Origin of Merkel Cell Carcinomas No Longer Murky

Hensin Tsao, MD, PhD

Journal Watch. 2008;7(2) 

Eight of 10 Merkel cell tumors tested showed the presence of a novel polyomavirus.

Although Merkel cell carcinoma (MCC) is rare, it is highly malignant. Research into the etiologic basis of many other skin cancers has progressed significantly, but MCC causation remains obscure. The group that discovered the Kaposi sarcoma herpes virus has now cracked the MCC mystery, finding that 80% of MCCs harbor a novel polyomavirus (an icosahedral dsDNA virus that lacks a lipoprotein envelope). Because of its close association with MCC, the novel entity is designated Merkel cell virus (MCV).

Using a technique termed digital transcriptome subtraction, the investigators used high-throughput sequencing to identify foreign genetic sequences in MCC tumors. One such transcript revealed a foreign sequence that defined a new 5387-base-pair human polyomavirus. The simian polyomavirus SV40 has long been known to induce a malignant phenotype in cell culture systems. In a systematic survey, 8 of 10 MCCs (80%) showed evidence of MCV, compared with only 5 of 59 normal control tissue samples (8%; P<0.0001) and 4 of 25 skin and non-MCC skin tumor samples (16%; P=0.0007). MCV appears to integrate into a single site in the human genome at chromosome 3p14 within the PTPRG locus.

This discovery regarding the pathogenesis of MCCs is exciting news. Just as the large T antigen of SV40 has been shown to be immortalizing, the large T antigen of MCV may also play a carcinogenic role. MCV appears to reproducibly integrate into the PTPRG locus, so it is also possible that disruption of the PTPRG gene is the cancer-causing event. Finally, simultaneous expression of MCV genes and PTPRG inactivation may act together to produce MCC. Much remains to be learned about MCC virus and its relation to MCC and possibly to other cancers. Here is another piece of evidence showing that ubiquitous viruses cause more than just the sniffles.

— Hensin Tsao, MD, PhD

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