Cargando…
Multidisciplinary Treatment, Including Locoregional Chemotherapy, for Merkel-Polyomavirus-Positive Merkel Cell Carcinomas: Perspectives for Patients Exhibiting Oncogenic Alternative Δ exon 6–7 TrkAIII Splicing of Neurotrophin Receptor Tropomyosin-Related Kinase A
Merkel cell carcinomas (MCCs) are rare, aggressive, cutaneous neuroendocrine tumours, approximately 80% of which are caused by the genomic integration of Merkel cell polyomavirus (MCPyV). MCPyV-positive MCCs carry poor prognosis in approximately 70% of cases, highlighting the need for greater unders...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662965/ https://www.ncbi.nlm.nih.gov/pubmed/33153070 http://dx.doi.org/10.3390/ijms21218222 |
_version_ | 1783609517223706624 |
---|---|
author | Guadagni, Stefano Farina, Antonietta Rosella Cappabianca, Lucia Annamaria Sebastiano, Michela Maccarone, Rita Zelli, Veronica Clementi, Marco Chiominto, Alessandro Bruera, Gemma Ricevuto, Enrico Fiorentini, Giammaria Sarti, Donatella Mackay, Andrew Reay |
author_facet | Guadagni, Stefano Farina, Antonietta Rosella Cappabianca, Lucia Annamaria Sebastiano, Michela Maccarone, Rita Zelli, Veronica Clementi, Marco Chiominto, Alessandro Bruera, Gemma Ricevuto, Enrico Fiorentini, Giammaria Sarti, Donatella Mackay, Andrew Reay |
author_sort | Guadagni, Stefano |
collection | PubMed |
description | Merkel cell carcinomas (MCCs) are rare, aggressive, cutaneous neuroendocrine tumours, approximately 80% of which are caused by the genomic integration of Merkel cell polyomavirus (MCPyV). MCPyV-positive MCCs carry poor prognosis in approximately 70% of cases, highlighting the need for greater understanding of the oncogenic mechanisms involved in pathogenesis, progression and post-therapeutic relapse, and translation into novel therapeutic strategies. In a previous pilot study, we reported a potential relationship between MCPyV gene expression and oncogenic alternative Δ exon 6–7 TrkAIII splicing in formalin-fixed paraffin-embedded (FFPE) MCC tissues from a 12-patient cohort of >90% MCPyV-positive MCCs, diagnosed at San Salvatore Hospital, L’Aquila, Italy, characterising a new MCC subgroup and unveiling a novel potential MCPyV oncogenic mechanism and therapeutic target. This, however, could not be fully verified due to poor RNA quality and difficulty in protein extraction from FFPE tissues. Here, therefore, we extend our previous observations to confirm the relationship between MCPyV and oncogenic alternative Δ exon 6–7 TrkAIII splicing in fresh, nonfixed, MCPyV-positive MCC metastasis by detecting sequence-verified RT-PCR products, including full-length Δ exon 6–7 TrkAIII, and by Western blot detection of a 100 kDa TrkA protein isoform of identical size to 100 kDa Δ exon 6–7 TrkAIII expressed by stable transfected SH-SY5Y cells. We also report that in three MCC patients submitted for multidisciplinary treatment, including locoregional chemotherapy, MCPyV large T-antigen mRNA expression, Δ exon 6–7 TrkAIII mRNA expression and intracellular indirect immunofluorescence (IF) TrkA and phosphorylation protein isoform(s) immunoreactivity in FFPE tissues were not reduced in postchemotherapeutic-relapsed MCCs compared to pretherapeutic MCCs, extending the possible roles of this novel potential MCPyV oncogenic mechanism from MCC pathogenesis to post-therapeutic relapse and progression. Detection of alternative Δ exon 6–7 TrkAIII splicing in MCC, therefore, not only characterises a new MCPyV-positive MCC subgroup and unveils a novel potential MCPyV oncogenic mechanism but also identifies patients who may benefit from inhibitors of MCPyV T-antigen and/or TrkAIII expression or clinically approved Trk kinase inhibitors such as larotrectinib or entrectinib, which are known to inhibit activated TrkA oncogenes and to elicit durable responses in TrkA-fusion oncogene-driven cancers, supporting the call for a large-scale multicentre clinical study. |
format | Online Article Text |
