Diverse Repetitive Element RNA Expression Define Epigenetic and Immunologic Features of Colon Cancer

ABSTRACT: There is tremendous excitement for the potential of epigenetic therapies in cancer, but the ability to predict and monitor response to these drugs remains elusive. This is in part due to the inability to differentiate the direct cytotoxic and the immunomodulatory effects of these drugs on cancers. The DNA hypomethylating agent 5-azacytdine (AZA) has shown these distinct effects in a variety of cancers, and appears to be linked to the de-repression of repetitive element RNA. Although AZA generally induces global de-repression of repeats, we have found that there is significant diversity of repeat behavior that has not been well characterized in cancer. LINE and HERV are two of the largest classes of repeat elements in the human genome, and despite many commonalities, we find there is heterogeneity in behavior amongst different subtypes of repeats. Specifically, the LINE-1 and HERV-H subtypes were found to be abundant across colon cancers by RNA-seq and RNA in situ hybridization, but had distinct expression patterns, which suggested that these repeats are correlated to transcriptional programs marking different biological states in cancer cells. We find that low LINE-1 expression correlates with global DNA hypermethylation, wildtype TP53 status, and responsiveness to AZA. HERV-H repeats were not concordant with LINE-1 expression, but were found to be linked with differences in FOXP3+ regulatory T-cell tumor infiltrates. Together, distinct repeat RNA expression patterns define new molecular classifications of colon cancer and provide biomarkers that better distinguish cytotoxic from immunomodulatory effects by epigenetic drugs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE90966 | GEO | 2017/08/01

SECONDARY ACCESSION(S): PRJNA356457

REPOSITORIES: GEO