Deep Sequencing Analysis Identified a Specific Subset of Mutations Distinctive of Biphasic Malignant Pleural Mesothelioma

Our plain-English summary of Deep Sequencing Analysis Identified a Specific Subset of Mutations Distinctive of Biphasic Malignant Pleural Mesothelioma, by F. Torricelli, F. Lococo, T.S. Di Stefano, et al (Cancers, 2020).

The study

• Authors: F. Torricelli, F. Lococo, T.S. Di Stefano, E. Lorenzini, S. Piana, R. Valli, O. Rena, G. Veronesi, A. Billè, A. Ciarrocchi
• Journal: Cancers
• Published: 2020;12(9)
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant Pleural Mesothelioma (MPM) is a heterogeneous disease. Morphologically, three different phenotypes are distinguishable: epithelioid (e-), sarcomatoid (s-) and biphasic (biph-) MPM, the latest, being a mixture of e- and s-MPM cells. Being an intermediate entity, management of biph-MPM, remains debatable and controversial, with different guidelines recommending distinct approaches. Identification of biph-MPM associated genetic alterations, through deep sequencing analysis, may provide useful tools to understand these lesions. A retrospective cohort of 69 surgically resected MPMs, 39 biph-MPMs (56.5%) and 30 e-MPMs (43.5%) was selected. A separate set of 16 biph-MPM was used as validation set. Deep sequencing analysis on an MPM-specific custom panel (MPM_geneset) comprising 1041 amplicons spanning 34 genes was performed. A total of 588 variants and 5309 mutational events were detected. In total, 91.3% of MPMs showed at least one mutation and 76.8% showed co-occurrence of more than one alteration. Mutations in MXRA5 (p = 0.05) and NOD2 (p = 0.018) were significantly associated with biph-MPM both in the training and validation cohort and correlated with the extent of the sarcomatoid component. Mutations in NOD2 and XRCC6 correlated with patients' survival. We demonstrated that biph-MPM are associated with a specific mutation set, and that genetic analysis at diagnosis may improve patients' risk stratification.

In plain English

The authors used deep sequencing of a 34-gene panel to look for mutations in tumour tissue from 69 people who had surgery for malignant pleural mesothelioma. Of these, 39 had the biphasic type (a mix of epithelioid and sarcomatoid cells) and 30 had the epithelioid type. A separate set of 16 biphasic tumours was used to check the findings. Of 52 patients with exposure information, 46 had direct or indirect asbestos exposure. At least one mutation was found in 63 tumours (91.3%). MXRA5 mutations were found in 51.3% (20/39) of biphasic versus 26.7% (8/30) of epithelioid tumours (p = 0.050). NOD2 mutations were found in 25.6% (10/39) versus 3.3% (1/30) (p = 0.018). Among biphasic patients, XRCC6 mutations were associated with shorter survival. NOD2 mutations were associated with longer survival only in an adjusted model. The authors concluded that four genes were preferentially altered in biphasic tumours and that genetic analysis at diagnosis may improve risk stratification. They noted the small retrospective cohort, possible selection bias, varied treatments and the limited gene panel.

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: Retrospective, multicentre case-control genetic study: tumour DNA was sequenced with a custom 34-gene panel, followed by survival analysis
• Who was studied: 69 patients with surgically resected malignant pleural mesothelioma: 39 biphasic (56.5%) and 30 epithelioid (43.5%). A separate validation set of 16 biphasic tumours was also sequenced, and 11 sarcomatoid tumours were explored for comparison. Samples came from the participating institutions; the article does not state the years of diagnosis.
• Exposure: The study compared mesothelioma subtypes and tumour mutations, not asbestos doses. Asbestos history was known for 52 patients. Of these, 46 (88.5%) had exposure: 40 direct (77%) and 6 indirect (11.5%). No fiber types were reported.
• Main results:
  • Across all 69 tumours, 63 (91.3%) had at least one mutation, 76.8% had more than one, and 6 (8.7%) had none in the genes analysed.
  • MXRA5 was mutated in 51.3% (20/39) of biphasic versus 26.7% (8/30) of epithelioid tumours (p = 0.050).
  • NOD2 was mutated in 25.6% (10/39) of biphasic versus 3.3% (1/30) of epithelioid tumours (p = 0.018).
  • ACTG1 mutations were more frequent in epithelioid tumours (p = 0.002). The table shows 9/30 (30.0%) in epithelioid versus 1/39 (2.6%) in biphasic tumours.
  • Within biphasic tumours, MXRA5 mutations were associated with a larger sarcomatoid component.
  • In the 16-tumour biphasic validation set, MXRA5 and NOD2 were the most frequently mutated genes.
  • Among the 39 biphasic patients, XRCC6 mutations and a poorer performance status were associated with reduced survival in both univariate and multivariate analysis. For XRCC6, the multivariate hazard ratio was 8.16 (95% CI 1.16–57.2, p = 0.035).
  • Among biphasic patients, NOD2 mutations were not associated with survival in univariate analysis (HR 0.93, 95% CI 0.42–2.05, p = 0.852). In the multivariable model they were associated with better survival (HR 0.21, 95% CI 0.06–0.79, p = 0.021).
  • Across the whole cohort, no significant correlations were found between mutated genes and tumour stage.
• The authors' conclusion: The authors concluded that four genes (MXRA5, NOD2, CDH8, XRCC6) were preferentially and frequently altered in biphasic mesothelioma and may help in diagnosing it. They also concluded that genetic analysis at diagnosis may improve risk-based stratification of patients.
• Limitations the authors state:
  • Retrospective multicentre study of a limited cohort, with possible selection bias and statistical limits due to sample size.
  • The small cohort and varied treatment protocols complicate survival evaluation. The authors also state that no single alteration alone was shown to predict outcome.
  • A targeted gene panel was used rather than a wider approach such as whole exome sequencing.
  • Gene amplification could not be evaluated with this method.

Topics

Medical terms in this study, explained in our Lexicon: Biphasic Mesothelioma, Pleural Mesothelioma, Epithelioid, Sarcomatoid.

Related studies

• Survival results in biphasic malignant pleural mesothelioma patients: A multicentric analysis — F. Lococo, F. Torricelli, et al. (2020)
• Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequent SETDB1 mutations in malignant pleural mesotheliomas — H.C. Kang, H.K. Kim, et al. (2016)
• Spatially resolved, high-dimensional transcriptomics sorts out the evolution of biphasic malignant pleural mesothelioma: new paradigms for immunotherapy — F. Torricelli, B. Donati, et al. (2023)
• Differentially expressed alternatively spliced genes in malignant pleural mesothelioma identified using massively parallel transcriptome sequencing — L. Dong, R.V. Jensen, et al. (2009)
• Mesothelioma cell heterogeneity identified by single cell RNA sequencing — L. Wu, Z. Wang, et al. (2025)
• A Subset of Mesotheliomas With Improved Survival Occurring in Carriers of BAP1 and Other Germline Mutations — S. Pastorino, Y. Yoshikawa, et al. (2018)

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