Viral Causality of Human Cancer and Potential Roles of Human Endogenous Retroviruses in the Multi-Omics Era: An Evolutionary Epidemiology Review

Abstract

Being responsible for almost 12% of cancers worldwide, viruses are among the oldest known and most prevalent oncogenic agents. The quality of the evidence for the in vivo tumorigenic potential of microorganisms varies, thus accordingly, viruses were classified in 4 evidence-based categories by the International Agency for Research on Cancer in 2009. Since then, our understanding of the role of viruses in cancer has significantly improved, firstly due to the emergence of high throughput sequencing technologies that allowed the “brute-force” recovery of unknown viral genomes. At the same time, multi-omics approaches unravelled novel virus-host interactions in stem-cell biology. We now know that viral elements, either exogenous or endogenous, have multiple sometimes conflicting roles in human pathophysiology and the development of cancer. Here we integrate emerging evidence on viral causality in human cancer from basic mechanisms to clinical studies. We analyze viral tumorigenesis under the scope of deep-in-time human-virus evolutionary relationships and critically comment on the evidence through the eyes of clinical epidemiology, firstly by reviewing recognized oncoviruses and their mechanisms of inducing tumorigenesis, and then by examining the potential role of integrated viruses in our genome in the process of carcinogenesis.

A Systems Biology Approach on the Regulatory Footprint of Human Endogenous Retroviruses (HERVs)

“…HERV genes are associated with ovary, hepatocellular and prostate cancer, as well as lynch syndrome, a hereditary type of nonpolyposis colorectal cancer ( Figure 5 ). The probable involvement of HERVs in cancer is a long-enduring concept [ 68 , 99 , 100 ]. Specifically, HERV transcripts have been found upregulated in prostate [ 101 ], kidney [ 102 ] breast [ 102 , 103 , 104 , 105 ], hepatocellular [ 106 ], ovarian [ 107 ] and colorectal cancer [ 108 , 109 ], as well as in soft tissue sarcoma [ 110 ] and leukemia [ 111 ].…”

Epigenetics and Helicobacter pylori

“…Viral infections contribute to 15-20% of all human cancers [39][40][41]. Hp and Epstein-Barr virus (EBV) are both oncogenic and induce chronic inflammation, which promotes gastric cancer [41]. In addition, Hp and EBV can establish a lifelong infection of the host [42].…”

EBV-associated diseases: Current therapeutics and emerging technologies

“…Oncogenic viruses cause approximately 15-20% of all human cancers ( 1 , 2 ). According to the International Agency for Research on Cancer (IARC), there are seven major human oncogenic viruses ( 3 ). These include DNA viruses, such as Epstein–Barr virus (EBV; also known as HHV4), Kaposi sarcoma-associated herpesvirus (KSHV; also known as HHV8), Hepatitis B virus (HBV), human papillomaviruses (HPV) and Merkel cell polyomavirus (MCPyV) and RNA viruses, such as human T-lymphotropic virus 1 (HTLV-1) and Hepatitis C virus (HCV).…”