Gene fusions during the early evolution of mesothelioma correlate with impaired DNA repair and Hippo pathways

Author:

Jama Maymun1,Zhang Min23,Poile Charlotte2,Nakas Apostolos4,Sharkey Annabel5,Dzialo Joanna2,Dawson Alan4,Kutywayo Kudazyi25,Fennell Dean A.124,Hollox Edward J.1ORCID

Affiliation:

1. Department of Genetics and Genome Biology University of Leicester Leicester UK

2. Mesothelioma Research Programme, Leicester Cancer Research Centre University of Leicester Leicester UK

3. Novogene Corpotation Ltd., Building 301 Beijing China

4. Thoracic Medical Oncology University Hospitals of Leicester NHS Trust Leicester UK

5. Department of Cardio‐Thoracic Surgery Sheffield Teaching Hospital NHS Trust Sheffield UK

Abstract

AbstractMalignant pleural mesothelioma (MPM), a rare cancer a long latency period (up to 40 years) between asbestos exposure and disease presentation. The mechanisms coupling asbestos to recurrent somatic alterations are poorly defined. Gene fusions arising through genomic instability may create novel drivers during early MPM evolution. We explored the gene fusions that occurred early in the evolutionary history of the tumor. We conducted multiregional whole exome sequencing (WES) of 106 samples from 20 patients undergoing pleurectomy decortication and identified 24 clonal nonrecurrent gene fusions, three of which were novel (FMO9P‐OR2W5, GBA3, and SP9). The number of early gene fusion events detected varied from zero to eight per tumor, and presence of gene fusions was associated with clonal losses involving the Hippo pathway genes and homologous recombination DNA repair genes. Fusions involved known tumor suppressors BAP1, MTAP, and LRP1B, and a clonal oncogenic fusion involving CACNA1D‐ERC2, PARD3BNT5DC2, and STAB2NT5DC2 fusions were also identified as clonal fusions. Gene fusions events occur early during MPM evolution. Individual fusions are rare as no recurrent truncal fusions event were found. This suggests the importance of early disruption of these pathways in generating genomic rearrangements resulting in potentially oncogenic gene fusions.

Funder

British Lung Foundation

Publisher

Wiley

Subject

Cancer Research,Genetics

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