Integrated genomics point to immune vulnerabilities in pleural mesothelioma
| Autor: | Hima Anbunathan, Anne M. Bowcock, Yu Zhi Zhang, William O.C.M. Cookson, Miriam F. Moffatt, Tatyana Chernova, S. Gennatas, Anne E. Willis, Mark Lathrop, I. Alex Bowman, Eric Lim, A. Mandal, Marion MacFarlane, Anthony Newman Taylor, Sanjay Popat, Tim Benepal, A. Nastase, Matthew S. Edwards, Deborah J. Morris-Rosendahl, Robert C. Rintoul, Andrew G. Nicholson, Xiao-Ming Sun, Shir Kiong Lu |
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| Přispěvatelé: | Guys & St Thomas NHS Foundation Trust, Department of Health, Rintoul, Robert [0000-0003-3875-3780], Willis, Anne [0000-0002-1470-8531], Apollo - University of Cambridge Repository, Mandal, Amit [0000-0002-2530-8103], Willis, Anne E [0000-0002-1470-8531] |
| Rok vydání: | 2021 |
| Předmět: |
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Molecular biology medicine.medical_treatment Biopsy Aurora kinase CDKN2A Medicine Mesothelioma Cancer YAP1 Aged 80 and over Multidisciplinary 631/250 article Genomics Middle Aged Gene Expression Regulation Neoplastic Oncology Pleura Female 631/337 medicine.drug 631/67 DNA Copy Number Variations Science Pleural Neoplasms Immunology 692/308 Primary Cell Culture Antineoplastic Agents Malignancy 692/4028 Medical research 692/53 Biomarkers Tumor Humans Hippo Signaling Pathway Hedgehog Aged Whole Genome Sequencing business.industry Gene Expression Profiling Mesothelioma Malignant Immunotherapy medicine.disease Computational biology and bioinformatics Mutation Cancer research 631/114 business Biomarkers Interferon type I |
| Zdroj: | Scientific Reports, Vol 11, Iss 1, Pp 1-15 (2021) Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.17863/cam.78636 |
| Popis: | Funder: Libor Fund grant from the UK Department of Health, by the British Lung Foundation and by the Asmarley Foundation Funder: UK Medical Research Council 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. |
| Databáze: | OpenAIRE |
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