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

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Malignant pleural mesothelioma (MPM) has a poor prognosis, necessitating research into its underlying molecular drivers.
• Understanding the genetic landscape of MPM is crucial for developing targeted therapies and improving patient outcomes.

Purpose of the Study:

• To investigate the presence and clinical significance of activating mutations in the telomerase reverse transcriptase (TERT) gene promoter in MPM.
• To determine the association of TERT promoter mutations with disease progression, cellular immortalization, and genomic alterations in MPM.

Main Methods:

• Sequencing of TERT promoters in 182 MPM samples and correlation with clinicopathologic data.
• In vitro immortalization assays, array comparative genomic hybridization, gene expression profiling, exome sequencing, and functional promoter assays on MPM cell models.

Main Results:

• TERT promoter mutations were found in 10.4% of MPM cases, associated with advanced disease and nonepithelioid histology.
• Mutations independently predicted shorter overall survival and were linked to cellular immortalization and enforced TERT promoter activity.
• TERT promoter-mutated MPM exhibited reduced chromosomal alterations and specific mutation patterns, with exclusive BAP1 alterations and enriched RBFOX1/GSTT1 deletions.

Conclusions:

• TERT promoter mutations are independent predictors of a poor prognosis in human MPM.
• These mutations define a novel, aggressive MPM subtype characterized by a distinct genomic aberration profile and specific malignant transformation process.