Integrated genomics point to immune vulnerabilities in pleural mesothelioma.
Lu, Shir Kiong
Zhang, Yu Zhi
Taylor, Anthony Newman
Nicholson, Andrew G
Bowcock, Anne M
Moffatt, Miriam F
Cookson, William OCM
Springer Science and Business Media LLC
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Nastase, A., Mandal, A., Lu, S. K., Anbunathan, H., Morris-Rosendahl, D., Zhang, Y. Z., Sun, X., et al. (2021). Integrated genomics point to immune vulnerabilities in pleural mesothelioma.. Sci Rep, 11 (1), 19138. https://doi.org/10.1038/s41598-021-98414-w
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.
External DOI: https://doi.org/10.1038/s41598-021-98414-w
This record's URL: https://www.repository.cam.ac.uk/handle/1810/331189
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/