Throughout most of the 20th Century, the question of cancer causation divided oncologists between the infectious and the mutation fields. Both sides counted innumerable pieces of evidence in their favor, but the mutation theory of the origins of cancer eventually won the contest and constitutes now the paradigm in oncology.

Nonetheless, a number of human malignant tumors are caused, in part, by infections. Among these are most carcinomas of the uterine cervix, many oral and liver cancers, Burkitt's lymphoma, Kaposi's sarcoma, and a number of others. Still more malignancies are suspected to have a partially infectious origin, though this contention has not yet been proved. One example in point is prostate cancer, whose incidence is higher in men with a history of venereal diseases and risky sexual behavior.

It is legitimate to ask the question: how many and which other human tumors are caused — if only in part — by microorganisms? Answers to such question would carry inestimable medical value. Infectious diseases are the ones medicine best deals with, thanks to an array of tools ranging from hygiene and vaccines to chemotherapeutic drugs and antibiotics. Converting a neoplasia into an infectious disease would make it much more amenable to prevention and therapy.

Classical tools to identify infectious diseases and their causative agents are blunted in the case of cancer (1). Epidemiology is hindered by the extremely long incubation time — tens of years — between infection and tumor appearance. Furthermore, there is typically only a weak association between infection and cancer, since very few of those infected by a tumorigenic agent develop the corresponding malignancy. Microbiological approaches are also severely impeded by the fact that, in most instances of viral tumorigenesis, the virus cannot be cultured and isolated from the tumor, which only contains fragments of the viral genome.

How, then, can we find potentially unknown tumorigenic microbes and where should we look for them?

In very recent years, high-throughput sequencing technology has provided a potential answer. We can now entirely sequence the genomes and/or transcriptomes of suspicious tumors and look for non-human sequences as clues to tumorigenic agents. Needless to say, most non-human sequences prove to be harmless. Sifting through them in a search for a potential oncogenic agent is no easy task, which anyway ultimately requires external epidemiological and biological validation.

Despite the difficulties, this approach has succeeded once. In 2008, the transcriptome of the rare Merkel cell carcinoma (MCC) was sequenced and, of 400,000 reads, two turned out to belong to a new polyomavirus (2). Now called Merkel cell polyomavirus (MCV or MCPyV), it is widely believed to concur to cause at least a large fraction of these tumors.

Interestingly, this case also indicates where we should start to look for new tumorigenic agents. Much like Kaposi's sarcoma, another virus-induced tumor, MCC incidence is higher in immunodeficient subjects, often transplantation or AIDS patients. It is in these persons, known to be at high risk for both infections and a number of tumors (3,4), that new oncogenic microorganisms should be sought.

The success of the metagenomic approach in the case of MCC, though so far an isolated case, provides a guide for future efforts.

1. Zur Hausen H (2009) The search for infectious causes of human cancers: where and why. Virology 392: 1-10.
2. Feng H, Shuda M, Chang Y, Moore PS (2008) Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 319: 1096-1100.
3. Vajdic CM, McDonald SP, McCredie MR, van Leeuwen MT, Stewart JH, Law M, Chapman JR, Webster AC, Kaldor JM, Grulich AE (2006) Cancer incidence before and after kidney transplantation. JAMA 296: 2823-2831.
4. Schulz TF (2009) Cancer and viral infections in immunocompromised individuals. Int J Cancer 125: 1755-1763.