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

Malignant 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. We conducted multiregional whole exome sequencing (WES) of 106 samples from 20 patients undergoing pleurectomy decortication and identified 24 clonal non-recurrent 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 tumour, and presence of gene fusions was associated with clonal SCNAs involving the Hippo pathway genes and homologous recombination DNA repair genes. Fusions involved known tumour suppressors BAP1 , MTAP , and LRP1B, and a clonal oncogenic fusion involving CACNA1D-ERC2, PARD3B - NT5DC2 and STAB2 - NT5DC2 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.