Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy

// Gerald Goh 1, 2 , Trent Walradt 3 , Vladimir Markarov 4 , Astrid Blom 5 , Nadeem Riaz 6, 7 , Ryan Doumani 5 , Krista Stafstrom 5 , Ata Moshiri 5 , Lola Yelistratova 5 , Jonathan Levinsohn 3 , Timothy A. Chan 4, 6 , Paul Nghiem 5, 7, 8 , Richard P. Lifton 1, 2 , Jaehyuk Choi 3, 9, 10 1 Department of Genetics, Yale School of Medicine, New Haven, CT, USA 2 Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT, USA 3 Department of Dermatology, Yale School of Medicine, New Haven, CT, USA 4 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA 5 Department of Dermatology, University of Washington, Seattle, WA, USA 6 Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA 7 Department of Pathology, University of Washington, Seattle, WA, USA 8 Fred Hutchinson Cancer Center, Seattle, WA, USA 9 Department of Dermatology, Veterans Affairs Healthcare, West Haven, CT, USA 10 Current address: Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Correspondence to: Jaehyuk Choi, e-mail: Jaehyuk.choi@northwestern.edu Richard P. Lifton, e-mail: richard.lifton@yale.edu Keywords: Merkel cell carcinoma, merkel cell polyomavirus, TP53, cancer genetics, tumor neoantigens Received: August 27, 2015      Accepted: November 20, 2015      Published: December 07, 2015 ABSTRACT Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine carcinoma, associated with the Merkel cell polyomavirus (MCPyV) in 80% of cases. To define the genetic basis of MCCs, we performed exome sequencing of 49 MCCs. We show that MCPyV-negative MCCs have a high mutation burden (median of 1121 somatic single nucleotide variants (SSNVs) per-exome with frequent mutations in RB1 and TP53 and additional damaging mutations in genes in the chromatin modification ( ASXL1, MLL2 , and MLL3 ), JNK ( MAP3K1 and TRAF7 ), and DNA-damage pathways ( ATM, MSH2 , and BRCA1 ). In contrast, MCPyV-positive MCCs harbor few SSNVs (median of 12.5 SSNVs/tumor) with none in the genes listed above. In both subgroups, there are rare cancer-promoting mutations predicted to activate the PI3K pathway ( HRAS, KRAS, PIK3CA, PTEN , and TSC1 ) and to inactivate the Notch pathway ( Notch1 and Notch2 ). TP53 mutations appear to be clinically relevant in virus-negative MCCs as 37% of these tumors harbor potentially targetable gain-of-function mutations in TP53 at p.R248 and p.P278. Moreover, TP53 mutational status predicts death in early stage MCC (5-year survival in TP53 mutant vs wild-type stage I and II MCCs is 20% vs. 92%, respectively; P = 0.0036). Lastly, we identified the tumor neoantigens in MCPyV-negative and MCPyV-positive MCCs. We found that virus-negative MCCs harbor more tumor neoantigens than melanomas or non-small cell lung cancers (median of 173, 65, and 111 neoantigens/sample, respectively), two cancers for which immune checkpoint blockade can produce durable clinical responses. Collectively, these data support the use of immunotherapies for virus-negative MCCs.