Cancer Res. 2015 Aug 3. pii: canres.0702.2015. [Epub ahead of print]
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, Chinnaiyan AM.
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 per 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 per 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.
Copyright © 2015, American Association for Cancer Research.
Copyright © 2015, American Association for Cancer Research.
- PMID:26238782[PubMed - as supplied by publisher]
