Global Hypomethylation of Genomic DNA in Cancer-Associated Myofibroblasts

L. Jiang, T. A. Gonda, M. V. Gamble, M. Salas, V. Seshan, S. Tu, W. S. Twaddell, P. Hegyi, G. Lazar, I. Steele, A. Varro, T. C. Wang (+1 others)
2008 Cancer Research  
Global hypomethylation has long been recognized as a feature of the malignant epithelial component in human carcinomas. Here we show evidence for this same type of epigenetic alteration in cancer-associated stromal myofibroblasts. We used methylation-sensitive SNP array analysis (MSNP) to profile DNA methylation in early-passage cultures of stromal myofibroblasts isolated from human gastric cancers. The MSNP data indicated widespread hypomethylation in these cells, with rare focal gains of
more » ... lation, conclusions that were independently validated by bisulfite sequencing and by a methylation-sensitive cytosine incorporation assay. Immunohistochemistry with anti-5-methylcytosine (anti-5-methyl-C) in a series of gastrectomy specimens showed frequent loss of methylation in nuclei of both the malignant epithelial cells and A-smooth muscle actin (ASMA)-positive stromal myofibroblasts of both intestinal-type and diffuse carcinomas. We confirmed this phenomenon and established its onset at the stage of noninvasive dysplastic lesions by immunohistochemistry for anti-5-methyl-C in a transgenic mouse model of multistage gastric carcinogenesis. These findings indicate similar general classes of epigenetic alterations in carcinoma cells and their accompanying reactive stromal cells and add to accumulating evidence for biological differences between normal and cancer-associated myofibroblasts. [Cancer Res 2008;68(23):9900-8] Results MSNP analysis of DNA from early-passage cancer-associated myofibroblasts. Using the MSNP procedure, we analyzed genomic 9
doi:10.1158/0008-5472.can-08-1319 pmid:19047171 pmcid:PMC2670548 fatcat:4avxvhhy6bec3oavnk2t2xg4xq