Publication in Clinical Cancer Research

 Clin Cancer Res

. 2021 Feb 5;clincanres.0864.2020.

 doi: 10.1158/1078-0432.CCR-20-0864. Online ahead of print.

Virus-positive Merkel cell carcinoma is an independent prognostic group with distinct predictive biomarkers

Kelly Harms 1, Lili Zhao 2, Bryan Johnson 3, Xiaoming Wang 4, Shannon Carskadon 5, Nallasivam Palanisamy 5, Daniel R Rhodes 6, Rahul Mannan 4, Josh Vo 7, Jae Eun Choi 8, May P Chan 9, Douglas R Fullen 7, Rajiv M Patel 7, Javed Siddiqui 7, Vincent T Ma 10, Steven Hrycaj 7, Scott A McLean 11, Tasha M Hughes 12, Christopher K Bichakjian 13, Scott A Tomlins 14, Paul W Harms 15

Affiliations

• 1
  Dermatology, University of Michigan–Ann Arbor.
• 2
  Department of Biostatistics, University of Michigan School of Medicine.
• 3
  Strata Oncology.
• 4
  Pathology, Michigan Center for Translational Pathology, University of Michigan–Ann Arbor.
• 5
  Urology, Henry Ford Health System.
• 6
  Diagnostics, Strata Oncology.
• 7
  Pathology, University of Michigan–Ann Arbor.
• 8
  Pathology, University of Michigan Medical School.
• 9
  Department of Pathology, University of Michigan–Ann Arbor.
• 10
  Internal Medicine and Hematology/Oncology, University of Michigan–Ann Arbor.
• 11
  Otolaryngology-Head and Neck Surgery, University of Michigan–Ann Arbor.
• 12
  Surgery, University of Michigan–Ann Arbor.
• 13
  University of Michigan–Ann Arbor.
• 14
  Department of Pathology, Department of Urology, Michigan Center for Translational Pathology, Comprehensive Cancer Center, University of Michigan–Ann Arbor.
• 15
  Pathology, Dermatology, Michigan Center for Translational Pathology, University of Michigan–Ann Arbor paulharm@med.umich.edu.

• PMID: 33547200
 
• DOI: 10.1158/1078-0432.CCR-20-0864

Abstract

Purpose: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that can be divided into two classes: virus-positive (VP) MCC, associated with oncogenic Merkel cell polyomavirus (MCPyV); and virus-negative (VN) MCC, associated with photodamage.

Experimental design: We classified 346 MCC tumors from 300 patients for MCPyV using a combination of immunohistochemistry, in situ hybridization, and quantitative PCR assays. In a subset of tumors, we profiled mutation status and expression of cancer-relevant genes. MCPyV and molecular profiling results were correlated with disease-specific outcomes. Potential prognostic biomarkers were further validated by immunohistochemistry.

Results: 177 tumors were classified as VP-MCC, 151 tumors were VN-MCC, and 17 tumors were indeterminate. MCPyV positivity in primary tumors was associated with longer disease-specific and recurrence-free survival in univariate analysis, and in multivariate analysis incorporating age, sex, immune status, and stage at presentation. Prioritized oncogene or tumor suppressor mutations were frequent in VN-MCC but rare in VP-MCC. TP53 mutation developed with recurrence in one VP-MCC case. Importantly, for the first time we find that VP-MCC and VN-MCC display distinct sets of prognostic molecular biomarkers. For VP-MCC, shorter survival was associated with decreased expression of immune markers including granzyme and IDO1. For VN-MCC, shorter survival correlated with high expression of several genes including UBE2C Conclusions: MCPyV status is an independent prognostic factor for MCC. Features of the tumor genome, transcriptome, and microenvironment may modify prognosis in a manner specific to viral status. MCPyV status has clinicopathologic significance and allows for identification of additional prognostic subgroups.

Copyright ©2021, American Association for Cancer Research.