Abstract
We applied a newly developed bioinformatics system called VirusScan to investigate the viral basis of 6,813 human tumors and 559 adjacent normal samples across 23 cancer types and identified 505 virus positive samples with distinctive, organ system- and cancer type-specific distributions. We found that herpes viruses (e.g., subtypes HHV4, HHV5, and HHV6) that are highly prevalent across cancers of the digestive tract showed significantly higher abundances in tumor versus adjacent normal samples, supporting their association with these cancers. We also found three HPV16-positive samples in brain lower grade glioma (LGG). Further, recurrent HBV integration at the KMT2B locus is present in three liver tumors, but absent in their matched adjacent normal samples, indicating that viral integration induced host driver genetic alterations are required on top of viral oncogene expression for initiation and progression of liver hepatocellular carcinoma. Notably, viral integrations were found in many genes, including novel recurrent HPV integrations at PTPN13 in cervical cancer. Finally, we observed a set of HHV4 and HBV variants strongly associated with ethnic groups, likely due to viral sequence evolution under environmental influences. These findings provide important new insights into viral roles of tumor initiation and progression and potential new therapeutic targets.
Highlights
Much of the community’s collective sequencing capacity has been devoted to cancer genomics over the last several years, with the result being that DNA and RNA data are available for thousands of tumor samples across many different cancer types
We plotted the distribution of 505 virus-positive samples in each cancer type (Fig. 1A), noting that esophageal cancer (ESCA), stomach, colon, and rectal adenocarcinomas (STAD, COAD, and READ), liver hepatocellular carcinoma (LIHC), cervical carcinoma and endocervical adenocarcinoma (CESC), and head/neck squamous cell carcinoma (HNSC) all show frequent viral presence (>5 %)
HHV4 is often present at RPHM > 104 and two STAD samples and one COAD sample are positive for both HHV4 and HHV5
Summary
Much of the community’s collective sequencing capacity has been devoted to cancer genomics over the last several years, with the result being that DNA and RNA data are available for thousands of tumor samples across many different cancer types. Human papillomavirus (HPV), Human hepatitis B and C (HBV and HCV), and Epstein-Barr virus (EBV or HHV4) are all well-known agents of viral-related cancers Other viruses such as human T-cell lymphotropic virus (HTLV), Kaposi’s sarcoma virus (HHV8), Merkel cell polyomavirus (MCV), Human immunodeficiency virus-1 (HIV-1) are associated with cancer[11,12,13]. The Pan-Cancer TCGA data collection is a useful, large-sample resource for studying virus-host interactions and their implications for human cancer. Results have been obtained[23,24], including HPV and HBV integration sites on host genes, but larger-scale studies of viruses in human cancers are otherwise limited. Three important issues are explicitly addressed in the present study: 1) differential viral expression and integration patterns between tumors and adjacent normal samples, 2) the discovery and implications of novel rare viral insertions and 3) differences among ethnicities that may point to environmental influences on viral sequence evolution. Our findings extend previous work and provide new insights to virus infection, viral gene expression, integration, and virus variants across different cancer types
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