PT  - JOURNAL ARTICLE
AU  - Harms, Paul William
AU  - Vats, Pankaj
AU  - Verhaegen, Monique Elise
AU  - Robinson, Dan R.
AU  - Wu, Yi-Mi
AU  - Dhanasekaran, Saravana Mohan
AU  - Palanisamy, Nallasivam
AU  - Siddiqui, Javed
AU  - Cao, Xuhong
AU  - Su, Fengyun
AU  - Wang, Rui
AU  - Xiao, Hong
AU  - Kunju, Lakshmi P.
AU  - Mehra, Rohit
AU  - Tomlins, Scott A.
AU  - Fullen, Douglas Randall
AU  - Bichakjian, Christopher Keram
AU  - Johnson, Timothy M
AU  - Dlugosz, Andrzej Antoni
AU  - Chinnaiyan, Arul M.
TI  - The Distinctive Mutational Spectra of Polyomavirus-Negative Merkel Cell Carcinoma
AID  - 10.1158/0008-5472.CAN-15-0702
DP  - 2015 Aug 03
TA  - Cancer Research
PG  - canres.0702.2015
4099  - http://cancerres.aacrjournals.org/content/early/2015/08/01/0008-5472.CAN-15-0702.short
4100  - http://cancerres.aacrjournals.org/content/early/2015/08/01/0008-5472.CAN-15-0702.full
AB  - 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.