Merkel cell polyomavirus in gastrointestinal neuroendocrine tumors

4120 Background: Cutaneous Merkel cell carcinoma (MCC) is a high grade neuroendocrine carcinoma potentially induced by Merkel Cell Polyomavirus (MCPyV), a clonally integrated host in the tumor cell genome. Integration of viral DNA and truncating mutations in the helicase domain of the large T (LT) antigen, a protein implicated in the viral life cycle, have been detected in all MCPyV associated MCCs. These results suggest a role of the virus in tumor pathogenesis according to a two step model: a necessary but not sufficient integration of viral DNA followed by LT antigen premature truncations. Gastrointestinal neuroendocrine tumors (GI-NETs) share common phenotypical features with MCCs, therefore we evaluated whether MCPyVs may be present in GI-NET. Methods: Formalin–fixed and paraffin-embedded samples from 14 cases of liver metastases of G2 GI-NETs, 9 small cell lung cancer (SCLCs) and 4 MCCs of the skin were screened for MCPyV-DNA positivity using two PCR primer sets mapping the LT antigen gene. Then to confirm the putative pathogenetic role of the virus, we seeked for premature truncation of LT antigen by sequencing the helicase portion using seven amplicons mapping 1356-2210 region of the MCPyV complete genome (RefSeq: NC_010277.1). Results: Viral DNA was detected in 7/14 GI-NETs, in 0/9 SCLCs and in 4/4 MCCs. We found a premature stop codon truncating the helicase domain in two GI-NETs. Both the patients had a rapid disease progression. We also found previously not reported alterations in MCCs: a single aminoacid deletion in 3 cases and a point mutation causing a single aminoacid substitution in another case. Conclusions: For the first time the potential tumorigenic signature of MCPyV has been detected in GI-NETs, suggesting a possible role in pathogenesis. The study is ongoing to confirm these observations that could support new diagnostic and therapeutical perspectives of a subset of GI NETs. Moreover we have shown that the clonal integration of MCPyV in MCCs produces different genetic alterations with unknown effects on cell biology.