Aberrant Hypomethylated KRAS and RASGRF2 as a Candidate Biomarker of Low Level Benzene Hematotoxicity

Benzene is an important industrial chemical and an environmental contaminant. The mechanisms of low level benzene-induced hematotoxicity are unresolved. Aberrant DNA methylation, which may lead to genomic instability and the altered gene expression, is frequently observed in hematological cancers. The purpose of the present study was to conduct a genome-wide investigation to examine comprehensively whether low level benzene induces DNA methylation alteration in the benzene-exposed workers. Infinium 450K methylation array was used to compare methylation levels of the low level benzene-exposed individuals and health controls and the differentially expressed DNA methylation pattern critical for benzene hematotoxicity were screened. Signal net analysis showed that two key hypomethylated KRAS and RASGRF2 associated with low level benzene exposure were identified. Further, the hypomethylated RASGRF2 gene played central roles through regulation of Rho protein, MAPK, small GTPase mediated signal transduction. While the hypomethylated KRAS gene played important roles through small GTPase, Ras protein, MAPK cascade, Gap junction, Axon guidance, Tight junction, GnRH, T cell receptor signaling pathway, Acute myeloid leukemia, B cell receptor signaling pathway, Chronic myeloid leukemia, ErbB signaling pathway. Our preliminary study indicated that aberrant hypomethylated KRAS and RASGRF2 might be a potential methylated biomarker of low level benzene hematotoxicity.