Transcriptomic Analysis of the Claudin Interactome in Malignant Pleural Mesothelioma: Evaluation of the Effect of Disease Phenotype, Asbestos Exposure, and CDKN2A Deletion Status

Our plain-English summary of Transcriptomic Analysis of the Claudin Interactome in Malignant Pleural Mesothelioma: Evaluation of the Effect of Disease Phenotype, Asbestos Exposure, and CDKN2A Deletion Status, by E. Rouka, G.D. Vavougios, E.I. Solenov, et al (Frontiers in Physiology, 2017).

The study

• Authors: E. Rouka, G.D. Vavougios, E.I. Solenov, K.I. Gourgoulianis, C. Hatzoglou, S.G. Zarogiannis
• Journal: Frontiers in Physiology
• Published: 2017;8:156
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor primarily associated with asbestos exposure. Early detection of MPM is restricted by the long latency period until clinical presentation, the ineffectiveness of imaging techniques in early stage detection and the lack of non-invasive biomarkers with high sensitivity and specificity. In this study we used transcriptome data mining in order to determine which CLAUDIN (CLDN) genes are differentially expressed in MPM as compared to controls. Using the same approach we identified the interactome of the differentially expressed CLDN genes and assessed their expression profile. Subsequently, we evaluated the effect of tumor histology, asbestos exposure, CDKN2A deletion status, and gender on the gene expression level of the claudin interactome. We found that 5 out of 15 studied CLDNs (4, 5, 8, 10, 15) and 4 out of 27 available interactors (S100B, SHBG, CDH5, CXCL8) were differentially expressed in MPM specimens vs. healthy tissues. The genes encoding the CLDN-15 and S100B proteins present differences in their expression profile between the three histological subtypes of MPM. Moreover, CLDN-15 is significantly under-expressed in the cohort of patients with previous history of asbestos exposure. CLDN-15 was also found significantly underexpressed in patients lacking the CDKN2A gene. These results warrant the detailed in vitro investigation of the role of CDLN-15 in the pathobiology of MPM.

In plain English

This study reanalyzed existing, publicly available microarray gene-activity data on malignant pleural mesothelioma (MPM). It looked at claudin genes, which help form tight junctions between cells, and at genes that interact with them. In one dataset (40 MPM samples, 9 controls), CLDN-15 was more active in MPM, and CLDN-4, -5, -8 and -10 were less active. Four interacting genes (S100B, SHBG, CDH5, CXCL8) were also less active. A second dataset had 69 epithelioid, 10 sarcomatoid and 20 biphasic tumors. In it, CLDN-15 was higher in epithelioid than biphasic or sarcomatoid tumors, and S100B was higher in sarcomatoid than epithelioid tumors. Among these patients, CLDN-15 was less active in the 58 who reported asbestos exposure than in the 29 reporting none (p = 0.004). It was also less active in patients with a homozygous (both-copy) CDKN2A gene deletion than in those without one (p = 0.035). No statistically significant differences between male and female patients were found for any of these genes. The authors concluded that the results underline an epigenetic effect of asbestos on CLDN-15. They noted the first dataset lacked asbestos exposure information.

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: Secondary analysis (data mining) of previously published microarray gene-expression datasets from the Oncomine database, plus database searches for genes that interact with the claudins
• Who was studied: Gordon Mesothelioma study dataset: 40 surgically excised MPM samples and 9 controls (5 pleura, 4 lung). Lopez-Rios Mesothelioma study dataset: 69 epithelioid, 10 sarcomatoid and 20 biphasic MPM samples. Data were downloaded from Oncomine in March 2013.
• Exposure: Reported asbestos exposure history (exposed or unexposed) in the Lopez-Rios dataset: 58 exposed, 29 unexposed, and 12 unknown (excluded). No fiber types, products, jobs or doses are given. The study also looked at CDKN2A gene deletion status (59 deletion, 29 no deletion, 19 not available), tumor histology and gender.
• Main results:
  • MPM samples compared with healthy controls: CLDN-15 was over-expressed (q less than 0.002; fold change 6.351 in Table 2).
  • MPM samples compared with controls: CLDN-4, -5, -8 and -10 were under-expressed (q = 0.036, 0.001, 0.003 and 0.001 respectively).
  • MPM samples compared with controls: four of the 27 claudin-interacting genes with available data were under-expressed: S100B (q = 0.001), SHBG (q = 0.004), CDH5 (q = 0.015) and CXCL8 (q = 0.007).
  • Within MPM tumors: CLDN-15 expression was higher in the epithelioid subtype than in the biphasic (p less than 0.01) and sarcomatoid (p less than 0.001) subtypes.
  • Within MPM tumors: S100B expression was higher in the sarcomatoid subtype than in the epithelioid subtype (p less than 0.05).
  • Among MPM patients: CLDN-15 was under-expressed in those with reported asbestos exposure compared with unexposed patients (p = 0.004).
  • Among MPM patients: CLDN-15 was under-expressed in those with homozygous deletion of CDKN2A compared with patients without the deletion (p = 0.035).
  • Among MPM patients: expression of the other differentially expressed genes was not influenced by asbestos exposure or CDKN2A deletion status.
  • Among MPM patients: the male/female comparison (t-test or Mann-Whitney test, significance set at p less than 0.05) found no difference for CLDN-4, -5, -8, -10, -15, S100B, SHBG, CDH5 or CXCL8. The authors described this as not influenced by gender.
• The authors' conclusion: The authors concluded that the results suggest a distinct gene expression profile of the claudin interactome in MPM and underline an epigenetic effect of asbestos on the transcriptional level of the CLDN-15 gene. They stated that CLDN-15 and S100B should be investigated further as gene biomarkers, including for telling the MPM subtypes apart.
• Limitations the authors state:
  • The Gordon dataset (MPM compared with controls) had no information on asbestos exposure history, so asbestos-related gene expression differences between patients and controls could not be assessed.
  • The authors stated that the results need further investigation in the clinical setting, in a large series of MPM patients compared with healthy asbestos-exposed controls.
  • Duration and type of asbestos exposure (environmental or occupational) were not available; the authors stated these should be included in future research.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Asbestos Exposure, CDKN2A, Latency, Biomarker, Histology, Histological Subtype.

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