Oncogenic Merkel Cell Polyomavirus T Antigen Truncating Mutations are Mediated by APOBEC3 Activity in Merkel Cell Carcinoma.

Abstract

Merkel cell carcinoma (MCC) is an aggressive skin cancer, which is frequently caused by Merkel cell polyomavirus (MCPyV). Mutations of MCPyV tumor (T) antigens are major pathologic events of virus-positive (MCPyV+) MCCs, but their source is unclear. Activation-induced cytidine deaminase (AID)/APOBEC family cytidine deaminases contribute to antiviral immunity by mutating viral genomes and are potential carcinogenic mutators. We studied the contribution of AID/APOBEC cytidine deaminases to MCPyV large T (LT) truncation events. The MCPyV LT area in MCCs was enriched with cytosine-targeting mutations, and a strong APOBEC3 mutation signature was observed in MCC sequences. AICDA and APOBEC3 expression were detected in the Finnish MCC sample cohort, and LT expression correlated with APOBEC3H and APOBEC3G. Marginal but statistically significant somatic hypermutation targeting activity was detected in the MCPyV regulatory region. Our results suggest that APOBEC3 cytidine deaminases are a plausible cause of the LT truncating mutations in MCPyV+ MCC, while the role of AID in MCC carcinogenesis is unlikely.

Significance:

We uncover APOBEC3 mutation signature in MCPyV LT that reveals the likely cause of mutations underlying MCPyV+ MCC. We further reveal an expression pattern of APOBECs in a large Finnish MCC sample cohort. Thus, the findings presented here suggest a molecular mechanism underlying an aggressive carcinoma with poor prognosis.

• Authors: Anni I Soikkeli, Minna K Kyläniemi, Harri Sihto, Jukka Alinikula
• Journal: Cancer research communications (Cancer Res Commun) Vol. 2 Issue 11 Pg. 1344-1354 (11 2022) ISSN: 2767-9764 [Electronic] United States
• PMID: 36970060 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Antigens, Viral, Tumor
• Cytidine
• APOBEC Deaminases

Topics

• Humans
• Carcinoma, Merkel Cell (genetics)
• Merkel cell polyomavirus (genetics)
• Antigens, Viral, Tumor (genetics)
• Polyomavirus Infections (genetics)
• Skin Neoplasms (genetics)
• Carcinogenesis (genetics)
• Mutation
• Cytidine
• APOBEC Deaminases (genetics)