The Distinctive Mutational Spectra of Polyomavirus-Negative Merkel Cell Carcinoma.
Harms PW, Vats P, Verhaegen ME, Robinson DR, Wu YM, Dhanasekaran SM, Palanisamy N, Siddiqui J, Cao X, Su F, Wang R, Xiao H, Kunju LP, Mehra R, Tomlins SA, Fullen DR, Bichakjian CK, Johnson TM, Dlugosz AA, and Chinnaiyan AM. The distinctive mutational spectra of polyomavirus-negative merkel cell carcinoma. Cancer Res 2015; 75(18):3720-3727.
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