학술논문
Integrated genomics point to immune vulnerabilities in pleural mesothelioma.
Document Type
Article
Author
Nastase, Anca; Mandal, Amit; 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; Willis, Anne E.; MacFarlane, Marion; Lathrop, Mark
Source
Subject
*TYPE I interferons
*MESOTHELIOMA
*AURORA kinases
*DRUG target
*
*
*
Language
ISSN
2045-2322
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. [ABSTRACT FROM AUTHOR]