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

Autor: Zhang M; Novogene Co., Ltd, Building 301, Beijing, China., Luo JL; Bioinformatics and Biostatistics Support Hub, University of Leicester, Leicester, UK., Sun Q; Novogene Co., Ltd, Building 301, Beijing, China., Harber J; Department of Genetics and Genome Biology, University of Leicester, Leicester, UK., Dawson AG; Department of Genetics and Genome Biology, University of Leicester, Leicester, UK.; Department of Cardiothoracic Surgery, Glenfield Hospital, Leicester, UK., Nakas A; Department of Cardiothoracic Surgery, Glenfield Hospital, Leicester, UK., Busacca S; Department of Genetics and Genome Biology, University of Leicester, Leicester, UK., Sharkey AJ; University of Sheffield Teaching Hospitals, Leicester, UK., Waller D; Barts Health NHS Trust, The Royal London Hospital, London, UK., Sheaff MT; Barts Health NHS Trust, The Royal London Hospital, London, UK., Richards C; Department of Pathology, Leicester Royal Infirmary, Infirmary Square, Leicester, Leicestershire, UK., Wells-Jordan P; Department of Pathology, Leicester Royal Infirmary, Infirmary Square, Leicester, Leicestershire, UK., Gaba A; Department of Genetics and Genome Biology, University of Leicester, Leicester, UK., Poile C; Department of Genetics and Genome Biology, University of Leicester, Leicester, UK., Baitei EY; Department of Genetics and Genome Biology, University of Leicester, Leicester, UK.; Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia., Bzura A; Department of Genetics and Genome Biology, University of Leicester, Leicester, UK., Dzialo J; Department of Genetics and Genome Biology, University of Leicester, Leicester, UK., Jama M; Department of Genetics and Genome Biology, University of Leicester, Leicester, UK., Le Quesne J; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, UK., Bajaj A; Department of Radiology, Glenfield Hospital, Leicester, UK., Martinson L; Department of Genetics and Genome Biology, University of Leicester, Leicester, UK., Shaw JA; Department of Genetics and Genome Biology, University of Leicester, Leicester, UK., Pritchard C; Department of Genetics and Genome Biology, University of Leicester, Leicester, UK., Kamata T; Department of Genetics and Genome Biology, University of Leicester, Leicester, UK., Kuse N; Department of Genetics and Genome Biology, University of Leicester, Leicester, UK., Brannan L; Department of Health Sciences, University of Leicester, Leicester, UK., De Philip Zhang P; Department of Informatics, University of Leicester, Leicester, UK., Yang H; Department of Informatics, University of Leicester, Leicester, UK., Griffiths G; Southampton Clinical Trials Unit, University of Southampton, Southampton, UK., Wilson G; The Francis Crick Institute, London, UK., Swanton C; The Francis Crick Institute, London, UK., Dudbridge F; Department of Health Sciences, University of Leicester, Leicester, UK., Hollox EJ; Department of Genetics and Genome Biology, University of Leicester, Leicester, UK., Fennell DA; Department of Genetics and Genome Biology, University of Leicester, Leicester, UK. df132@leicester.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Mar 19; Vol. 12 (1), pp. 1751. Date of Electronic Publication: 2021 Mar 19.
DOI: 10.1038/s41467-021-21798-w
Abstrakt: 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.
Databáze: MEDLINE
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