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

Our plain-English summary of Genomic sequencing of multicystic mesothelioma finds cohesin complex mutations associated with disease recurrence in patients referred for cytoreductive surgery and HIPEC, by J. Gibson, N.J. Carr, S. Stanford, et al (British Journal of Cancer, 2026).

The study

• Authors: J. Gibson, N.J. Carr, S. Stanford, A. Mirandari, T.D. Cecil, R.J. Pengelly, S. Turner, J.W. Essex, K. Boukas, K. Hocking, M. Dominguez, F. Mohamed, S.P. Dayal, A. Tzivanakis, B.J. Moran, G. Adeleke, A. Mirnezami, S. Ennis
• Journal: British Journal of Cancer
• Published: 2026;134(9):1352-1359
• Read it: PubMed · Publisher · Free full text

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.

© 2026. The Author(s).

In plain English

This study examined genes in tumour tissue from 46 patients referred to the Peritoneal Malignancy Institute in Basingstoke, UK, for cytoreductive surgery and HIPEC (heated chemotherapy inside the abdomen). Of these, 25 had multicystic mesothelioma (MCM), a rare peritoneal growth debated as a true tumour (neoplasm) or reactive growth, and 21 had malignant peritoneal mesothelioma (MPeM). The article reports no asbestos-exposure data. A panel of common cancer genes found mutations in only 4/24 MCM samples. MPeM samples showed mutations in genes including BAP1 and TP53 (each in 5/18). Wider sequencing of 11 MCMs found mutations clustered in cohesin genes. Across exome and follow-up sequencing, 10/19 MCM cases had a mutation at one site (codon E1144) of the SMC3 gene, and none of 20 MPeM cases did. Computer simulations suggested these changes disrupt the protein's function. All five MCM cases whose disease came back carried an SMC3 or SMC1A mutation, a statistically significant association with recurrence (p = 0.0302). The authors concluded the findings are consistent with MCM being a true neoplasm, not a reactive process. They noted the modest sample size.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory genomic sequencing study (targeted panel, whole-exome and amplicon sequencing) of tumour samples, with computer protein modelling and Kaplan-Meier analysis of recurrence-free survival
• Who was studied: 46 patients with peritoneal mesothelioma (25 multicystic mesothelioma, 21 malignant peritoneal mesothelioma) referred for consideration of cytoreductive surgery and HIPEC at the Peritoneal Malignancy Institute, Basingstoke, UK; study dates not given
• Exposure: The article reports no asbestos-exposure data. The exposure examined was genetic mutation in tumour tissue. The introduction states that the link between asbestos exposure and MCM remains uncertain.
• Main results:
  • Targeted cancer gene panel: mutations found in 4/24 (16.6%) MCM tumour samples
  • Targeted cancer gene panel in 18 MPeM cases: BAP1 and TP53 were the most frequently mutated genes, each in 5/18 (27.8%)
  • Whole-exome sequencing of 11 MCM cases: SMC3 was the most frequently mutated gene, in 5/11 (45%)
  • Across exome and amplicon sequencing, SMC3 mutations were found in 10/19 (53%) MCM cases, and SMC1A mutations in 2/11 (18%), never in the same case
  • No SMC3 codon E1144 mutations were found in the 20 MPeM cases tested
  • In computer simulations, all four mutant forms of SMC3 disrupted an interaction the protein uses to break down ATP
  • All five MCM cases with recurrence carried an SMC3 or SMC1A mutation. Kaplan-Meier analysis showed significantly more recurrence in mutated cases (p = 0.0302).
• The authors' conclusion: The authors concluded that recurrent mutations in MCM are consistent with it being a true neoplasm rather than a reactive process, and that SMC3 or SMC1A mutations are associated with a higher risk of recurrence
• Limitations the authors state:
  • Modest sample size
  • The methods used could not accurately detect BAP1 copy number changes, which may partly explain the lower BAP1 mutation rate found in MPeM

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Multicystic Mesothelioma (MCM), Cytoreductive Surgery, HIPEC, Peritoneal Mesothelioma, Recurrence-Free Survival, Somatic Mutation.

Related studies

• Early recurrence after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) — G.H.C. Tan, C.S. Chia, et al. (2018)
• Iterative procedures combining cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for isolated peritoneal recurrence — M. Vaira, M. Robella, et al. (2014)
• Repeat Cytoreductive Surgery and HIPEC for Peritoneal Surface Malignancy and Peritoneal Carcinomatosis — J.F. Wong, G.H. Tan, et al. (2015)
• Repeated cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with recurrent peritoneal carcinomatosis — N. Vassos, T. Förtsch, et al. (2016)
• Outcomes of multicystic peritoneal mesothelioma treatment with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy — A. Zahid, L. Clarke, et al. (2021)
• Multicystic peritoneal mesothelioma: outcomes and patho-biological features in a multi-institutional series treated by cytoreductive surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) — D. Baratti, M. Vaira, et al. (2010)

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