Fundamental differences exist between human cancers and genetically engineered mice

A specific epigenetic modification may be fundamentally different between primary human medulloblastomas and genetically engineered mouse models (GEMMs) of medulloblastoma, according to a new study.

Development of cancer is a multistep process that involves complex interactions between genes and epigenetic information. Epigenetic changes modify gene expression at the molecular level without altering the DNA sequence. DNA methylation, where the small chemical group known as methane is added to DNA, is one type of epigenetic modification.

Primary human medulloblastomas have extensive DNA hypermethylation in critical developmental pathways. However, when genome-wide DNA methylation was examined in three different mouse models of medulloblastoma, very few loci with DNA hypermethylation were detected. The degree of methylation was modest compared with the dense hypermethylation in the human cancers, according to a study published in Epigenetics (2013; doi:10.4161/epi.26486) by Scott J. Diede, MD, PhD, and colleagues of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

GEMMs of cancer have been used to study many aspects of cancer biology in humans including early detection, metastasis, targeted therapeutic agents, drug resistance, and cancer prevention. Most cancer GEMMs either have overexpressed oncogenes or targeted deletions of tumor suppressor genes. Few studies report genome-wide DNA methylation in GEMMs.

This study also found that DNA methylation was not increased in two other GEMMs of Burkitt lymphoma and breast cancer. These results suggest that human cancers and at least some GEMMs are fundamentally different with respect to DNA methylation.

DNA hypermethylation appears to be an early step in the process of immortalization in both mouse and human fibroblasts. This may be part of the mechanism for bypassing senescence, which is the process of stopping cellular replication. Senescence serves as an important barrier to cancer development.In mice, chronic inflammatory states can lead to tumor formation. Global changes in DNA methylation may be an early event in the pathway from chronic inflammatory states to the development of cancer.

The full significance of the differences in methylation between primary human medulloblastomas and GEMMs of medulloblastomas is not known. Further studies are needed to examine the mechanisms of aberrant DNA methylation in human cancer and construct better mouse models of human cancer.

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