Integrated genomics point to immune vulnerabilities in pleural mesothelioma.

Nastase, Anca 
Mandal, Amit 
Lu, Shir Kiong 
Anbunathan, Hima 
Morris-Rosendahl, Deborah 

Change log

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.

Publication Date
Online Publication Date
Acceptance Date
Aged, Aged, 80 and over, Antineoplastic Agents, Biomarkers, Tumor, Biopsy, DNA Copy Number Variations, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genomics, Hippo Signaling Pathway, Humans, Male, Mesothelioma, Malignant, Middle Aged, Mutation, Pleura, Pleural Neoplasms, Primary Cell Culture, Whole Genome Sequencing
Journal Title
Sci Rep
Journal ISSN
Volume Title
Springer Science and Business Media LLC