Integrated genomics point to immune vulnerabilities in pleural mesothelioma.
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Authors
Nastase, Anca
Lu, Shir Kiong
Anbunathan, Hima
Morris-Rosendahl, Deborah
Zhang, Yu Zhi
Sun, Xiao-Ming
Gennatas, Spyridon
Rintoul, Robert C
Edwards, Matthew
Bowman, Alex
Chernova, Tatyana
Benepal, Tim
Lim, Eric
Taylor, Anthony Newman
Nicholson, Andrew G
Popat, Sanjay
MacFarlane, Marion
Lathrop, Mark
Bowcock, Anne M
Moffatt, Miriam F
Cookson, William O C M
Publication Date
2021-09-27Journal Title
Scientific reports
ISSN
2045-2322
Volume
11
Issue
1
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
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.. Scientific reports, 11 (1) https://doi.org/10.1038/s41598-021-98414-w
Description
Funder: Libor Fund grant from the UK Department of Health, by the British Lung Foundation and by the Asmarley Foundation
Funder: Medical Research Council
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.
Identifiers
PMC8476593, 34580349
External DOI: https://doi.org/10.1038/s41598-021-98414-w
This record's URL: https://www.repository.cam.ac.uk/handle/1810/330095
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