitutive low levels of 5-methylcy-tosine in their genomes (P 0.002), and tumors in these patients do notachieve severe degrees of global hypomethylation (P 0.047). Second,tumors occurring in homozygous carriers of the methionine synthase2756G allele show a lower number of hypermethylated CpG islands oftumor suppressor genes (P 0.029). The existence of these associationsmay provide another example of the interplay between genetic and epi-genetic factors in the cancer cell.