Merkel cell carcinoma of the skin: pathological and molecular evidence for a causative role of MCV in oncogenesis

Abstract

Merkel cell carcinoma (MCC), a skin tumour with neuroendocrine features, was recently found to be associated with a new type of human polyomavirus, called Merkel cell virus (MCV). We investigated the specificity of this association as well as a causal role of MCV in oncogenesis. DNA and RNA from ten cases of MCC were analysed using PCR and RT-PCR. DNA from 1241 specimens of a wide range of human tumours was also analysed. The DIPS technique was used to identify the integration locus of viral DNA sequences. Array CGH was performed to analyse structural alterations of the cell genome. MCV DNA sequences were found in all ten cases of MCC and in none of the 1241 specimens of other tumour types. Clonal integration of MCV into the host genome was seen in all MCC cases and was checked by FISH in one case. A recurrent pattern of conserved viral sequences which encompassed the replication origin, the small tumour (ST), and the 5' part of the large tumour (LT) antigen DNA sequences was observed. Both ST and LT viral sequences were found to be significantly expressed in all MCCs. Neither recurrent site of integration nor alteration of cellular genes located near the viral sequences was observed. The tight association of MCV with MCC, the clonal pattern of MCV integration, and the expression of the viral oncoproteins strongly support a causative role for MCV in the tumour process. This information will help the development of novel approaches for the assessment and therapy of MCC and biologically related tumours.

Detection of a novel truncating Merkel cell polyomavirus large T antigen deletion in chronic lymphocytic leukemia cells

“…7,21 The loss of the helicase activity prevents MCPyV replication and clearly indicates that MCPyV is not a passenger virus in the tumor. 17 6 of the 19 MCPyV-positive CLL cases revealed a novel 246 bp deletion within the viral helicase gene ( Figure 1A-B).…”

Retinoblastoma gene mutations detected by whole exome sequencing of Merkel cell carcinoma

“…13,14 Emerging data implicate maintenance and expression of the polyomavirus large T antigen in cell cycle dysregulation and the pathogenesis of viral transformation leading to Merkel cell carcinoma. 12,[15][16][17][18][19][20][21] Although the molecular role of Merkel cell polyomavirus is quickly evolving, the overall biology of Merkel cell carcinoma is poorly understood. Moreover, the presence of polyomavirus alone is not sufficient for carcinogenesis, namely in those Merkel cell carcinoma cases considered as polyomavirusnegative.…”

Polyomavirus Infection in a Free-Ranging California Sea Lion (Zalophus Californianus) with Intestinal T-Cell Lymphoma

“…Although polyomavirus infection has been associated with skin tumors in hamsters and with Merkel cell carcinoma in humans, the relationship between polyomavirus infection and the glossal fibropapilloma in this sea lion is not clear. 6,20 In Merkel cell carcinomas, viral DNA can be detected within tumor cells but not in nonneoplastic cells. 20 As viral particles were noted within only endothelial cells and not within epithelial or stromal cells within the glossal mass, it is possible that neoplasia and severe renal disease caused reactivation of latent viral infection.…”

“…9 In humans, reactivation can occur in immune-suppressed individuals, leading to severe and sometimes fatal disease including hemorrhagic cystitis, progressive multifocal leukoencephalopathy, and Merkel cell carcinoma. 5,9,10,20 Some human polyomaviruses, including Simian virus 40 (SV40), BK polyomavirus, and JC polyomavirus, can cause cancer in animal models or neoplastic transformation of cell cultures. 15 Hamster polyomavirus is associated with skin tumors.…”