Telomerase Reverse Transcriptase Promoter Mutations Identify a Genomically Defined and Highly Aggressive Human Pleural Mesothelioma Subgroup.

Abstract

Human malignant pleural mesothelioma (MPM) is characterized by dismal prognosis. Consequently, dissection of molecular mechanisms driving malignancy is of key importance. Here we investigate whether activating mutations in the telomerase reverse transcriptase (<i>TERT</i>) gene promoter are present in MPM and associated with disease progression, cell immortalization, and genomic alteration patterns. <i>TERT</i> promoters were sequenced in 182 MPM samples and compared with clinicopathologic characteristics. Surgical specimens from 45 patients with MPM were tested for <i>in vitro</i> immortalization. The respective MPM cell models (<i>N</i> = 22) were analyzed by array comparative genomic hybridization, gene expression profiling, exome sequencing as well as TRAP, telomere length, and luciferase promoter assays. <i>TERT</i> promoter mutations were detected in 19 of 182 (10.4%) MPM cases and significantly associated with advanced disease and nonepithelioid histology. Mutations independently predicted shorter overall survival in both histologic MPM subtypes. Moreover, 9 of 9 (100%) mutated but only 13 of 36 (36.1%) wild-type samples formed immortalized cell lines<i>. TERT</i> promoter mutations were associated with enforced promoter activity and <i>TERT</i> mRNA expression, while neither telomerase activity nor telomere lengths were significantly altered. <i>TERT</i> promoter-mutated MPM cases exhibited distinctly reduced chromosomal alterations and specific mutation patterns. While <i>BAP1</i> mutations/deletions were exclusive with <i>TERT</i> promoter mutations, homozygous deletions at the <i>RBFOX1</i> and the <i>GSTT1</i> loci were clearly enriched in mutated cases. <i>TERT</i> promoter mutations independently predict a dismal course of disease in human MPM. The altered genomic aberration pattern indicates that <i>TERT</i> promoter mutations identify a novel, highly aggressive MPM subtype presumably based on a specific malignant transformation process.