Investigating the role of genomic drivers of MET pathway dysregulation in the heterogeneity of pleomorphic lung carcinoma
Imperial College London, 2019
Online
Hochschulschrift
Zugriff:
Background: Pleomorphic Lung Carcinoma (PC) is a rare lung cancer that is aggressive and poorly responsive to treatments. It is a highly heterogenous tumour and unique as it has at least 10% dedifferentiated sarcomatoid component alongside its epithelial components. Recent data have demonstrated a high frequency of mutations in the MET receptor that may support epithelial to mesenchymal transition (EMT) as an important pathway in PCs oncogenesis. The hypothesis was that MET, along with other key components of the MET pathway, would be dysfunctional and exhibit damaging aberrations. Methods: 80 cases of PC were identified from the biobank and diagnostic archives of the Royal Brompton Hospital and Imperial College Healthcare NHS trusts. FFPE sections were obtained and DNA was isolated from histologically distinct areas and epithelial and sarcomatoid areas. Differences in the mutational and expression profiles of a select set of genes/proteins of these areas were determined. Correlative analyses were performed with the genetic and expression profiles against clinicopathological features. Biomarkers of the MET pathway were evaluated with immunohistochemistry and MET copy number was determined with ddPCR. Ultra-deep next generation sequencing was performed on a gene panel selected from earlier findings in PC or that play a role in MET signalling (including MET, KRAS, CBL and HGF). Results: This cohort was comparable to that of other PC studies in terms of patient survival and other clinical characteristics. Median OS was poor (16.3 months) and predicted by tumour size, nodal status and composite stage (P=0.04; 0.008; 0.01). The most commonly mutated genes were TP53 (55%) and KRAS (27%). PCs with paired samples from across both phenotypic components shared oncogenic drivers although differing frequencies of TP53 LOH and KRAS activating mutations were observed. KRAS mutations were mutually exclusive to MET mutations (P=0.03). MET pathway aberrations were present in 44% of cases where there was an increase in MET copy number or MET mutations. MET copy number was significantly higher in the sarcomatoid component (P=0.046). Novel CBL deletions were present in 9.6% of PCs and HGF mutations were present in 8.2% of PCs, albeit at low frequency. There was a significant increase in PD-L1 expression across PCs with higher expression in the sarcomatoid components (p = 0.001). Conclusions: The frequency of alleles with TP53 and KRAS mutations supports the development of PC from an early totipotent progenitor with potential to develop into an epithelial or sarcomatoid tumour. PCs have frequent aberrations of the MET pathway and novel CBL deletions and HGF mutations that warrant further investigation.
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Investigating the role of genomic drivers of MET pathway dysregulation in the heterogeneity of pleomorphic lung carcinoma
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Autor/in / Beteiligte Person: | Januszewski, Adam ; Bowcock, Anne ; Popat, Sanjay |
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Veröffentlichung: | Imperial College London, 2019 |
Medientyp: | Hochschulschrift |
DOI: | 10.25560/78719 |
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