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

British Journal of Cancer 2026 May [Link]

Jane Gibson, Norman John Carr, Sophia Stanford, Amatta Mirandari, Thomas Desmond Cecil, Reuben J Pengelly, Steven Turner, Jonathan W Essex, Konstantinos Boukas, Kevin Hocking, Manuel Dominguez, Faheez Mohamed, Sanjeev Paul Dayal, Alexios Tzivanakis, Brendan John Moran, Gbadebo Adeleke, Alex Mirnezami, Sarah Ennis

Abstract

Background: Multicystic 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.

Methods: We 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.

Results: Few 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.

Conclusions: We 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.