Define the Two Molecular Subtypes of Epithelioid Malignant Pleural Mesothelioma

Our plain-English summary of Define the Two Molecular Subtypes of Epithelioid Malignant Pleural Mesothelioma, by U.A.K. Saddozai, F. Wang, S. Khattak, et al (Cells, 2022).

The study

• Authors: U.A.K. Saddozai, F. Wang, S. Khattak, M.U. Akbar, M. Badar, N.H. Khan, L. Zhang, W. Zhu, L. Xie, Y. Li, X. Ji, X. Guo
• Journal: Cells
• Published: 2022;11(18)
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a fatal disease of respiratory system. Despite the availability of invasive biomarkers with promising results, there are still significant diagnostic and therapeutic challenges in the treatment of MPM. One of three main mesothelioma cell types, epithelioid mesothelioma makes up approximately 70% of all mesothelioma cases. Different observational findings are under process, but the molecular heterogeneity and pathogenesis of epithelioid malignant pleural mesothelioma (eMPM) are still not well understood. Through molecular analysis, expression profiling data were used to determine the possibility and optimal number of eMPM molecular subtypes. Next, clinicopathological characteristics and different molecular pathways of each subtype were analyzed to prospect the clinical applications and advanced mechanisms of eMPM. In this study, we identified two distinct epithelioid malignant pleural mesothelioma subtypes with distinct gene expression patterns. Subtype I eMPMs were involved in steroid hormone biosynthesis, porphyrin and chlorophyll metabolism, and drug metabolism, while subtype II eMPMs were involved in rational metabolism, tyrosine metabolism, and chemical carcinogenesis pathways. Additionally, we identified potential subtype-specific therapeutic targets, including CCNE1, EPHA3, RNF43, ROS1, and RSPO2 for subtype I and CDKN2A and RET for subtype II. Considering the need for potent diagnostic and therapeutic biomarkers for eMPM, we are anticipating that our findings will help both in exploring underlying mechanisms in the development of eMPM and in designing targeted therapy for eMPM.

In plain English

This study re-analyzed existing gene expression data (measurements of how active each gene is) from tumors of patients with epithelioid malignant pleural mesothelioma (eMPM), a cancer of the lining around the lungs. It did not study asbestos exposure. The authors used a computer clustering method on 57 cases from The Cancer Genome Atlas (TCGA) and 39 cases from a public dataset called GSE29354. In TCGA, 55 of the 57 cases were clearly assigned: 44 to subtype I and 11 to subtype II. The second dataset also split into two subtypes, and the authors reported that the subtypes matched across the two datasets. In TCGA, median overall survival was 463 days for subtype II patients and 791 days for subtype I patients (p = 0.0049). The subtypes differed in which genes and biological pathways were more active. By comparing these genes with a database of drug targets, the authors listed CCNE1, EPHA3, RNF43, ROS1 and RSPO2 as possible targets for subtype I, and CDKN2A and RET for subtype II. The authors concluded that the subtypes could help develop subtype-specific therapies, and noted that further studies may be required before clinical use.

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: Bioinformatics analysis of existing tumor gene expression datasets: consensus clustering to define molecular subtypes, with checking in a second independent dataset
• Who was studied: Epithelioid malignant pleural mesothelioma tumor cases from two public databases: 57 cases from TCGA and 39 samples from the GEO dataset GSE29354. The study's own text gives no locations or dates for these patients.
• Exposure: Not studied. The article analyzed tumor gene expression; asbestos exposure is mentioned only as background from other studies.
• Main results:
  • In the TCGA cohort, two subtypes were found. 55 of 57 samples had a positive silhouette value and were analyzed: 44 were subtype I and 11 were subtype II.
  • In the GSE29354 dataset (39 cases), clustering also identified two molecular subtypes.
  • SubMap analysis found that the two TCGA subtypes were significantly correlated with the two GSE29354 subtypes.
  • In TCGA, median overall survival was 463 days for subtype II patients and 791 days for subtype I patients (p = 0.0049).
  • Right-sided tumors made up 72.2% of subtype I and 54.5% of subtype II; this difference was not statistically significant (p = 0.3492).
  • 1520 genes differed in expression between the subtypes: 1161 were higher in subtype I and 359 were higher in subtype II.
  • Genes more active in subtype I were enriched in 15 KEGG pathways, including steroid hormone biosynthesis, porphyrin and chlorophyll metabolism, and drug metabolism. Subtype II was enriched in 7 KEGG pathways, including rational metabolism, tyrosine metabolism and chemical carcinogenesis.
  • Comparison with the TARGET database identified five potential target genes for subtype I (CCNE1, EPHA3, RNF43, ROS1, RSPO2) and two for subtype II (CDKN2A, RET).
  • In a survival analysis of these seven genes using TCGA data in GEPIA, expression was significantly related to overall survival for CCNE1 (p = 2.1 times 10 to the minus 5), ROS1 (p = 0.0035), RSPO2 (p = 0.03) and CDKN2A (p = 5.9 times 10 to the minus 7). It was not significant for EPHA3 (p = 0.25), RNF43 (p = 0.77) or RET (p = 0.46).
• The authors' conclusion: The authors concluded that they defined distinct molecular subtypes of eMPM in two independent cohorts. In their view, this provides information for developing individualized, subtype-specific therapies.
• Limitations the authors state:
  • The authors state that further studies may be required before the targeted genes can be translated into clinical use.
  • The authors note that limited prognosis and survival data are available for the epithelioid subtype.

Topics

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

Medical terms in this study, explained in our Lexicon: Epithelioid, Pleural Mesothelioma, Biomarker, Mesothelioma, Carcinogenesis, ROS1, CDKN2A, Targeted Therapy.

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