Endogenous Retrovirus Transcript Levels Are Associated with Immunogenic Signatures in Multiple Metastatic Cancer Types

Abstract

◥Next-generation sequencing of solid tumors has revealed variable signatures of immunogenicity across tumors, but underlying molecular characteristics driving such variation are not fully understood. Although expression of endogenous retrovirus (ERV)-containing transcripts can provide a source of tumor-specific neoantigen in some cancer models, associations between ERV levels and immunogenicity across different types of metastatic cancer are not well established. We performed bioinformatics analysis of genomic, transcriptomic, and clinical data across an integrated cohort of 199 patients with metastatic breast, colorectal, and pancreatic ductal adenocarcinoma tumors. Within each cancer type, we identified a subgroup of viral mimicry tumors in which increased ERV levels were coupled with transcriptional signatures of autonomous antiviral response and immunogenicity. In addition, viral mimicry colorectal and pancreatic tumors showed increased expression of DNA demethylation gene TET2. Taken together, these data demonstrate the existence of an ERV-associated viral mimicry phenotype across three distinct metastatic cancer types, while indicating links between ERV abundance, epigenetic dysregulation, and immunogenicity.

Evolutionary analysis of endogenous intronic retroviruses in primates reveals an enrichment in transcription binding sites associated with key regulatory processes

“…In addition, the clinical variants annotated in the ERV regions coincide with variants associated with tumors, reinforcing the idea that the analyzed ERV sections have important roles in cell cycle regulation and their misregulation leads to cancer. In agreement with these observations, several authors have described an association between ERVs and cancer; moreover, this relationship is explained by ERV activation ( Ibba et al, 2018 ; Topham et al, 2020 ). Following our data, another possibility for disrupting the cell cycle and producing tumors could be through TFBS mutations that prevent TFs from binding to DNA.…”

Association between ten-eleven methylcytosine dioxygenase 2 genetic variation and viral load in people with HIV

“…The SNPs themselves are in high LD and are spread out across the TET2 gene (although those associated with higher HIV-VL tend to congregate in the 5’ end of TET2). Given the previous evidence associating TET2 with transcriptional regulation of endogenous retroviral elements [ 29 – 31 ], it may be that TET2 is playing a role in transcriptional regulation of HIV. Alternatively, previously studies have suggested two independent mechanisms for TET2 related enhancement of HIV-VL, mediated through the VPR.…”

Locus-Specific Characterization of Human Endogenous Retrovirus Expression in Prostate, Breast, and Colon Cancers

“…Here, TET and APOBEC genes-which are important to DNA demethylation pathways-were differentially expressed in all three cancer types. Previous work has associated TET2 overexpression with increased HERV expression and antiviral immune response signatures (27), suggesting a link between demethylation and HERV activation in cancer. TET2 was downregulated in COAD, while TET3 was upregulated in BRCA and PRAD, with TET1 also being upregulated in PRAD.…”

“…HERV expression has also been shown to contribute to immunomodulation of host cells and HERVs have been implicated in the regulation of innate immunity (25,26). Furthermore, a viral mimicry phenotype has been identified in subsets of metastatic tumors, which correspond to increased HERV expression, further suggesting the contribution of HERVs to inflammatory immune responses supporting tumor survival (27). Thus, an understanding of host cell factors including epigenetics and immunogenicity, in addition to HERV expression, is highly relevant to translational applications.…”