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Integrated genomics point to immune vulnerabilities in pleural mesothelioma.

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cam.issuedOnline2021-09-27
dc.contributor.authorNastase, Anca
dc.contributor.authorMandal, Amit
dc.contributor.authorLu, Shir Kiong
dc.contributor.authorAnbunathan, Hima
dc.contributor.authorMorris-Rosendahl, Deborah
dc.contributor.authorZhang, Yu Zhi
dc.contributor.authorSun, Xiao-Ming
dc.contributor.authorGennatas, Spyridon
dc.contributor.authorRintoul, Robert C
dc.contributor.authorEdwards, Matthew
dc.contributor.authorBowman, Alex
dc.contributor.authorChernova, Tatyana
dc.contributor.authorBenepal, Tim
dc.contributor.authorLim, Eric
dc.contributor.authorTaylor, Anthony Newman
dc.contributor.authorNicholson, Andrew G
dc.contributor.authorPopat, Sanjay
dc.contributor.authorWillis, Anne E
dc.contributor.authorMacFarlane, Marion
dc.contributor.authorLathrop, Mark
dc.contributor.authorBowcock, Anne M
dc.contributor.authorMoffatt, Miriam F
dc.contributor.authorCookson, William OCM
dc.contributor.orcidRintoul, Robert [0000-0003-3875-3780]
dc.contributor.orcidWillis, Anne [0000-0002-1470-8531]
dc.date.accessioned2022-03-21T16:01:05Z
dc.date.available2022-03-21T16:01:05Z
dc.date.issued2021-09-27
dc.date.submitted2021-03-23
dc.date.updated2022-03-21T16:01:04Z
dc.descriptionFunder: Libor Fund grant from the UK Department of Health, by the British Lung Foundation and by the Asmarley Foundation
dc.descriptionFunder: UK Medical Research Council
dc.description.abstractPleural 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.
dc.identifier.doi10.17863/CAM.82687
dc.identifier.eissn2045-2322
dc.identifier.issn2045-2322
dc.identifier.others41598-021-98414-w
dc.identifier.other98414
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/335255
dc.languageen
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.1038/s41598-021-98414-w
dc.subjectAged
dc.subjectAged, 80 and over
dc.subjectAntineoplastic Agents
dc.subjectBiomarkers, Tumor
dc.subjectBiopsy
dc.subjectDNA Copy Number Variations
dc.subjectFemale
dc.subjectGene Expression Profiling
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectGenomics
dc.subjectHippo Signaling Pathway
dc.subjectHumans
dc.subjectMale
dc.subjectMesothelioma, Malignant
dc.subjectMiddle Aged
dc.subjectMutation
dc.subjectPleura
dc.subjectPleural Neoplasms
dc.subjectPrimary Cell Culture
dc.subjectWhole Genome Sequencing
dc.titleIntegrated genomics point to immune vulnerabilities in pleural mesothelioma.
dc.typeArticle
dcterms.dateAccepted2021-09-02
prism.issueIdentifier1
prism.publicationNameSci Rep
prism.volume11
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/s41598-021-98414-w

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