Abstract
Pleural mesothelioma is an aggressive malignancy with limited effective therapies. In order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells. Previously unrecognised deletions of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary mesothelioma cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin. Our results suggest new therapeutic avenues in mesothelioma and indicate targets and biomarkers for immunotherapy.
Highlights
Pleural mesothelioma is an aggressive malignancy with limited effective therapies
We explored the mutational spectrum with whole exome sequencing (WES) in 50 subjects (21 of which had paired blood samples for germline DNA), before extending mutation detection to all tumours with a 57-gene targeted capture nextgeneration sequencing (TC-NGS) panel (Supplementary File 1_Fig. 1a, b and Supplementary File 1_Table 1)
The median overall survival (OS) for all subjects was 9.9 months with sarcomatoid patients showing a worse outcome than others, (P = 0.065), as d escribed[13]
Summary
Pleural mesothelioma is an aggressive malignancy with limited effective therapies. We found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary mesothelioma cells. Pleural mesothelioma is an aggressive malignancy associated with asbestos exposure. In the UK MesobanK tumour r epository6 65% of mesothelioma have < 25% of tumour cells visible on surgical biopsy and only 8% of mesothelioma comprise > 75% malignant cells. This suggests the tumour-matrix interaction to be a feature of the disease. Larger structural variations in mesothelioma are c ommon[11], and recurrent deletions are recognised for CDKN2A (located at chromosome 9p21.3), NF2 (22q12) and BAP1 (3p21.3)
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