id | pubmed-7662965 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-76629652020-11-14 Multidisciplinary Treatment, Including Locoregional Chemotherapy, for Merkel-Polyomavirus-Positive Merkel Cell Carcinomas: Perspectives for Patients Exhibiting Oncogenic Alternative Δ exon 6–7 TrkAIII Splicing of Neurotrophin Receptor Tropomyosin-Related Kinase A Guadagni, Stefano Farina, Antonietta Rosella Cappabianca, Lucia Annamaria Sebastiano, Michela Maccarone, Rita Zelli, Veronica Clementi, Marco Chiominto, Alessandro Bruera, Gemma Ricevuto, Enrico Fiorentini, Giammaria Sarti, Donatella Mackay, Andrew Reay Int J Mol Sci Article Merkel cell carcinomas (MCCs) are rare, aggressive, cutaneous neuroendocrine tumours, approximately 80% of which are caused by the genomic integration of Merkel cell polyomavirus (MCPyV). MCPyV-positive MCCs carry poor prognosis in approximately 70% of cases, highlighting the need for greater understanding of the oncogenic mechanisms involved in pathogenesis, progression and post-therapeutic relapse, and translation into novel therapeutic strategies. In a previous pilot study, we reported a potential relationship between MCPyV gene expression and oncogenic alternative Δ exon 6–7 TrkAIII splicing in formalin-fixed paraffin-embedded (FFPE) MCC tissues from a 12-patient cohort of >90% MCPyV-positive MCCs, diagnosed at San Salvatore Hospital, L’Aquila, Italy, characterising a new MCC subgroup and unveiling a novel potential MCPyV oncogenic mechanism and therapeutic target. This, however, could not be fully verified due to poor RNA quality and difficulty in protein extraction from FFPE tissues. Here, therefore, we extend our previous observations to confirm the relationship between MCPyV and oncogenic alternative Δ exon 6–7 TrkAIII splicing in fresh, nonfixed, MCPyV-positive MCC metastasis by detecting sequence-verified RT-PCR products, including full-length Δ exon 6–7 TrkAIII, and by Western blot detection of a 100 kDa TrkA protein isoform of identical size to 100 kDa Δ exon 6–7 TrkAIII expressed by stable transfected SH-SY5Y cells. We also report that in three MCC patients submitted for multidisciplinary treatment, including locoregional chemotherapy, MCPyV large T-antigen mRNA expression, Δ exon 6–7 TrkAIII mRNA expression and intracellular indirect immunofluorescence (IF) TrkA and phosphorylation protein isoform(s) immunoreactivity in FFPE tissues were not reduced in postchemotherapeutic-relapsed MCCs compared to pretherapeutic MCCs, extending the possible roles of this novel potential MCPyV oncogenic mechanism from MCC pathogenesis to post-therapeutic relapse and progression. Detection of alternative Δ exon 6–7 TrkAIII splicing in MCC, therefore, not only characterises a new MCPyV-positive MCC subgroup and unveils a novel potential MCPyV oncogenic mechanism but also identifies patients who may benefit from inhibitors of MCPyV T-antigen and/or TrkAIII expression or clinically approved Trk kinase inhibitors such as larotrectinib or entrectinib, which are known to inhibit activated TrkA oncogenes and to elicit durable responses in TrkA-fusion oncogene-driven cancers, supporting the call for a large-scale multicentre clinical study. MDPI 2020-11-03 /pmc/articles/PMC7662965/ /pubmed/33153070 http://dx.doi.org/10.3390/ijms21218222 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Guadagni, Stefano Farina, Antonietta Rosella Cappabianca, Lucia Annamaria Sebastiano, Michela Maccarone, Rita Zelli, Veronica Clementi, Marco Chiominto, Alessandro Bruera, Gemma Ricevuto, Enrico Fiorentini, Giammaria Sarti, Donatella Mackay, Andrew Reay Multidisciplinary Treatment, Including Locoregional Chemotherapy, for Merkel-Polyomavirus-Positive Merkel Cell Carcinomas: Perspectives for Patients Exhibiting Oncogenic Alternative Δ exon 6–7 TrkAIII Splicing of Neurotrophin Receptor Tropomyosin-Related Kinase A |
title | Multidisciplinary Treatment, Including Locoregional Chemotherapy, for Merkel-Polyomavirus-Positive Merkel Cell Carcinomas: Perspectives for Patients Exhibiting Oncogenic Alternative Δ exon 6–7 TrkAIII Splicing of Neurotrophin Receptor Tropomyosin-Related Kinase A |
title_full | Multidisciplinary Treatment, Including Locoregional Chemotherapy, for Merkel-Polyomavirus-Positive Merkel Cell Carcinomas: Perspectives for Patients Exhibiting Oncogenic Alternative Δ exon 6–7 TrkAIII Splicing of Neurotrophin Receptor Tropomyosin-Related Kinase A |
title_fullStr | Multidisciplinary Treatment, Including Locoregional Chemotherapy, for Merkel-Polyomavirus-Positive Merkel Cell Carcinomas: Perspectives for Patients Exhibiting Oncogenic Alternative Δ exon 6–7 TrkAIII Splicing of Neurotrophin Receptor Tropomyosin-Related Kinase A |
