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.
Highlights
The pathogenic effect of viruses has led to the misconception that viruses could only be harmful, with scientific research being oriented in this direction for many years
In the era of the implementation of Human Papillomavirus (HPV) vaccinations, when the elimination of cervical cancer as a major public health issue is feasible, the genotype replacement by HPV types not included in the available vaccines is an ongoing subject of research and there is no clear evidence suggesting toward this direction [82, 83], according to a transmission model by Man et al, it is still early to make clear inferences about the potential of an HPV genotype replacement, as this will depend on the ecological competition between HPV types in the community, “cross-protection” of vaccine-covered genotypes and natural immunity of the host [84]
One of the most important polyomaviruses with an oncogenic potential is the recently discovered Merkel-Cell Polyoma Virus (MCPyV), which is found in about 80% of Merkel Cell Carcinomas (MCC) [89] and MCPyV induces its carcinogenic potential mainly through its large T antigen (LT)- full-length LT and truncated LT antigen mutation - which is a hallmark of MCC tissue, its small T antigen and the integration of the viral DNA into the host’s genome (Figure 2) [89, 90]
Summary
The pathogenic effect of viruses has led to the misconception that viruses could only be harmful, with scientific research being oriented in this direction for many years. We know that viruses are neither necessary nor sufficient to cause cancer, research has led to linking viruses with the development of cancer and the foundation of cancer biology. According to the International Agency for Research on Cancer (IARC), seven viruses have been characterized as Group 1 carcinogens for humans but their part in cancer pathogenesis seems to vary among different viruses and different disease forms [4, 5]. While tumorigenesis might be seen as an underachieved adaptation, the preservation of oncoproteins in tumor-viruses, as demonstrated by phylogenetic analyses, suggests the evolutionary advantages of viruses as life forms and the coevolutionary dynamics in the virus-host interaction during chronic infection leading to carcinogenesis. The development of HTS has provided a more detailed perspective on the understanding of the virus-cancer link, concerning viral types and geographic prevalence of viruses and related malignancies. Metagenomic pipelines have been designed for the detection of viral species and quantification of their gene
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