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Oncogenic Merkel Cell Polyomavirus T Antigen Truncating Mutations are Mediated by APOBEC3 Activity in Merkel Cell Carcinoma
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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Association for Cancer Research
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10035372/ https://www.ncbi.nlm.nih.gov/pubmed/36970060 http://dx.doi.org/10.1158/2767-9764.CRC-22-0211 |
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author | Soikkeli, Anni I. Kyläniemi, Minna K. Sihto, Harri Alinikula, Jukka |
author_facet | Soikkeli, Anni I. Kyläniemi, Minna K. Sihto, Harri Alinikula, Jukka |
author_sort | Soikkeli, Anni I. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10035372 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-100353722023-03-24 Oncogenic Merkel Cell Polyomavirus T Antigen Truncating Mutations are Mediated by APOBEC3 Activity in Merkel Cell Carcinoma Soikkeli, Anni I. Kyläniemi, Minna K. Sihto, Harri Alinikula, Jukka Cancer Res Commun Research Article 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. American Association for Cancer Research 2022-11-04 /pmc/articles/PMC10035372/ /pubmed/36970060 http://dx.doi.org/10.1158/2767-9764.CRC-22-0211 Text en © 2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by/4.0/This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license. |
spellingShingle | Research Article Soikkeli, Anni I. Kyläniemi, Minna K. Sihto, Harri Alinikula, Jukka Oncogenic Merkel Cell Polyomavirus T Antigen Truncating Mutations are Mediated by APOBEC3 Activity in Merkel Cell Carcinoma |
title | Oncogenic Merkel Cell Polyomavirus T Antigen Truncating Mutations are Mediated by APOBEC3 Activity in Merkel Cell Carcinoma |
title_full | Oncogenic Merkel Cell Polyomavirus T Antigen Truncating Mutations are Mediated by APOBEC3 Activity in Merkel Cell Carcinoma |
title_fullStr | Oncogenic Merkel Cell Polyomavirus T Antigen Truncating Mutations are Mediated by APOBEC3 Activity in Merkel Cell Carcinoma |
title_full_unstemmed | Oncogenic Merkel Cell Polyomavirus T Antigen Truncating Mutations are Mediated by APOBEC3 Activity in Merkel Cell Carcinoma |
title_short | Oncogenic Merkel Cell Polyomavirus T Antigen Truncating Mutations are Mediated by APOBEC3 Activity in Merkel Cell Carcinoma |
title_sort | oncogenic merkel cell polyomavirus t antigen truncating mutations are mediated by apobec3 activity in merkel cell carcinoma |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10035372/ https://www.ncbi.nlm.nih.gov/pubmed/36970060 http://dx.doi.org/10.1158/2767-9764.CRC-22-0211 |
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