학술논문
Integrated genomics point to immune vulnerabilities in pleural mesothelioma
Document Type
article
Author
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 Lathrop; Anne M. Bowcock; Miriam F. Moffatt; William O. C. M. Cookson
Source
Scientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
Subject
Language
English
ISSN
2045-2322
Abstract
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.