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 (MCV) or UV-linked mutations. MCV is found integrated into MCC tumor genomes, accompanied by truncation mutations that render the MCV large T antigen replication incompetent. We used the open access HPV Detector/ Cancervirus Detector tool to determine the MCV integration sites in whole exome sequencing data from 5 MCC cases, thereby adding to the limited published MCV integration site junction data. We also systematically reviewed published data on integration for MCV in the human genome, presenting a collation of 123 MCC cases and their linked chromosomal sites. We confirm that there are no highly recurrent specific sites of integration. We found that, chromosome 5 is the chromosome most frequently involved by MCV integration and that integration sites are 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 integration involving the tumor suppressor gene KMT2D for the first time, adding to previous reports of rare MCV integration into host tumor suppressor genes in MCC.