Pervasive chromothripsis drives pleural mesothelioma to impact gene function and patient survival
- 1Institute of Cancer and Genetics
Abstract
Pleural mesothelioma (PM) is a tumour type showing high structural complexity but the full spectrum of variants present and their impacts are poorly understood. We comprehensively describe the mutational landscape of mesothelioma, exploiting a large (N=443) cohort profiling the tumour genome and transcriptome in parallel. We find that the majority of candidate driver variants are mediated by copy number alterations (CNAs) and discover high frequencies of complex rearrangements across most tumours, dominated by chromothripsis (74% of tumours) and chromoplexy (59%). Chromothripsis contributes to significant CNA hotspots to delete known PM tumour suppressor genes such as CDKN2A, NF2 and BAP1, thought to be among the earliest events in PM development; and the presence of chromothripsis is associated with significantly worse patient survival. We also discover multi-faceted crosstalk between the mitochondrial and nuclear genomes during PM evolution, involving alterations to both genomes, and mitochondrial expression changes associated with subtypes and chromothripsis.
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BibTeX
@misc{semple2026pervasive,
title = {{Pervasive chromothripsis drives pleural mesothelioma to impact gene function and patient survival}},
author = {C. Semple and K. Sherwood and S. Aitken and R. Silk and M. Halachev and S. Fox and D. Bendixsen and A. Hamdan and K. G. Blyth},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.04.762854},
url = {https://www.biorxiv.org/content/10.64898/2026.11.04.762854v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Pervasive chromothripsis drives pleural mesothelioma to impact gene function and patient survival
AU - C. Semple
AU - K. Sherwood
AU - S. Aitken
AU - R. Silk
AU - M. Halachev
AU - S. Fox
AU - D. Bendixsen
AU - A. Hamdan
AU - K. G. Blyth
PY - 2026
DA - 2026/11/04
PB - bioRxiv
DO - 10.64898/2026.11.04.762854
UR - https://www.biorxiv.org/content/10.64898/2026.11.04.762854v1
AB - Pleural mesothelioma (PM) is a tumour type showing high structural complexity but the full spectrum of variants present and their impacts are poorly understood. We comprehensively describe the mutational landscape of mesothelioma, exploiting a large (N=443) cohort profiling the tumour genome and transcriptome in parallel. We find that the majority of candidate driver variants are mediated by copy number alterations (CNAs) and discover high frequencies of complex rearrangements across most tumours, dominated by chromothripsis (74% of tumours) and chromoplexy (59%). Chromothripsis contributes to significant CNA hotspots to delete known PM tumour suppressor genes such as CDKN2A, NF2 and BAP1, thought to be among the earliest events in PM development; and the presence of chromothripsis is associated with significantly worse patient survival. We also discover multi-faceted crosstalk between the mitochondrial and nuclear genomes during PM evolution, involving alterations to both genomes, and mitochondrial expression changes associated with subtypes and chromothripsis.
ER -