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

Abstract

Acquisition of immortality as a hallmark of malignant transformation is achieved by telomerase reactivation in the majority of human cancers. Point mutations in the telomerase reverse transcriptase (TERT) gene promoter were recently discovered as one fundamental driver of this process correlating with worse prognosis in several cancer types. The potential role of these mutations in human malignant pleural mesothelioma (MPM) aggressiveness was unknown far. Here we show that presence of TERT promoter mutations identifies a distinct MPM patient subgroup with extremely dismal prognosis. The respective MPM cell explants with TERT promoter mutations are characterized by a profoundly enhanced in vitro immortalization potential, reduced chromosomal instability and a specific mutation/deletion pattern compared to the wild-type counterparts. Consequently, our MPM-based results indicate a unique way of malignant transformation of TERT promoter-mutated tumors which has broad implications also for multiple other cancer types harboring this non-coding genomic alteration.Research.

Telomere length is key to hepatocellular carcinoma diversity and telomerase addiction is an actionable therapeutic target

“…Alternatively, BAP1 inactivation may have a role in TERT expression through epigenetic regulation, 38 , 38 but in our series, the weak level of TERT expression in this subgroup rather suggests that BAP1 inactivation could be associated with an alternative mechanism of telomere maintenance that remains to be determined. Of note, in malignant pleural mesothelioma, a cancer with high prevalence of BAP1 alterations, a similar exclusion between BAP1 and TERT promoter alteration has recently been described by 2 independent groups, 39,40 suggesting a functional link between BAP1 and telomere maintenance. In addition, we identified another subset of HCCs (3%) showing elongated telomeres despite no TERT or BAP1 alteration nor TERT overexpression.…”

Therapeutic Landscape of Malignant Pleural Mesothelioma: Collateral Vulnerabilities and Evolutionary Dependencies in the Spotlight

“…TERT promoter mutations, the first recurrent oncogenic muation identified in MPM, are frequent in MPM with sarcomatoid subtype and significantly associated with worse clinical outcome (56,57). As expected, MPM cells carrying TERT promoter mutations show increased sensitivity to telomerase inhibition than those with wide-type TERT, indicating that targeting telomerase activity might be a promising treatment strategy for this MPM subset (57).…”

Multicellular contractility contributes to the emergence of mesothelioma nodules

“…1 c). In a recent study we described the major molecular alterations for our MPM cell line panel 22 . Among the MPM tumor cell lines, we did not identify significant associations between tumor nodule formation and histological subtype or major molecular alterations in MPM including BAP1, TP53, NF2 or TERT promoter mutations (Supplementary Fig.…”

“…All cell lines were tested for mycoplasma contamination using the MycoSensor PCR Assay Kit 302108 (Agilent). Genetical characterization of MPM cell lines was carried out by identification of alterations in TERT promoter region, BAP1, TP53 and NF2 described in 22 .…”