The landscape of viral associations in human cancers

Abstract

Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, for which whole-genome and-for a subset-whole-transcriptome sequencing data from 2,658 cancers across 38 tumor types was aggregated, we systematically investigated potential viral pathogens using a consensus approach that integrated three independent pipelines. Viruses were detected in 382 genome and 68 transcriptome datasets. We found a high prevalence of known tumor-associated viruses such as Epstein-Barr virus (EBV), hepatitis B virus (HBV) and human papilloma virus (HPV; for example, HPV16 or HPV18). The study revealed significant exclusivity of HPV and driver mutations in head-and-neck cancer and the association of HPV with APOBEC mutational signatures, which suggests that impaired antiviral defense is a driving force in cervical, bladder and headand-neck carcinoma. For HBV, HPV16, HPV18 and adeno-associated virus-2 (AAV2), viral integration was associated with local variations in genomic copy numbers. Integrations at the TERT promoter were associated with high telomerase expression evidently activating this tumor-driving process. High levels of endogenous retrovirus (ERV1) expression were linked to a worse survival outcome in patients with kidney cancer.

Characterization of the mechanism by which the RB/E2F pathway controls expression of the cancer genomic DNA deaminase APOBEC3B

“…For instance, the HPV E7 and PyV TAg oncoproteins may trigger A3B upregulation directly by dissociating repressive E2F complexes. Accordingly, cervical cancers are almost invariably HPV-positive, A3B-overexpressing, and enriched for APOBEC signature mutations (Burns, Temiz, et al, 2013;Cancer Genome Atlas Research et al, 2017;Roberts et al, 2013;Zapatka et al, 2020). HPV-positive head/neck cancers also show A3Boverexpression and APOBEC mutation signature enrichment (Burns, Temiz, et al, 2013;Cancer Genome Atlas, 2015;Cannataro et al, 2019;Faden et al, 2017;Roberts et al, 2013;Vieira et al, 2014;Zapatka et al, 2020).…”

“…Accordingly, cervical cancers are almost invariably HPV-positive, A3B-overexpressing, and enriched for APOBEC signature mutations (Burns, Temiz, et al, 2013;Cancer Genome Atlas Research et al, 2017;Roberts et al, 2013;Zapatka et al, 2020). HPV-positive head/neck cancers also show A3Boverexpression and APOBEC mutation signature enrichment (Burns, Temiz, et al, 2013;Cancer Genome Atlas, 2015;Cannataro et al, 2019;Faden et al, 2017;Roberts et al, 2013;Vieira et al, 2014;Zapatka et al, 2020). Importantly, many HPV-negative cancers elicit similarly high A3B expression levels and APOBEC mutation burdens (Burns, Temiz, et al, 2013;Cancer Genome Atlas, 2015;Cannataro et al, 2019;Gillison et al, 2019).…”

“…Importantly, many HPV-negative cancers elicit similarly high A3B expression levels and APOBEC mutation burdens (Burns, Temiz, et al, 2013;Cancer Genome Atlas, 2015;Cannataro et al, 2019;Gillison et al, 2019). Moreover, HPV status in head/neck cancer appears mutually exclusive with alterations of RB/E2F axis genes, such that HPV-negative cancers often display copy number loss of CDKN2A (encoding p16) and overexpression of CCND1 (encoding Cyclin D1) (Cancer Genome Atlas, 2015; Gillison et al, 2019;Zapatka et al, 2020), which effectively mimics a subset of the oncogenic effects of E7.…”

High MHC-II expression in Epstein–Barr virus-associated gastric cancers suggests that tumor cells serve an important role in antigen presentation

“…nuclear antigen 1 (EBNA-1), and sensitive methods detect the mRNA expression of other latency-associated genes 9,10,12 . Importantly, mRNAs for a subset of EBV lytic genes, as well as many viral miRNAs are also frequently detected in EBVaGCs 10,12,13 .…”

Contribution of Macrophages and T Cells in Skeletal Metastasis

“…Mutations are not the only source of tumor-specific antigens (TSA). Viruses were detected in~17% of the datasets of the Pan-Cancer Analysis of Whole Genomes Consortium, mostly human papilloma (HPV), hepatitis B (HBV), and Epstein-Barr viruses (EBV) [206]. Viral proteins such as E6 and E7 for HPV or EBNA-1 for EBV can lead to the detection of viral antigens, and a specific immune response [207,208].…”