Merkel Cell Polyomavirus in Merkel Cell Carcinoma: Integration Sites and Involvement of the KMT2D Tumor Suppressor Gene

Merkel cell carcinoma (MCC) is an uncommon, lethal cancer of the skin caused by either Merkel cell polyomavirus (MCPyV) or UV-linked mutations. MCPyV is found integrated into MCC tumor genomes, accompanied by truncation mutations that render the MCPyV large T antigen replication incompetent. We used...

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Main Authors: Reety Arora, Jae Eun Choi, Paul W. Harms, Pratik Chandrani
Format: Article
Language:English
Published: MDPI AG 2020-08-01
Series:Viruses
Subjects:
Online Access:https://www.mdpi.com/1999-4915/12/9/966
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spelling doaj-2315dbf30bc74d1db506fecb6a8703022020-11-25T03:52:11ZengMDPI AGViruses1999-49152020-08-011296696610.3390/v12090966Merkel Cell Polyomavirus in Merkel Cell Carcinoma: Integration Sites and Involvement of the KMT2D Tumor Suppressor GeneReety Arora0Jae Eun Choi1Paul W. Harms2Pratik Chandrani3Cellular Organization and Signalling Group, National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore 560065, IndiaDepartment of Pathology, University of Michigan, Ann Arbor, MI 48109, USADepartment of Pathology, University of Michigan, Ann Arbor, MI 48109, USAMedical Oncology Molecular Laboratory, Medical Oncology Department, Tata Memorial Hospital, Mumbai 400012, IndiaMerkel cell carcinoma (MCC) is an uncommon, lethal cancer of the skin caused by either Merkel cell polyomavirus (MCPyV) or UV-linked mutations. MCPyV is found integrated into MCC tumor genomes, accompanied by truncation mutations that render the MCPyV large T antigen replication incompetent. We used the open access HPV Detector/Cancer-virus Detector tool to determine MCPyV integration sites in whole-exome sequencing data from five MCC cases, thereby adding to the limited published MCPyV integration site junction data. We also systematically reviewed published data on integration for MCPyV in the human genome, presenting a collation of 123 MCC cases and their linked chromosomal sites. We confirmed that there were no highly recurrent specific sites of integration. We found that chromosome 5 was most frequently involved in MCPyV integration and that integration sites were significantly enriched for genes with binding sites for oncogenic transcription factors such as LEF1 and ZEB1, suggesting the possibility of increased open chromatin in these gene sets. Additionally, in one case we found, for the first time, integration involving the tumor suppressor gene <i>KMT2D</i>, adding to previous reports of rare MCPyV integration into host tumor suppressor genes in MCC.https://www.mdpi.com/1999-4915/12/9/966Merkel cell polyomavirusMerkel cell carcinomaviral integrationKMT2D
collection DOAJ
language English
format Article
sources DOAJ
author Reety Arora
Jae Eun Choi
Paul W. Harms
Pratik Chandrani
spellingShingle Reety Arora
Jae Eun Choi
Paul W. Harms
Pratik Chandrani
Merkel Cell Polyomavirus in Merkel Cell Carcinoma: Integration Sites and Involvement of the KMT2D Tumor Suppressor Gene
Viruses
Merkel cell polyomavirus
Merkel cell carcinoma
viral integration
KMT2D
author_facet Reety Arora
Jae Eun Choi
Paul W. Harms
Pratik Chandrani
author_sort Reety Arora
title Merkel Cell Polyomavirus in Merkel Cell Carcinoma: Integration Sites and Involvement of the KMT2D Tumor Suppressor Gene
title_short Merkel Cell Polyomavirus in Merkel Cell Carcinoma: Integration Sites and Involvement of the KMT2D Tumor Suppressor Gene
title_full Merkel Cell Polyomavirus in Merkel Cell Carcinoma: Integration Sites and Involvement of the KMT2D Tumor Suppressor Gene
title_fullStr Merkel Cell Polyomavirus in Merkel Cell Carcinoma: Integration Sites and Involvement of the KMT2D Tumor Suppressor Gene
title_full_unstemmed Merkel Cell Polyomavirus in Merkel Cell Carcinoma: Integration Sites and Involvement of the KMT2D Tumor Suppressor Gene
title_sort merkel cell polyomavirus in merkel cell carcinoma: integration sites and involvement of the kmt2d tumor suppressor gene
publisher MDPI AG
series Viruses
issn 1999-4915
publishDate 2020-08-01
description Merkel cell carcinoma (MCC) is an uncommon, lethal cancer of the skin caused by either Merkel cell polyomavirus (MCPyV) or UV-linked mutations. MCPyV is found integrated into MCC tumor genomes, accompanied by truncation mutations that render the MCPyV large T antigen replication incompetent. We used the open access HPV Detector/Cancer-virus Detector tool to determine MCPyV integration sites in whole-exome sequencing data from five MCC cases, thereby adding to the limited published MCPyV integration site junction data. We also systematically reviewed published data on integration for MCPyV in the human genome, presenting a collation of 123 MCC cases and their linked chromosomal sites. We confirmed that there were no highly recurrent specific sites of integration. We found that chromosome 5 was most frequently involved in MCPyV integration and that integration sites were significantly enriched for genes with binding sites for oncogenic transcription factors such as LEF1 and ZEB1, suggesting the possibility of increased open chromatin in these gene sets. Additionally, in one case we found, for the first time, integration involving the tumor suppressor gene <i>KMT2D</i>, adding to previous reports of rare MCPyV integration into host tumor suppressor genes in MCC.
topic Merkel cell polyomavirus
Merkel cell carcinoma
viral integration
KMT2D
url https://www.mdpi.com/1999-4915/12/9/966
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