Identification of Novel Diagnostic Markers for Malignant Pleural Mesothelioma Using a Reverse Translational Approach Based on a Rare Synchronous Tumor

Our plain-English summary of Identification of Novel Diagnostic Markers for Malignant Pleural Mesothelioma Using a Reverse Translational Approach Based on a Rare Synchronous Tumor, by T. Naka, Y. Hatanaka, Y. Tabata, et al (Diagnostics, 2022).

The study

• Authors: T. Naka, Y. Hatanaka, Y. Tabata, A. Takasawa, H. Akiyama, Y. Hida, H. Okada, K.C. Hatanaka, T. Mitsuhashi, K. Kushitani, V.J. Amatya, Y. Takeshima, K. Inai, K. Kaga, Y. Matsuno
• Journal: Diagnostics
• Published: 2022;12(2)
• Read it: PubMed · Publisher · Free full text

Abstract

Although the routine use of immunohistochemistry has improved the accuracy of histopathologic diagnosis in clinical practice, new methods for discovering novel diagnostic markers are still needed. We sought new diagnostic markers for malignant pleural mesothelioma (MPM) using a reverse translational approach with limited archival tissues from a very rare case. Total RNA extracted from formalin-fixed paraffin-embedded (FFPE) tissues of a synchronous collision tumor consisting of MPM and pulmonary adenocarcinoma (PAC) was employed for gene expression profiling (GEP) analysis. Among the 54 genes selected by GEP analysis, we finally identified the following two candidate MPM marker genes: PHGDH and TRIM29. Immunohistochemical analysis of 48 MM and 20 PAC cases showed that both PHGDH and TRIM29 had sensitivity and specificity almost equivalent to those of calretinin (sensitivity 50% and 46% vs. 63%, and specificity 95% and 100% vs. 100%, respectively). Importantly, of the 23 epithelioid MMs, all 3 calretinin-negative cases were positive for TRIM29. These two markers may be diagnostically useful for immunohistochemical distinction between MPMs and PACs. This successful reverse translational approach based on FFPE samples from one very rare case encourages the further use of such samples for the development of novel diagnostic markers.

In plain English

This laboratory study looked for new tissue-staining markers to help pathologists tell malignant pleural mesothelioma apart from pulmonary adenocarcinoma, a lung cancer. It started from one rare tumor, removed from the right lung of a 77-year-old man with a history of long-term smoking and asbestos exposure, in which a mesothelioma and an adenocarcinoma had grown together. Comparing gene activity in the two parts, the authors found 54 genes more than eight-fold more active in the mesothelioma, and finally selected two, PHGDH and TRIM29. They then stained 48 mesotheliomas and 20 adenocarcinomas from two Japanese university hospitals. The text reported sensitivity of 50% for PHGDH and 46% for TRIM29, against 63% for the standard marker calretinin. It reported specificity of 95% for PHGDH and 100% for TRIM29, each tested on 20 adenocarcinomas, against 100% for calretinin, which was tested on only 14. All 3 calretinin-negative epithelioid mesotheliomas stained for TRIM29. No sarcomatoid mesothelioma stained for either new marker. Both markers also stained some other cancers, including lung squamous cell carcinoma. The authors concluded the markers may be diagnostically useful. They named retrospective case collection as a limitation.

