Mutational Profiling of Driver Tumor Suppressor and Oncogenic Genes in Brazilian Malignant Pleural Mesotheliomas

Background:Malignant pleural mesothelioma (MPM) is a highly lethal disease comprising a heterogeneous group of tumors with challenging to predict biological behavior. The diagnosis is complex, and the histologic classification includes 2 major subtypes of MPM: epithelioid (similar to 60% of cases) and sarcomatous (similar to 20%). Its identification depends upon pathological investigation supported by clinical and radiological evidence and more recently ancillary molecular testing. Treatment options are currently limited, with no known targeted therapies available.Objectives:To elucidate the mutation profile of driver tumor suppressor and oncogenic genes in a cohort of Brazilian patients.Methods:We sequenced 16 driver genes in a series of 43 Brazilian malignant mesothelioma (MM) patients from 3 distinct Brazilian centers. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor tissue blocks, and theTERTpromoter region was amplified by PCR followed by direct capillary sequencing. The Illumina TruSight Tumor 15 was used to evaluate 250 amplicons from 15 genes associated with solid tumors (AKT1, GNA11, NRAS, BRAF, GNAQ, PDGFRA, EGFR, KIT, PIK3CA, ERBB2, KRAS, RET, FOXL2, MET,andTP53). Library preparation with the TruSight Tumor 15 was performed before sequencing at the MiSeq platform. Data analysis was performed using Sophia DDM software.Results:Out of 43 MPM patients, 38 (88.4%) were epithelioid subtype and 5 (11.6%) were sarcomatoid histotype. Asbestos exposure was present in 15 (39.5%) patients with epithelioid MPM and 3 (60%) patients with sarcomatoid MPM. We founda TERTpromoter mutation in 11.6% of MM, and the c.-146C>T mutation was the most common event. The next-generation sequencing was successful in 33 cases. A total of 18 samples showed at least 1 pathogenic, with a median of 1.8 variants, ranging from 1 to 6. The most mutated genes wereTP53andERBB2with 7 variants each, followed byNRASBRAF,PI3KCA,EGFRandPDGFRAwith 2 variants each.KIT,AKT1, andFOXL2genes exhibited 1 variant each. Interestingly, 2 variants observed in thePDGFRAgene are classic imatinib-sensitive therapy.Conclusions:We concluded that Brazilian MPM harbor mutation in classic tumor suppressor and oncogenic genes, which might help in the guidance of personalized treatment of MPM.