Integrated genomics point to immune vulnerabilities in pleural mesothelioma

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 (10q2...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f4c03b22d13e4a60887cc31103bca100
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spelling	oai:doaj.org-article:f4c03b22d13e4a60887cc31103bca1002021-12-02T17:37:35ZIntegrated genomics point to immune vulnerabilities in pleural mesothelioma10.1038/s41598-021-98414-w2045-2322https://doaj.org/article/f4c03b22d13e4a60887cc31103bca1002021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-98414-whttps://doaj.org/toc/2045-2322Abstract 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.Anca NastaseAmit MandalShir Kiong LuHima AnbunathanDeborah Morris-RosendahlYu Zhi ZhangXiao-Ming SunSpyridon GennatasRobert C. RintoulMatthew EdwardsAlex BowmanTatyana ChernovaTim BenepalEric LimAnthony Newman TaylorAndrew G. NicholsonSanjay PopatAnne E. WillisMarion MacFarlaneMark LathropAnne M. BowcockMiriam F. MoffattWilliam O. C. M. CooksonNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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 Integrated genomics point to immune vulnerabilities in pleural mesothelioma
description	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.
format	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
author_facet	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
author_sort	Anca Nastase
title	Integrated genomics point to immune vulnerabilities in pleural mesothelioma
title_short	Integrated genomics point to immune vulnerabilities in pleural mesothelioma
title_full	Integrated genomics point to immune vulnerabilities in pleural mesothelioma
title_fullStr	Integrated genomics point to immune vulnerabilities in pleural mesothelioma
title_full_unstemmed	Integrated genomics point to immune vulnerabilities in pleural mesothelioma
title_sort	integrated genomics point to immune vulnerabilities in pleural mesothelioma
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f4c03b22d13e4a60887cc31103bca100
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Integrated genomics point to immune vulnerabilities in pleural mesothelioma

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