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*

*Corresponding author for this work

Research output: Contribution to journalArticle

123 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3403-3415
Number of pages13
JournalOncotarget
Volume7
Issue number3
DOIs
StatePublished - Jan 1 2016

Fingerprint

Merkel cell polyomavirus
Merkel Cell Carcinoma
Immunotherapy
Mutation
Exome
Neoplasms
Nucleotides
Viruses
Neuroendocrine Carcinoma
Phosphatidylinositol 3-Kinases
Non-Small Cell Lung Carcinoma
Genes
DNA Damage
Chromatin
Melanoma
Skin

Keywords

  • Cancer genetics
  • Merkel cell carcinoma
  • Merkel cell polyomavirus
  • TP53
  • Tumor neoantigens

ASJC Scopus subject areas

  • Oncology

Cite this

Goh, Gerald ; Walradt, Trent ; Markarov, Vladimir ; Blom, Astrid ; Riaz, Nadeem ; Doumani, Ryan ; Stafstrom, Krista ; Moshiri, Ata ; Yelistratova, Lola ; Levinsohn, Jonathan ; Chan, Timothy A. ; Nghiem, Paul ; Lifton, Richard P. ; Choi, Jaehyuk. / Mutational landscape of MCPyV-positive and MCPyV-negative merkel cell carcinomas with implications for immunotherapy. In: Oncotarget. 2016 ; Vol. 7, No. 3. pp. 3403-3415.
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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.",
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author = "Gerald Goh and Trent Walradt and Vladimir Markarov and Astrid Blom and Nadeem Riaz and Ryan Doumani and Krista Stafstrom and Ata Moshiri and Lola Yelistratova and Jonathan Levinsohn and Chan, {Timothy A.} and Paul Nghiem and Lifton, {Richard P.} and Jaehyuk Choi",
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Goh, G, Walradt, T, Markarov, V, Blom, A, Riaz, N, Doumani, R, Stafstrom, K, Moshiri, A, Yelistratova, L, Levinsohn, J, Chan, TA, Nghiem, P, Lifton, RP & Choi, J 2016, 'Mutational landscape of MCPyV-positive and MCPyV-negative merkel cell carcinomas with implications for immunotherapy', Oncotarget, vol. 7, no. 3, pp. 3403-3415. https://doi.org/10.18632/oncotarget.6494

Mutational landscape of MCPyV-positive and MCPyV-negative merkel cell carcinomas with implications for immunotherapy. / Goh, Gerald; Walradt, Trent; Markarov, Vladimir; Blom, Astrid; Riaz, Nadeem; Doumani, Ryan; Stafstrom, Krista; Moshiri, Ata; Yelistratova, Lola; Levinsohn, Jonathan; Chan, Timothy A.; Nghiem, Paul; Lifton, Richard P.; Choi, Jaehyuk.

In: Oncotarget, Vol. 7, No. 3, 01.01.2016, p. 3403-3415.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mutational landscape of MCPyV-positive and MCPyV-negative merkel cell carcinomas with implications for immunotherapy

AU - Goh, Gerald

AU - Walradt, Trent

AU - Markarov, Vladimir

AU - Blom, Astrid

AU - Riaz, Nadeem

AU - Doumani, Ryan

AU - Stafstrom, Krista

AU - Moshiri, Ata

AU - Yelistratova, Lola

AU - Levinsohn, Jonathan

AU - Chan, Timothy A.

AU - Nghiem, Paul

AU - Lifton, Richard P.

AU - Choi, Jaehyuk

PY - 2016/1/1

Y1 - 2016/1/1

N2 - 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.

AB - 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.

KW - Cancer genetics

KW - Merkel cell carcinoma

KW - Merkel cell polyomavirus

KW - TP53

KW - Tumor neoantigens

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