# Molecular Characterization of Polyomavirus-Positive and Negative Merkel Cell Carcinoma

## TL;DR

This study compares the molecular profiles of Merkel Cell Carcinoma cases with and without a virus, identifying potential new treatment targets.

## Contribution

The study reveals distinct transcriptomic differences between virus-positive and virus-negative Merkel Cell Carcinoma.

## Key findings

- Higher tumor mutational burden was observed in virus-negative Merkel Cell Carcinoma.
- Virus-negative tumors showed upregulated MAPK Pathway Activity Score and immune checkpoint gene CD276.
- No overall survival difference was found between virus-positive and virus-negative cases after immune checkpoint inhibitors.

## Abstract

Unresectable and metastatic Merkel Cell Carcinoma is treated with immune checkpoint inhibitors, regardless of Merkel Cell polyomavirus status. However, many cases are either refractory to checkpoint inhibition or develop resistance after initial response. There remains an unmet clinical need to identify alternative therapeutic targets. Prior studies have implicated distinct molecular profiles of virus-positive and virus-negative disease. Here, whole exome sequencing confirmed known mutation differences between virus-positive and virus-negative disease, while whole transcriptome sequencing identified key differences in MAPK Pathway Activity Score (MPAS), NK cell infiltration, and expression of immune checkpoint genes.

Background/Objectives: Immune checkpoint inhibitors (ICIs) are frontline treatment for advanced Merkel Cell Carcinoma (MCC), regardless of viral status. Frontline ICIs provide durable benefit to only half of patients, highlighting a need for alternative therapies. In this study, the objective is to leverage whole exome sequencing (WES) and transcriptome sequencing (WTS) to distinguish genomic alterations associated with ICI response. Investigate differential genomic alterations between virus-positive (VP) and virus-negative (VN)-MCC to identify novel therapeutic targets. Methods: A total of 95 MCC cases underwent WES and WTS. Utilizing computational pipelines applied to WES, we identified viral status and tumor mutational burden (TMB). RNA-seq data was used to characterize the immune microenvironment. Results: Of 95 MCC cases, 57 (60%) were VP-MCC and 38 (40%) were VN-MCC. Median TMB was higher in VN-MCC (27.5 vs. 1 Muts/Mb). Mutations in TP53, RB1, NOTCH1, KMTD2, KMT2C, and PIK3CA were primarily found in VN-MCC. MAPK Pathway Activity Score, NK cell infiltration, and the immune checkpoint gene CD276 in VN-MCC tumors were upregulated. No overall survival (OS) difference was identified between VP and VN-MCC, even after ICIs. Conclusions: MCC oncogenesis and treatment response transcend viral status. While mutational analysis confirms previous findings, assessment of the transcriptome and tumor microenvironment suggests alternate therapeutic targets.