title: Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy.
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.
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, CT, USA.|Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Gerald
authors.initials: G
authors.lastname: Goh
authors.affiliation: Department of Dermatology, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Trent
authors.initials: T
authors.lastname: Walradt
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Markarov
authors.affiliation: Department of Dermatology, University of Washington, Seattle, WA, USA.
authors.forename: Astrid
authors.initials: A
authors.lastname: Blom
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Nadeem
authors.initials: N
authors.lastname: Riaz
authors.affiliation: Department of Dermatology, University of Washington, Seattle, WA, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Doumani
authors.affiliation: Department of Dermatology, University of Washington, Seattle, WA, USA.
authors.forename: Krista
authors.initials: K
authors.lastname: Stafstrom
authors.affiliation: Department of Dermatology, University of Washington, Seattle, WA, USA.
authors.forename: Ata
authors.initials: A
authors.lastname: Moshiri
authors.affiliation: Department of Dermatology, University of Washington, Seattle, WA, USA.
authors.forename: Lola
authors.initials: L
authors.lastname: Yelistratova
authors.affiliation: Department of Dermatology, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Levinsohn
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
authors.affiliation: Department of Dermatology, University of Washington, Seattle, WA, USA.|Department of Pathology, University of Washington, Seattle, WA, USA.|Fred Hutchinson Cancer Center, Seattle, WA, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Nghiem
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, CT, USA.|Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.affiliation: Department of Dermatology, Yale School of Medicine, New Haven, CT, USA.|Department of Dermatology, Veterans Affairs Healthcare, West Haven, CT, USA.|Current address: Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Jaehyuk
authors.initials: J
authors.lastname: Choi
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D015266:Carcinoma, Merkel Cell / Q000235:genetics* / Q000276:immunology / Q000821:virology; D059472:Exome / Q000235:genetics; D016147:Genes, Tumor Suppressor; D006801:Humans; D007167:Immunotherapy; D059965:Merkel cell polyomavirus / Q000276:immunology*; D009154:Mutation / Q000235:genetics*; D009857:Oncogenes / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics* / Q000276:immunology / Q000821:virology; D014412:Tumor Virus Infections / Q000235:genetics* / Q000276:immunology / Q000821:virology
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger
keywords: Merkel cell carcinoma; Merkel cell polyomavirus; TP53; cancer genetics; tumor neoantigens