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Clonal architecture in mesothelioma is prognostic and shapes the tumour microenvironment.

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posted on 24.03.2021, 11:50 by Min Zhang, Jin-Li Luo, Qianqian Sun, James Harber, Alan G Dawson, Apostolos Nakas, Sara Busacca, Annabel J Sharkey, David Waller, Michael T Sheaff, Cathy Richards, Peter Wells-Jordan, Aarti Gaba, Charlotte Poile, Essa Y Baitei, Aleksandra Bzura, Joanna Dzialo, Maymun Jama, John Le Quesne, Amrita Bajaj, Luke Martison, Jacqui A Shaw, Catrin Pritchard, Tamihiro Kamata, Nathaniel Kuse, Lee Brannan, Pan De Philip Zhang, Hongji Yang, Gareth Griffiths, Gareth Wilson, Charles Swanton, Frank Dudbridge, Edward J Hollox, Dean A Fennell
Malignant 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.

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Crick (Grant ID: 10169, Grant title: Swanton FC001169)

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