Gene Expression Analysis of Biphasic Pleural Mesothelioma: New Potential Diagnostic and Prognostic Markers

Our plain-English summary of Gene Expression Analysis of Biphasic Pleural Mesothelioma: New Potential Diagnostic and Prognostic Markers, by R. Bruno, A.M. Poma, G. Alì, et al (Diagnostics, 2022).

The study

• Authors: R. Bruno, A.M. Poma, G. Alì, C. Distefano, A. Proietti, A. Chella, M. Lucchi, F. Melfi, R. Franco, G. Fontanini
• Journal: Diagnostics
• Published: 2022;12(3)
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Biphasic is the second most common histotype of pleural mesothelioma (PM). It shares epithelioid and sarcomatoid features and is challenging to diagnose. The aim of this study was to identify biphasic PM markers to improve subtyping and prognosis definition. The expression levels of 117 cancer genes, evaluated using the nanoString system, were compared between the three major histotypes (epithelioid, sarcomatoid, and biphasic), and expression differences within biphasic PM were evaluated in relation to the percentage of epithelioid components. Biphasic PM overexpressed CTNNA1 and TIMP3 in comparison to sarcomatoid, and COL16A1 and SDC1 in comparison to epithelioid PM. CFB, MSLN, CLDN15, SERPINE1, and PAK4 were deregulated among all histotypes, leading to the hypothesis of a gradual expression from epithelioid to sarcomatoid PM. According to gene expression, biphasic PM samples were divided in two clusters with a significant difference in the epithelioid component. ADCY4, COL1A1, and COL4A2 were overexpressed in the biphasic group with a low percentage of epithelioid component. Survival analysis using TCGA data showed that high COL1A1 and COL4A2 expression levels correlate with poor survival in PM patients. Herein, we identified markers with the potential to improve diagnosis and prognostic stratification of biphasic PM, which is still an orphan tumor.

In plain English

This laboratory study examined gene activity in archived pleural mesothelioma tumor samples from Pisa and Naples, Italy. It focused on the biphasic type, which mixes epithelioid and sarcomatoid features. The authors measured 117 cancer-related genes in 25 biphasic, 32 epithelioid and 18 sarcomatoid samples. Asbestos exposure was not examined. In their overall gene patterns, biphasic tumors partly overlapped with the other types. Four genes were more active only in biphasic tumors: CTNNA1 and TIMP3 compared with sarcomatoid tumors, and COL16A1 and SDC1 compared with epithelioid tumors. Five genes (CFB, MSLN, CLDN15, SERPINE1 and PAK4) differed among all three types. The biphasic samples split into two gene-based groups whose share of epithelioid tissue differed (median 40% versus 55%, p = 0.03). ADCY4, COL1A1 and COL4A2 were more active in the group with less epithelioid tissue. In a separate public dataset (TCGA), high COL1A1 and COL4A2 levels were associated with worse overall survival. The authors proposed these genes as potential diagnostic and prognostic markers. They noted a limited sample size, no clinical data for their own patients, and few biphasic cases in TCGA.

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 laboratory study of gene expression in archived tumor samples, with survival analysis in a separate public dataset (TCGA)
• Who was studied: 75 pleural mesothelioma samples from the pathology archives of University Hospital of Pisa and Luigi Vanvitelli University Hospital of Naples, Italy: 25 biphasic (13 biopsies, 12 surgical resections), 32 epithelioid (10 biopsies, 22 resections) and 18 sarcomatoid (11 biopsies, 7 resections); collection dates not given
• Exposure: Asbestos exposure was not studied; the study measured expression of 117 cancer genes previously reported as deregulated in pleural mesothelioma, using the nanoString system
• Main results:
  • In principal component analysis, epithelioid and sarcomatoid tumors separated clearly, while biphasic tumors were more heterogeneous and overlapped with the other two types
  • 34 genes differed between biphasic and epithelioid tumors, 68 between sarcomatoid and epithelioid tumors, and 34 between sarcomatoid and biphasic tumors
  • Only four genes were specifically up-regulated in biphasic tumors: CTNNA1 and TIMP3 compared with sarcomatoid tumors, and COL16A1 and SDC1 compared with epithelioid tumors
  • Five of the 117 genes (CFB, MSLN, CLDN15, SERPINE1 and PAK4) were deregulated among all three types
  • Biphasic samples fell into two gene-expression clusters whose percentage of epithelioid component differed significantly (p = 0.03): median 40% (interquartile range 20 to 52.5%) in group 1 and 55% (interquartile range 50 to 72.5%) in group 2
  • ADCY4, COL1A1 and COL4A2 were significantly up-regulated in the biphasic cluster with a low percentage of epithelioid component
  • In TCGA mesothelioma data, high COL1A1 and COL4A2 expression was correlated with worse overall survival in pleural mesothelioma patients
• The authors' conclusion: The authors concluded that CTNNA1, TIMP3, COL16A1, SDC1, CFB, MSLN, CLDN15, SERPINE1 and PAK4 are potential diagnostic markers that could help distinguish biphasic tumors from the other subtypes. They proposed ADCY4, COL1A1 and COL4A2 as potential prognostic markers in biphasic pleural mesothelioma.
• Limitations the authors state:
  • The sample size was limited, although the authors considered it relatively high given how rare these tumors are
  • Survival could not be analyzed in the authors' own cohort because clinical data were not available
  • The TCGA validation data contained mostly epithelioid cases, with few biphasic and sarcomatoid cases, so prospective validation is needed
  • The nanoString method requires specific equipment and expertise; validation with more common techniques such as immunohistochemistry is warranted

Topics

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

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