Mismatch Repair Protein Defects and Microsatellite Instability in Malignant Pleural Mesothelioma

Our plain-English summary of Mismatch Repair Protein Defects and Microsatellite Instability in Malignant Pleural Mesothelioma, by S. Arulananda, B. Thapa, M. Walkiewicz, et al (Journal of Thoracic Oncology, 2018).

The study

• Authors: S. Arulananda, B. Thapa, M. Walkiewicz, G.V. Zapparoli, D.S. Williams, A. Dobrovic, T. John
• Journal: Journal of Thoracic Oncology
• Published: 2018;13(10):1588-1594
• Cited by: 36 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma is an aggressive malignancy with limited systemic therapy options. Promising results have been reported with use of anti-programmed cell death 1 therapy; however, its benefits appear to be confined to a subgroup of patients. Microsatellite instability (MSI) results from the inactivation of DNA mismatch repair genes and results in a high tumor mutational burden, a phenomenon that has not been seen with mesothelioma. MSI and protein absence have been shown to correlate in colorectal cancer, such that most centers have adopted immunohistochemistry (IHC) to screen for MSI-high colorectal cancers. We profiled a large cohort of patients with mesothelioma to determine the rate of negative IHC staining results the four common mismatch repair proteins.

Design: A tissue microarray comprising 335 patients with malignant pleural mesothelioma were used. IHC for the four common mismatch repair proteins (mutL homolog 1; PMS1 homolog 2, mismatch repair system component; mutS homolog 2; and mutS homolog 6) was performed. Programmed death ligand 1 IHC staining with the E1L3N clone was also performed. DNA was isolated from IHC equivocal samples and analyzed for microsatellite instability by using the Promega MSI Analysis System (version 1.2, Promega, Madison, WI).

Results: Of the patients profiled, 329 had intact mismatch repair proteins by IHC. Six samples with IHC testing results indicating absent mismatch repair protein were analyzed for MSI and confirmed to be negative. Of the six IHC-negative samples, five were negative for programmed death ligand 1 staining and one sample had more than 5% staining.

Conclusion: In this large retrospective series, we were unable to identify any patients with malignant pleural mesothelioma with microsatellite instability. Response to anti-programmed cell death 1-based immunotherapy may be driven by other mechanisms.

Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

In plain English

This brief report looked for defects in DNA mismatch repair, and the resulting microsatellite instability (MSI), in malignant pleural mesothelioma. The authors stained archived tumor samples from 335 patients, collected at the Austin Hospital between December 1989 and December 2013, for four mismatch repair proteins (MLH1, PMS2, MSH2 and MSH6). Of these patients, 74% had known asbestos exposure. The article does not describe the exposures further. All four proteins were present in 329 of 335 cases (98%). Six cases lacked at least one protein, but DNA testing found no MSI in any of them. These six were all men with the epithelioid subtype. None had a significant family history of cancer, and none had been treated with an immune checkpoint inhibitor. Five of the six showed no staining for PD-L1, a protein that can help tumors evade the immune system. The article reports the sixth patient's PD-L1 result inconsistently. The authors concluded that their data suggest MSI is rare in mesothelioma. They noted that the small tissue samples and uneven staining carried a risk of false-negative results.

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 archived tumor tissue (tissue microarrays), using immunohistochemistry for mismatch repair proteins and follow-up DNA testing for microsatellite instability
• Who was studied: Archived tumor specimens from 335 patients with malignant pleural mesothelioma, obtained from the Austin Hospital pathology department and collected from December 1989 to December 2013. Patients were aged 24 to 87 (mean 66), 280 male and 55 female, and 65% had epithelioid, 13% sarcomatoid and 22% biphasic tumors.
• Exposure: Not an exposure study. Asbestos exposure was recorded as a patient characteristic: 247 of 335 patients (74%) had known exposure and 88 (26%) had no known exposure. No fiber types, products or jobs are described.
• Main results:
  • All four mismatch repair proteins (MLH1, PMS2, MSH2 and MSH6) were present by immunohistochemistry in 329 of 335 cases (98%).
  • Six cases showed absent staining for at least one mismatch repair protein. When tested for microsatellite instability, all six were negative.
  • In Table 2, three of the six lacked MSH2 alone, two lacked both MSH2 and MSH6, and one lacked both MLH1 and PMS2.
  • All six patients with absent protein staining were male and had the epithelioid subtype, aged 49 to 79 years.
  • None of the six had a significant family history of cancer.
  • None of the six patients with deficient mismatch repair had been treated with an immune checkpoint inhibitor, so response to such treatment could not be assessed.
  • Among the six, PD-L1 staining was negative in five. For the sixth patient, the Results text says less than 5%, while Table 2 and the abstract say more than 5%.
  • In PD-L1 data from 319 of the samples, previously reported by the same group, median overall survival was worse in patients with high PD-L1 positivity regardless of histological subtype. For example, in epithelioid tumors median survival was 14.9 months (PD-L1-negative), 15.2 months (PD-L1-positive) and 5.3 months (PD-L1-highly positive).
• The authors' conclusion: The authors concluded that their data suggest MSI is rare in mesothelioma, in agreement with the low mutational burden seen in other studies.
• Limitations the authors state:
  • The tissue microarrays contained only limited tumor sample, and immunohistochemical staining varied across tumor samples, with a risk of false-negative results.
  • Responses to immune checkpoint inhibitors could not be assessed, because none of the patients with deficient mismatch repair had received them.

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: Microsatellite Instability (MSI-H), Pleural Mesothelioma, Systemic Therapy, Tumor Mutational Burden (TMB), Mesothelioma, Colorectal Cancer, Immunohistochemistry, Immunotherapy.

Related studies

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• Mesothelioma Mouse Models with Mixed Genomic States of Chromosome and Microsatellite Instability — Y. Song, S.S. Baxter, et al. (2022)
• Unusual DNA mismatch repair-deficient tumors in Lynch syndrome: a report of new cases and review of the literature — Y. Karamurzin, Z. Zeng, et al. (2012)
• The Association of BAP1 Loss-of-Function With the Defect in Homologous Recombination Repair and Sensitivity to PARP-Targeted Therapy — H. Yang, D. Xu, et al. (2020)
• BRCA1-Associated Protein 1 (BAP1) Immunohistochemical Expression as a Diagnostic Tool in Malignant Pleural Mesothelioma Classification: A Large Retrospective Study — L. Righi, E. Duregon, et al. (2016)
• Immunohistochemical detection of MTAP and BAP1 protein loss for mesothelioma diagnosis: Comparison with 9p21 FISH and BAP1 immunohistochemistry — T. Hida, M. Hamasaki, et al. (2017)

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