Clonal architecture in mesothelioma is prognostic and shapes the tumour microenvironment

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 Quesne, Amrita Bajaj, Luke Martinson, Jacqui A. Shaw, Catrin Pritchard, Tamihiro Kamata, Nathaniel Kuse, Lee Brannan, Pan Philip Zhang, Hongji Yang, Gareth Griffiths, Gareth Wilson, Charles Swanton, Frank Dudbridge, Edward J. Hollox and Dean A. Fennell ()
Additional contact information
Min Zhang: Novogene Co., Ltd, Building 301
Jin-Li Luo: University of Leicester
Qianqian Sun: Novogene Co., Ltd, Building 301
James Harber: University of Leicester
Alan G. Dawson: University of Leicester
Apostolos Nakas: Glenfield Hospital
Sara Busacca: University of Leicester
Annabel J. Sharkey: University of Sheffield Teaching Hospitals
David Waller: Barts Health NHS Trust, The Royal London Hospital
Michael T. Sheaff: Barts Health NHS Trust, The Royal London Hospital
Cathy Richards: Leicester Royal Infirmary, Infirmary Square
Peter Wells-Jordan: Leicester Royal Infirmary, Infirmary Square
Aarti Gaba: University of Leicester
Charlotte Poile: University of Leicester
Essa Y. Baitei: University of Leicester
Aleksandra Bzura: University of Leicester
Joanna Dzialo: University of Leicester
Maymun Jama: University of Leicester
John Quesne: University of Glasgow, Garscube Estate
Amrita Bajaj: Glenfield Hospital
Luke Martinson: University of Leicester
Jacqui A. Shaw: University of Leicester
Catrin Pritchard: University of Leicester
Tamihiro Kamata: University of Leicester
Nathaniel Kuse: University of Leicester
Lee Brannan: University of Leicester
Pan Philip Zhang: University of Leicester
Hongji Yang: University of Leicester
Gareth Griffiths: University of Southampton
Gareth Wilson: The Francis Crick Institute
Charles Swanton: The Francis Crick Institute
Frank Dudbridge: University of Leicester
Edward J. Hollox: University of Leicester
Dean A. Fennell: University of Leicester

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-21798-w

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