Oncotarget

Research Papers:

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

Gerald Goh, Trent Walradt, Vladimir Markarov, Astrid Blom, Nadeem Riaz, Ryan Doumani, Krista Stafstrom, Ata Moshiri, Lola Yelistratova, Jonathan Levinsohn, Timothy A. Chan, Paul Nghiem, Richard P. Lifton, Jaehyuk Choi _

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Oncotarget. 2016; 7:3403-3415. doi: 10.18632/oncotarget.6494

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Abstract

Gerald Goh1,2, Trent Walradt3, Vladimir Markarov4, Astrid Blom5, Nadeem Riaz6,7, Ryan Doumani5, Krista Stafstrom5, Ata Moshiri5, Lola Yelistratova5, Jonathan Levinsohn3, Timothy A. Chan4,6, Paul Nghiem5,7,8, Richard P. Lifton1,2, Jaehyuk Choi3,9,10

1Department of Genetics, Yale School of Medicine, New Haven, CT, USA

2Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT, USA

3Department of Dermatology, Yale School of Medicine, New Haven, CT, USA

4Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

5Department of Dermatology, University of Washington, Seattle, WA, USA

6Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

7Department of Pathology, University of Washington, Seattle, WA, USA

8Fred Hutchinson Cancer Center, Seattle, WA, USA

9Department of Dermatology, Veterans Affairs Healthcare, West Haven, CT, USA

10Current 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.

Author Information

Gerald Goh

Trent Walradt

Vladimir Markarov

Astrid Blom

Nadeem Riaz

Ryan Doumani

Krista Stafstrom

Ata Moshiri

Lola Yelistratova

Jonathan Levinsohn

Timothy A. Chan

Paul Nghiem

Richard P. Lifton

Jaehyuk Choi
Primary Contact  _


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