Mismatch repair protein defects and microsatellite instability in malignant pleural mesothelioma.

Abstract

Malignant pleural mesothelioma is an aggressive malignancy with limited systemic therapy options. Promising results have been reported with use of anti-PD-1 therapy, however it appears 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 tumour 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 centres have adopted IHC to screen for MSI-high colorectal cancers. We profiled a large mesothelioma cohort to determine the rate of negative immunohistochemistry for the four common mismatch repair proteins. A tissue microarray comprising 335 patients with malignant pleural mesothelioma were used. Immunohistochemistry (IHC) for the four common mismatch repair proteins (MLH1, PMS2, MSH2 and MSH6) was performed. PD-L1 IHC staining with the E1L3N clone was also performed. DNA was isolated from IHC equivocal samples and analysed for microsatellite instability using the Promega MSI Analysis System, Version 1.2. Of 335 patients profiled, 329 had intact mismatch repair proteins by immunohistochemistry. Six samples with absent mismatch repair protein immunohistochemistry analysis were analysed for MSI and confirmed to be negative. Of the six IHC+ samples, five were absent for PD-L1 staining and one sample had more than 5% staining. In this large retrospective series, we were unable to identify any malignant pleural mesothelioma patients with microsatellite instability. Response to anti-PD-1 based immunotherapy may be driven by other mechanisms.