Epithelioid Mesothelioma Patients with Very Long Survival Display Defects in DNA Repair

SIMPLE SUMMARY: DNA repair has an important role in malignant pleural mesothelioma tumorigenesis and progression. The prognosis of mesothelioma patients is very poor and predictive biomarkers are needed for better management. We analyzed the expression of more than 700 genes involved in different cellular pathways using Nanostring technology in a cohort of 54 epithelioid malignant pleural mesothelioma patients. The median survival time of the cohort was 16.9 months and this cut-off was used to classify patients as long and short survivors (LS/SS) with, respectively, an overall survival ≥ and <16.9 months, as well as very long and very short survivors (VLS/VSS) with an overall survival ≥ than 33.8 and < than 8.45 months. A down-regulation of the DNA damage response pathway was found in LS versus SS. These data were validated by the finding that VLS had a lower number of RAD51- and BRCA1-positive tumor cells than VSS. If these data can be corroborated, an easy and cost-effective test could be routinely used to better manage epithelioid malignant pleural mesothelioma patients. ABSTRACT: Aim: DNA repair has an important role in malignant pleural mesothelioma (MPM) tumorigenesis and progression. Prognostic/predictive biomarkers for better management of MPM patients are needed. In the present manuscript, we analyzed the expression of more than 700 genes in a cohort of MPM patients to possibly find biomarkers correlated with survival. Methods: A total of 54 MPM patients, all with epithelioid histology, whose survival follow-up and formalin-fixed paraffin-embedded tumors were available, were included in the study. Gene expression profiles were evaluated using a Nanostring platform analyzing 760 genes involved in different cellular pathways. The percentages of proliferating tumor cells positive for RAD51 and BRCA1 foci were evaluated using an immunofluorescence assay, as a readout of homologous recombination repair status. Results: Patient median survival time was 16.9 months, and based on this value, they were classified as long and short survivors (LS/SS) with, respectively, an overall survival ≥ and <16.9 months as well as very long and very short survivors (VLS/VSS) with an overall survival ≥ than 33.8 and < than 8.45 months. A down-regulation in the DNA damage/repair expression score was observed in LS and VLS as compared to SS and VSS. These findings were validated by the lower number of both RAD51 and BRCA1-positive tumor cells in VLS as compared to VSS. Conclusions: The down-regulation of DNA repair signature in VLS was functionally validated by a lower % of RAD51 and BRCA1-positive tumor cells. If these data can be corroborated in a prospective trial, an easy, cost-effective test could be routinely used to better manage treatment in MPM patients.