Title

The Distinctive Mutational Spectra of Polyomavirus-Negative Merkel Cell Carcinoma.

Document Type

Article

Publication Date

9-15-2015

Publication Title

Cancer research

Abstract

Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine tumor. Merkel cell polyomavirus (MCPyV) may contribute to tumorigenesis in a subset of tumors via inhibition of tumor suppressors such as retinoblastoma (RB1) by mutated viral T antigens, but the molecular pathogenesis of MCPyV-negative MCC is largely unexplored. Through our MI-ONCOSEQ precision oncology study, we performed integrative sequencing on two cases of MCPyV-negative MCC, as well as a validation cohort of 14 additional MCC cases (n = 16). In addition to previously identified mutations in TP53, RB1, and PIK3CA, we discovered activating mutations of oncogenes, including HRAS and loss-of-function mutations in PRUNE2 and NOTCH family genes in MCPyV-negative MCC. MCPyV-negative tumors also displayed high overall mutation burden (10.09 ± 2.32 mutations/Mb) and were characterized by a prominent UV-signature pattern with C > T transitions comprising 85% of mutations. In contrast, mutation burden was low in MCPyV-positive tumors (0.40 ± 0.09 mutations/Mb) and lacked a UV signature. These findings suggest a potential ontologic dichotomy in MCC, characterized by either viral-dependent or UV-dependent tumorigenic pathways.

Medical Subject Headings

Aged; Carcinoma, Merkel Cell; Carrier Proteins; Cell Transformation, Neoplastic; DNA Mutational Analysis; DNA, Neoplasm; Exome; Gene Expression Profiling; Humans; Male; Membrane Proteins; Merkel cell polyomavirus; Middle Aged; Mutation; Neoplasm Proteins; Neoplasms, Radiation-Induced; Nerve Tissue Proteins; Oncogene Proteins, Fusion; Oncogenes; Parotid Neoplasms; Point Mutation; Receptors, Notch; Skin Neoplasms; Ultraviolet Rays

PubMed ID

26238782

Volume

75

Issue

18

First Page

3720

Last Page

3727

Share

COinS