Genomic Signatures of Poor Prognosis in Merkel Cell Carcinoma: A Single-Institution Prospective Study

Merkel cell carcinoma (MCC) is an aggressive disease with poor survival outcomes and increasing incidence. There is a clear and present need for enhanced understanding of cellular mechanisms of tumorigenesis, validation of robust genetic signatures predictive of aggressive disease, and novel informatics tools to simplify analysis of Merkel cell polyomavirus (MCPyV)-host genome interactions. Genomic DNA was harvested from 54 MCC tumors for exome sequencing and in-depth genetic profiling of a 226-gene panel. We further developed a robust informatics package (MCPyViewer) optimized for MCPyV integration site analysis with graphical output to simplify usability for end users. Finally, we assessed the prognostic impact of specific genetic signatures on MCC-specific survival in our cohort. Our study included 54 patients (n = 44 MCPyV positive), 11 (20.4%) of whom had died of MCC at last follow-up. Human genes altered at high frequency included LRP1B (n = 10, 18.5%), FAT1 (n = 9, 16.7%), KMT2D (n = 9, 16.7%), and RB1 (n = 7, 13.0%). In 36 of 44 (81.8%) MCPyV-positive tumors, we identified viral integration into the human genome with a median of two events per tumor. In six tumors, MCPyV integrated into Catalogue of Somatic Mutations in Cancer tier 1 or tier 2 cancer-related human genes.

A combined genomics score incorporating tumor mutational burden and copy-number variation was strongly prognostic of MCC-specific survival controlling for lymph node metastases and tumor MCPyV status; thus, our study adds critical understanding to prognostic markers and tumorigenic mechanisms in MCC.