UV-Associated Mutations Underlie the Etiology of MCV-Negative Merkel Cell Carcinomas

Abstract

Merkel cell carcinoma (MCC) is an uncommon, but highly malignant, cutaneous tumor. Merkel cell polyoma virus (MCV) has been implicated in a majority of MCC tumors; however, viralnegative tumors have been reported to be more prevalent in some geographic regions subject to high sun exposure. While the impact of MCV and viral T-antigens on MCC development has been extensively investigated, little is known about the etiology of viralnegative tumors. We performed targeted capture and massively parallel DNA sequencing of 619 cancer genes to compare the gene mutations and copy number alterations in MCV-positive (n ¼ 13) and -negative (n ¼ 21) MCC tumors and cell lines. We found that MCV-positive tumors displayed very low mutation rates, but MCV-negative tumors exhibited a high mutation burden associated with a UV-induced DNA damage signature. All viral-negative tumors harbored mutations in RB1, TP53, and a high frequency of mutations in NOTCH1 and FAT1. Additional mutated or amplified cancer genes of potential clinical importance included PI3K (PIK3CA, AKT1, PIK3CG) and MAPK (HRAS, NF1) pathway members and the receptor tyrosine kinase FGFR2. Furthermore, looking ahead to potential therapeutic strategies encompassing immune checkpoint inhibitors such as anti-PD-L1, we also assessed the status of T-cell-infiltrating lymphocytes (TIL) and PD-L1 in MCC tumors. A subset of viral-negative tumors exhibited high TILs and PD-L1 expression, corresponding with the higher mutation load within these cancers. Taken together, this study provides new insights into the underlying biology of viral-negative MCC and paves the road for further investigation into new treatment opportunities. Cancer Res; 75(24); 5228-34. Ó2015 AACR.

Rationale For Immune-Based Therapies in Merkel Polyomavirus-Positive and -Negative Merkel Cell Carcinomas

“…Specifically, several recent studies have shown that MCPyV-negative MCCs have a very high mutation burden (median 1,121 somatic single nucleotide variants per exome). These are dominated by C > T transitions, characteristic of UV-induced DNA damage [88][89][90]. This UV-induced signature was not observed in MCPyV-positive tumors and the mutation burden was 19-fold lower (median 12.5 somatic single nucleotide variants per exome) indicating that these tumor types arise through distinct mechanisms [88][89][90].…”

“…Conversely, several others have reported no significant survival difference between the two groups [85][86][87]. Importantly, genetic analysis indicates that these two subsets are etiologically distinct [88][89][90]. Specifically, several recent studies have shown that MCPyV-negative MCCs have a very high mutation burden (median 1,121 somatic single nucleotide variants per exome).…”

“…Strikingly, on average, MCPyV-negative tumors were found to contain more tumor neoantigens than either melanomas or nonsmall-cell lung cancers suggesting that these virus-negative MCCs have the potential to be highly immunogenic [88]. Furthermore, among virus-negative tumors, a subset expressed PD-L1 and these PD-L1-positive tumors harbor a higher mutational burden as compared with PD-L1-negative tumors, which may reflect immune recognition within these tumors [89]. Notably there were also varying grades of TIL within virus-negative tumors and an increased TIL infiltration correlated with improved survival, as has been described for MCC more generally [46,48,89].…”

Age and Gender Associations of Virus Positivity in Merkel Cell Carcinoma Characterized Using a Novel RNA In Situ Hybridization Assay

“…MCPyV is a DNA virus that likely mediates tumorigenesis via large T antigen (LTAg) binding to the tumor suppressor RB1 and small T antigen (sTAg) upregulation of oncoprotein stability and mTOR activation (1,2). Unlike MCPyV-positive tumors, MCPyV-negative MCC tumors display high mutation burdens, TP53 and RB1 mutations, and UV-signature mutational profiles, suggesting a molecular dichotomy between MCPyV-positive and MCPyV-negative tumors that may have translational relevance (4)(5)(6)(7).…”

Merkelzellkarzinom: kutane Manifestation einer hochmalignen Prä-/pro-B-Zell-Neoplasie?

“…Etwa 80 % der MZK sind assoziiert mit dem Merkelzell-Polyomavirus (MCPyV), das 2008 identifiziert wurde [15]. Die übri-gen 20 % der MZK sind MCPyV-negativ und zeichnen sich durch charakteristische UV-assoziierte Schäden auf genomischer Ebene aus [16,17] "Prä-/pro-B-Zell"-Hypothese: B-Vorläuferzellen als zellulärer Ursprung der Merkelzellkarzinome Sowohl der morphologisch blastäre Phä-notyp als auch das immunhistochemische Expressionsmuster (TdT-, PAX-5-und CD56-Expression) können da-zu führen, dass v. a. der intermediäre Typ der MZK mit kutanen Manifestationen lymphoproliferativer Neoplasien verwechselt wird [30,31]. Buresh et al [32] …”