Back to Search
Start Over
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.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2020 Nov 03; Vol. 21 (21). Date of Electronic Publication: 2020 Nov 03. - Publication Year :
- 2020
-
Abstract
- 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.
- Subjects :
- Aged
Aged, 80 and over
Alternative Splicing genetics
Antibodies, Monoclonal, Humanized administration & dosage
Antibodies, Monoclonal, Humanized adverse effects
Cell Transformation, Neoplastic genetics
Combined Modality Therapy
Drug Administration Routes
Female
Humans
Interdisciplinary Communication
Italy epidemiology
Male
Merkel cell polyomavirus isolation & purification
Merkel cell polyomavirus physiology
Middle Aged
Molecular Diagnostic Techniques
Mutation
Patient Care Team
Prognosis
Survival Analysis
Antineoplastic Combined Chemotherapy Protocols administration & dosage
Carcinoma, Merkel Cell diagnosis
Carcinoma, Merkel Cell genetics
Carcinoma, Merkel Cell mortality
Carcinoma, Merkel Cell therapy
Polyomavirus Infections diagnosis
Polyomavirus Infections genetics
Polyomavirus Infections mortality
Polyomavirus Infections therapy
Receptor, trkA genetics
Skin Neoplasms diagnosis
Skin Neoplasms genetics
Skin Neoplasms mortality
Skin Neoplasms therapy
Tumor Virus Infections diagnosis
Tumor Virus Infections genetics
Tumor Virus Infections mortality
Tumor Virus Infections therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 21
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 33153070
- Full Text :
- https://doi.org/10.3390/ijms21218222