Integrated genomics point to immune vulnerabilities in pleural mesothelioma.
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Authors
Nastase, Anca
Mandal, Amit
Lu, Shir Kiong
Anbunathan, Hima
Morris-Rosendahl, Deborah
Zhang, Yu Zhi
Sun, Xiao-Ming
Gennatas, Spyridon
Edwards, Matthew
Bowman, Alex
Chernova, Tatyana
Benepal, Tim
Lim, Eric
Taylor, Anthony Newman
Nicholson, Andrew G
Popat, Sanjay
Willis, Anne
MacFarlane, Marion
Lathrop, Mark
Bowcock, Anne M
Moffatt, Miriam F
Cookson, William OCM
Publication Date
2021-09-27Journal Title
Sci Rep
ISSN
2045-2322
Publisher
Springer Science and Business Media LLC
Volume
11
Issue
1
Pages
19138
Language
eng
Type
Article
This Version
VoR
Physical Medium
Electronic
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.. Sci Rep, 11 (1), 19138. https://doi.org/10.1038/s41598-021-98414-w
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
External DOI: https://doi.org/10.1038/s41598-021-98414-w
This record's URL: https://www.repository.cam.ac.uk/handle/1810/331189
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