title_full_unstemmed | Multidisciplinary Treatment, Including Locoregional Chemotherapy, for Merkel-Polyomavirus-Positive Merkel Cell Carcinomas: Perspectives for Patients Exhibiting Oncogenic Alternative Δ exon 6–7 TrkAIII Splicing of Neurotrophin Receptor Tropomyosin-Related Kinase A |
title_short | Multidisciplinary Treatment, Including Locoregional Chemotherapy, for Merkel-Polyomavirus-Positive Merkel Cell Carcinomas: Perspectives for Patients Exhibiting Oncogenic Alternative Δ exon 6–7 TrkAIII Splicing of Neurotrophin Receptor Tropomyosin-Related Kinase A |
title_sort | multidisciplinary treatment, including locoregional chemotherapy, for merkel-polyomavirus-positive merkel cell carcinomas: perspectives for patients exhibiting oncogenic alternative δ exon 6–7 trkaiii splicing of neurotrophin receptor tropomyosin-related kinase a |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662965/ https://www.ncbi.nlm.nih.gov/pubmed/33153070 http://dx.doi.org/10.3390/ijms21218222 |
work_keys_str_mv | AT guadagnistefano multidisciplinarytreatmentincludinglocoregionalchemotherapyformerkelpolyomaviruspositivemerkelcellcarcinomasperspectivesforpatientsexhibitingoncogenicalternativedexon67trkaiiisplicingofneurotrophinreceptortropomyosinrelatedkinasea AT farinaantoniettarosella multidisciplinarytreatmentincludinglocoregionalchemotherapyformerkelpolyomaviruspositivemerkelcellcarcinomasperspectivesforpatientsexhibitingoncogenicalternativedexon67trkaiiisplicingofneurotrophinreceptortropomyosinrelatedkinasea AT cappabiancaluciaannamaria multidisciplinarytreatmentincludinglocoregionalchemotherapyformerkelpolyomaviruspositivemerkelcellcarcinomasperspectivesforpatientsexhibitingoncogenicalternativedexon67trkaiiisplicingofneurotrophinreceptortropomyosinrelatedkinasea AT sebastianomichela multidisciplinarytreatmentincludinglocoregionalchemotherapyformerkelpolyomaviruspositivemerkelcellcarcinomasperspectivesforpatientsexhibitingoncogenicalternativedexon67trkaiiisplicingofneurotrophinreceptortropomyosinrelatedkinasea AT maccaronerita multidisciplinarytreatmentincludinglocoregionalchemotherapyformerkelpolyomaviruspositivemerkelcellcarcinomasperspectivesforpatientsexhibitingoncogenicalternativedexon67trkaiiisplicingofneurotrophinreceptortropomyosinrelatedkinasea AT zelliveronica multidisciplinarytreatmentincludinglocoregionalchemotherapyformerkelpolyomaviruspositivemerkelcellcarcinomasperspectivesforpatientsexhibitingoncogenicalternativedexon67trkaiiisplicingofneurotrophinreceptortropomyosinrelatedkinasea AT clementimarco multidisciplinarytreatmentincludinglocoregionalchemotherapyformerkelpolyomaviruspositivemerkelcellcarcinomasperspectivesforpatientsexhibitingoncogenicalternativedexon67trkaiiisplicingofneurotrophinreceptortropomyosinrelatedkinasea AT chiomintoalessandro multidisciplinarytreatmentincludinglocoregionalchemotherapyformerkelpolyomaviruspositivemerkelcellcarcinomasperspectivesforpatientsexhibitingoncogenicalternativedexon67trkaiiisplicingofneurotrophinreceptortropomyosinrelatedkinasea AT brueragemma multidisciplinarytreatmentincludinglocoregionalchemotherapyformerkelpolyomaviruspositivemerkelcellcarcinomasperspectivesforpatientsexhibitingoncogenicalternativedexon67trkaiiisplicingofneurotrophinreceptortropomyosinrelatedkinasea AT ricevutoenrico multidisciplinarytreatmentincludinglocoregionalchemotherapyformerkelpolyomaviruspositivemerkelcellcarcinomasperspectivesforpatientsexhibitingoncogenicalternativedexon67trkaiiisplicingofneurotrophinreceptortropomyosinrelatedkinasea AT fiorentinigiammaria multidisciplinarytreatmentincludinglocoregionalchemotherapyformerkelpolyomaviruspositivemerkelcellcarcinomasperspectivesforpatientsexhibitingoncogenicalternativedexon67trkaiiisplicingofneurotrophinreceptortropomyosinrelatedkinasea AT sartidonatella multidisciplinarytreatmentincludinglocoregionalchemotherapyformerkelpolyomaviruspositivemerkelcellcarcinomasperspectivesforpatientsexhibitingoncogenicalternativedexon67trkaiiisplicingofneurotrophinreceptortropomyosinrelatedkinasea AT mackayandrewreay multidisciplinarytreatmentincludinglocoregionalchemotherapyformerkelpolyomaviruspositivemerkelcellcarcinomasperspectivesforpatientsexhibitingoncogenicalternativedexon67trkaiiisplicingofneurotrophinreceptortropomyosinrelatedkinasea |