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 marker-discovery study: gene expression profiling of a single rare collision tumor, followed by immunohistochemical testing on retrospectively collected tumor tissue
• Who was studied: Starting case: a collision tumor (epithelioid MPM plus PAC) in the right lung of a 77-year-old man. Test series: 48 malignant mesotheliomas (23 epithelioid, 13 biphasic, 12 sarcomatoid; 45 pleural and one each from pericardium, peritoneum and tunica vaginalis) and 20 pulmonary adenocarcinomas, obtained January 1994 to December 2010 at Hokkaido University Hospital and Hiroshima University Hospital. A tissue microarray of 266 samples from 16 other tumor types (Hokkaido, 2000 to 2003) was also tested.
• Exposure: Asbestos exposure was not studied. The single index patient is described as having a history of long-term smoking and asbestos exposure; no fiber type, job or dose is given.
• Main results:
  • In the index collision tumor, 949 RNAs were identified (718 increased and 231 decreased in the MPM lesion relative to the PAC lesion). 54 genes showed more than 8-fold higher expression in the MPM lesion.
  • After excluding known MPM markers and validating nine genes, the authors identified two candidate MPM marker genes, PHGDH and TRIM29.
  • For the 48 mesotheliomas versus the pulmonary adenocarcinomas, the text gives sensitivity of 50% (PHGDH) and 46% (TRIM29) versus 63% (calretinin), and specificity of 95% and 100% versus 100%. Table 3 gives PHGDH 25/48 (52), TRIM29 22/48 (46) and calretinin 30/48 (63) positive in MM. In PAC, PHGDH was positive in 1/20, TRIM29 in 0/20 and calretinin in 0/14.
  • In the 23 epithelioid mesotheliomas, PHGDH and TRIM29 were each positive in 17/23 (74%) and calretinin in 20/23 (87).
  • All 3 calretinin-negative cases among the 23 epithelioid mesotheliomas were positive for TRIM29.
  • Sarcomatoid mesotheliomas (n = 12) were positive for PHGDH, TRIM29 and calretinin in 0%, 0% and 8% of cases, respectively.
  • Only 1 of 20 pulmonary adenocarcinomas showed intermediate (2+) PHGDH staining, in a limited area with a micropapillary growth pattern.
  • In other tumors, both markers were expressed in lung squamous cell carcinoma (PHGDH 6/9, TRIM29 9/9) and urothelial carcinoma (PHGDH 7/10, TRIM29 9/10). PHGDH was also expressed in prostatic, breast ductal, endometrial and ovarian cancers, and TRIM29 in squamous cell carcinoma of the uterine cervix.
  • In normal tissues, both markers were occasionally detected in cervical squamous epithelium, prostate basal cells, bronchial basal cells and mesothelial cells.
• The authors' conclusion: The authors concluded that PHGDH and TRIM29 may be useful diagnostic markers for distinguishing MPM from PAC. They also concluded that their approach, based on one rare collision tumor, encourages further use of such samples to develop new diagnostic markers.
• Limitations the authors state:
  • The cohort data were collected retrospectively, so selection bias was not completely eliminated.
  • Expression in other tumors and normal tissues was examined only on tissue microarrays, so variation within tumors was not examined.
  • The antibodies used were described as not really suited for routine paraffin-section immunohistochemistry.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Immunohistochemistry, Adenocarcinoma, Calretinin, Epithelioid.

Related studies

• Comparative genetic analysis of a rare synchronous collision tumor composed of malignant pleural mesothelioma and primary pulmonary adenocarcinoma — T. Naka, Y. Hatanaka, et al. (2016)
• Identification of DAB2 and Intelectin-1 as Novel Positive Immunohistochemical Markers of Epithelioid Mesothelioma by Transcriptome Microarray Analysis for Its Differentiation From Pulmonary Adenocarcinoma — M. Kuraoka, V.J. Amatya, et al. (2017)
• A novel translational approach for human malignant pleural mesothelioma: heparanase-assisted dual virotherapy — Y. Watanabe, T. Kojima, et al. (2010)
• MUC4, a novel immunohistochemical marker identified by gene expression profiling, differentiates pleural sarcomatoid mesothelioma from lung sarcomatoid carcinoma — V.J. Amatya, K. Kushitani, et al. (2017)
• Local Therapies and Modulation of Tumor Surrounding Stroma in Malignant Pleural Mesothelioma: A Translational Approach — D. Lisini, S. Lettieri, et al. (2021)
• Identification of novel markers for the diagnosis of malignant pleural mesothelioma — F. Gueugnon, S. Leclercq, et al. (2011)

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