Journal Article

Integrated genomics point to immune vulnerabilities in pleural mesothelioma

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

2021

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/114 / 631/250 / 631/337 / 631/67 / 692/308 / 692/4028 / 692/53 / Aged / Aged, 80 and over / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Aurora kinase / Biomarkers, Tumor - antagonists & inhibitors / Biomarkers, Tumor - genetics / Biopsy / Chromosome 10 / DNA Copy Number Variations / Female / Gene Expression Profiling / Gene Expression Regulation, Neoplastic - drug effects / Gene Expression Regulation, Neoplastic - immunology / Genomics / Genotyping / Hippo Signaling Pathway - drug effects / Hippo Signaling Pathway - genetics / Hippo Signaling Pathway - immunology / Humanities and Social Sciences / Humans / Immunotherapy / Interferon / Lymphocytes T / Male / Malignancy / Mesothelioma / Mesothelioma, Malignant - drug therapy / Mesothelioma, Malignant - genetics / Mesothelioma, Malignant - immunology / Mesothelioma, Malignant - pathology / Middle Aged / multidisciplinary / Mutation / Pleura - pathology / Pleural Neoplasms - drug therapy / Pleural Neoplasms - genetics / Pleural Neoplasms - immunology / Pleural Neoplasms - pathology / Polo-like kinase 1 / Primary Cell Culture / Science / Science (multidisciplinary) / Single-nucleotide polymorphism / Synapses / Therapeutic targets / Tumors / Whole Genome Sequencing / Yes-associated protein