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

Abstract

<div>Abstract<p>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, viral-negative 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 viral-negative 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 (<i>n</i> = 13) and -negative (<i>n</i> = 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 <i>RB1</i>, <i>TP53</i>, and a high frequency of mutations in <i>NOTCH1</i> and <i>FAT1</i>. Additional mutated or amplified cancer genes of potential clinical importance included PI3K (<i>PIK3CA</i>, <i>AKT1</i>, <i>PIK3CG</i>) and MAPK (<i>HRAS</i>, <i>NF1</i>) pathway members and the receptor tyrosine kinase <i>FGFR2</i>. 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. <i>Cancer Res; 75(24); 5228–34. ©2015 AACR</i>.</p></div>