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Patient-derived Orthotopic Xenograft Models for Human Urothelial Cell Carcinoma and Colorectal Cancer Tumor Growth and Spontaneous Metastasis
Published on: May 12, 2019
Urothelial Carcinoma With a Novel MET Exon 14 Skipping Alteration
Evmorfia Petropoulou1, Flora Stavridi2, Chrisanthi Bili1
1A-LAB Private Diagnostic Company S.A., Diagnostic Center for Genetic and Genomic Disorders, Athens, Greece.
Background/Aim:
Urothelial cancer (UC) is the most common malignancy of the urinary tract, and outcomes in advanced disease remain poor. Comprehensive genomic profiling has revealed rare but potentially actionable alterations, including mesenchymal-epithelial transition factor (MET) exon 14 skipping events, which are well established in non-small cell lung cancer but rarely described in UC. We hereby report a case of high-grade plasmacytoid UC harboring a novel MET exon 14 skipping alteration and discuss its potential clinical relevance.
Case Report:
A 78-year-old man presented with pelvic pain and hematuria. Imaging showed irregular thickening of the bladder wall with bilateral ureterovesical junction and distal ureter involvement and rectal invasion, consistent with unresectable stage IVA (cT4N0) plasmacytoid UC. He received carboplatin-gemcitabine followed by maintenance avelumab. Next-generation sequencing of tumor tissue identified a novel intronic MET splice-site alteration, NM_000245.4: c.2942-22_2942-19delCTTT, at high variant allele frequency, predicted to cause exon 14 skipping; this result was confirmed on an independent panel, and no additional driver variants were detected.
Conclusion:
This case broadens the spectrum of MET exon 14 skipping events in UC by documenting a novel intronic c.2942-22_2942-19delCTTT alteration in plasmacytoid carcinoma. It underscores the importance of routine genomic profiling in advanced and histologically rare UC to uncover targetable alterations and supports consideration of MET-directed therapies or enrollment in tumor-agnostic trials for selected patients, while highlighting the need for further functional and clinical validation.
Insights
This study reports a novel MET exon 14 skipping alteration in a patient with advanced urothelial cancer (UC). This finding highlights the importance of genomic profiling for identifying potential therapeutic targets in rare UC cases.
Area of Science:
- Oncology
- Genetics
- Genomics
Background:
- Urothelial cancer (UC) is a common urinary tract malignancy with poor outcomes in advanced stages.
- Mesenchymal-epithelial transition factor (MET) exon 14 skipping alterations are actionable targets in lung cancer but are rarely documented in UC.
- Comprehensive genomic profiling is crucial for identifying rare, targetable alterations in advanced UC.
Purpose of the Study:
- To report a case of high-grade plasmacytoid UC with a novel MET exon 14 skipping alteration.
- To discuss the potential clinical relevance of this finding in UC treatment.
Main Methods:
- A 78-year-old male patient with unresectable stage IVA plasmacytoid UC was treated with chemotherapy and immunotherapy.
- Next-generation sequencing (NGS) of tumor tissue identified a novel intronic MET splice-site alteration predicted to cause exon 14 skipping.
- The identified alteration was confirmed using an independent genomic panel.
Main Results:
- A novel intronic MET splice-site alteration (c.2942-22_2942-19delCTTT) was identified in a patient with high-grade plasmacytoid UC.
- This alteration was found at a high variant allele frequency and predicted to cause MET exon 14 skipping.
- No other driver variants were detected in the tumor tissue.
Conclusions:
- This case expands the known spectrum of MET exon 14 skipping alterations in UC.
- Routine genomic profiling in rare and advanced UC cases is essential for uncovering targetable alterations.
- MET-directed therapies or enrollment in tumor-agnostic trials may be considered for selected patients with this alteration, pending further validation.
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