Abstract B20: Malignant transformation initiates a stochastic DNA methylation alteration pattern distinct from that in senescence

Abstract

Abstract DNA methylation changes are a hallmark of cancers and occur during early tumorigenesis stages. Also, distinct DNA methylation patterns are reported to be characteristic of the anti-tumorigenic process of cell senescence. It is hypothesized that some cells escape senescence and retain the DNA methylation abnormalities manifest in cancers. We now re-visit, in a classic model of tumor progression in human fibroblasts, the relationships between genome-wide DNA methylation patterns associated with senescence, immortalization and transformation. We find that although DNA methylation alterations are a key feature during senescence, these changes are distinct from those we now find associated with malignant transformation in our model and which are classically seen in cancer. Both DNA methylation gains, predominantly at promoter CpG islands, and more balanced losses and gains at other loci, are seen by the time of pre-senescence and remain relatively stable until full senescence is reached. These DNA methylation alterations follow a reproducible pattern amongst independent senescent replicates involving genes in biological processes which positively regulate biosynthesis, gene transcription and macromolecule metabolism. In contrast, during immortalization and malignant transformation, the DNA methylation alterations appear to arise in a stochastic process resulting in heterogeneous methylation patterns amongst independently immortalized and transformed replicates. Gene ontology analysis shows that genes which gain DNA methylation in normally unmethylated promoter CpG island regions in independent transformation replicates enrich for functions involved in developmental regulation. Over the course of progression from immortalization to the transformed state in our model, gene promoter CpG island hypermethylation frequency increases, as does the numbers of associated genes that have decreased gene expression. Thus, a hallmark of the early transformation process is a stochastic accumulation of DNA methylation changes, distinct from those occurring during senescence, that converges to increasingly affect developmental biological processes and diminished transcription of many of the involved genes, which may help drive the process of tumor progression. Citation Format: Wenbing Xie, Yang W. Zhang, Li-Xia Pan, Fillipe Carvlho, Byung-Hak Kang, Limin Xia, Lauren Murphy, Cynthia A. Zahnow, Stephen B. Baylin, Hari Easwaran. Malignant transformation initiates a stochastic DNA methylation alteration pattern distinct from that in senescence. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr B20.