Integrated genomics point to immune vulnerabilities in pleural mesothelioma

Anca Nastase, Amit Mandal, Shir Kiong Lu, Hima Anbunathan, Deborah Morris-Rosendahl, Yu Zhi Zhang, Xiao Ming Sun, Spyridon Gennatas, Robert C. Rintoul, Matthew Edwards, Alex Bowman, Tatyana Chernova, Tim Benepal, Eric Lim, Anthony Newman Taylor, Andrew G. Nicholson, Sanjay Popat, Anne E. Willis, Marion MacFarlane, Mark LathropAnne M. Bowcock, Miriam F. Moffatt, William O.C.M. Cookson

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish
Article number19138
JournalScientific Reports
Volume11
Issue number1
DOIs
StatePublished - Dec 2021
Externally publishedYes

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