Clonal architecture in mesothelioma is prognostic and shapes the tumour microenvironment

Zhang, M. et al. (2021) Clonal architecture in mesothelioma is prognostic and shapes the tumour microenvironment. Nature Communications, 12, 1751. (doi: 10.1038/s41467-021-21798-w) (PMID:33741915) (PMCID:PMC7979861)

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.

• Item Type: Articles
• Additional Information: British Lung Foundation- Mesothelioma UK grant RM38G0071, Cancer Research UK Research grant C61811/A24218, Hope against Cancer research grant, A.J.S. was supported by a Royal College of Surgeons fellowship. A.D.G. was funded by an NIHR Academic Clinical Fellowship and a CRUK research bursary, A.B. was funded by a British Lung Foundation studentship M16-9.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Le Quesne, Professor John
• Authors: Zhang, M., Luo, J.-L., Sun, Q., Harber, J., Dawson, A. G., Nakas, A., Busacca, S., Sharkey, A. J., Waller, D., Sheaff, M. T., Richards, C., Wells-Jordan, P., Gaba, A., Poile, C., Baitei, E. Y., Bzura, A., Dzialo, J., Jama, M., Le Quesne, J., Bajaj, A., Martison, L., Shaw, J. A., Pritchard, C., Kamata, T., Kuse, N., Brannan, L., De Philip Zhang, P., Yang, H., Griffiths, G., Wilson, G., Swanton, C., Dudbridge, F., Hollox, E. J., and Fennell, D. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Nature Communications 12: 1751
• Publisher Policy: Reproduced under a Creative Commons License