Genomic sequencing of multicystic mesothelioma finds cohesin complex mutations associated with disease recurrence in patients referred for cytoreductive surgery and HIPEC.

backgroundMulticystic mesothelioma (MCM) is a rare disease and there is debate about it's neoplastic nature with a spectrum of disease behaviour and little known about the genomic profile. In contrast, the genomic profile of malignant peritoneal mesothelioma (MPeM) is characterised.

methodsWe characterized 24 MCM and 18 MPeM cases across a panel of cancer related regions and expanded to whole-exome sequencing for 11 MCMs. Validation by amplicon sequencing and functional assessment by molecular dynamic simulation were carried out. Kaplan-Meier analysis was carried out to assess recurrence-free survival.

resultsFew mutations were identified in MCMs across the panel. Exome sequencing revealed 28 genes mutated in >1 MCM case. We saw significant overrepresentation of mutations in the cohesin complex in SMC3, SMC1A, and STAG3. Multiple mutations in SMC3 at codon p.E1144 indicated a mutational hotspot. Molecular dynamics simulations showed mutation at this site impacts the protein function. Amplicon sequencing confirmed hotspot mutations in further MCMs. We observed a significant association (p = 0.0302) of mutation in SMC3 or SMC1A with disease recurrence.

conclusionsWe see recurrent somatic mutations in MCMs particularly at a novel mutational hotspot in SMC3, consistent with a neoplastic process. Mutations in cohesin complex genes are associated with disease recurrence.