Nucleic acid-based discovery of human cancer viruses began with zur Hausen’s identification of HPV16 and HPV18 and carried on later, through various modified methods, by Houghton in discovery of HCV and by our laboratory (Chang and Moore) in discovery of Kaposi sarcoma herpesvirus (KSHV) and Merkel cell polyomavirus (MCV). MCV was the first human pathogen discovered in 2007 by a nondirected transcriptomic search, using a method called digital transcriptome subtraction (DTS) but this approach is now readily available to almost any laboratory.
Each cancer virus discovery has opened new highlights in cancer biology. KSHV for example revealed the critical importance of rigorous epidemiology and showed the dual nature of tumor suppressor and innate immune signaling. MCV represents an unambiguous example in which mutations to the microbiome initiates carcinogenesis rather than mutations to the host cell itself. Sequencing can also rule out a persistent cancer virus as a cause for cancer when one is not found. Using this and other genome analyses, 11 new human polyomaviruses have been discovered over the past 6 years. But the hypersensitivity of sequencing (<0.01 ppm) opens the possibility of sequencing contamination as a major source for false-positive cancer virus discovery. Finally, some cancers likely to have an infectious origin, such as post-transplant non-melanoma skin cancers, but have failed to yield a new cancer agent. Understanding their origins may require development of new technologies and new approaches to causality.
