Clonal architecture in mesothelioma is prognostic and shapes the tumour microenvironment
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Published:2021-03-19
Issue:1
Volume:12
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Zhang Min, Luo Jin-Li, Sun Qianqian, Harber James, Dawson Alan G.ORCID, Nakas Apostolos, Busacca Sara, Sharkey Annabel J.ORCID, Waller David, Sheaff Michael T., Richards Cathy, Wells-Jordan Peter, Gaba Aarti, Poile Charlotte, Baitei Essa Y., Bzura Aleksandra, Dzialo JoannaORCID, Jama Maymun, Le Quesne John, Bajaj Amrita, Martinson Luke, Shaw Jacqui A.ORCID, Pritchard Catrin, Kamata TamihiroORCID, Kuse Nathaniel, Brannan Lee, De Philip Zhang Pan, Yang HongjiORCID, Griffiths Gareth, Wilson Gareth, Swanton CharlesORCID, Dudbridge FrankORCID, Hollox Edward J.ORCID, Fennell Dean A.ORCID
Abstract
AbstractMalignant Pleural Mesothelioma (MPM) is typically diagnosed 20–50 years after exposure to asbestos and evolves along an unknown evolutionary trajectory. To elucidate this path, we conducted multi-regional exome sequencing of 90 tumour samples from 22 MPMs acquired at surgery. Here we show that exomic intratumour heterogeneity varies widely across the cohort. Phylogenetic tree topology ranges from linear to highly branched, reflecting a steep gradient of genomic instability. Using transfer learning, we detect repeated evolution, resolving 5 clusters that are prognostic, with temporally ordered clonal drivers. BAP1/−3p21 and FBXW7/-chr4 events are always early clonal. In contrast, NF2/−22q events, leading to Hippo pathway inactivation are predominantly late clonal, positively selected, and when subclonal, exhibit parallel evolution indicating an evolutionary constraint. Very late somatic alteration of NF2/22q occurred in one patient 12 years after surgery. Clonal architecture and evolutionary clusters dictate MPM inflammation and immune evasion. These results reveal potentially drugable evolutionary bottlenecking in MPM, and an impact of clonal architecture on shaping the immune landscape, with potential to dictate the clinical response to immune checkpoint inhibition.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
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