title: TERT promoter mutations and prognosis in solitary fibrous tumor.
abstract: Solitary fibrous tumor is a mesenchymal neoplasm exhibiting a broad spectrum of biological behavior and harboring the NAB2-STAT6 fusion. Clinicopathologic parameters are currently used in risk-prediction models for solitary fibrous tumor, but the molecular determinants of malignancy in solitary fibrous tumors remain unknown. We proposed that the activation of telomere maintenance pathways confers a perpetual malignant phenotype to these tumors. Therefore, we investigated telomerase reverse transcriptase (TERT) reactivation induced by promoter mutations as a potential molecular mechanism for aggressive clinical behavior in solitary fibrous tumor. The retrospective study included tumor samples from 94 patients with solitary fibrous tumor (31 thoracic and 63 extra-thoracic). Follow-up information was available for 68 patients (median, 46 months). TERT promoter mutation analysis was performed by PCR and Sanger sequencing, and TERT mRNA expression was assessed by real-time quantitative reverse transcription PCR. Patients were stratified into clinicopathologic subgroups (high-risk (n=20), moderate-risk (n=28), and low-risk (n=46)) according to the risk-stratification model proposed by Demicco et al. TERT promoter mutations were identified in 26 of 94 (28%) solitary fibrous tumors: -124C>T in 23 tumors (88%), -124C>A in 1 tumor (4%), and -146C>T in 2 tumors (8%). Real-time quantitative reverse transcription PCR revealed that TERT mRNA expression was higher in all solitary fibrous tumors with the mutant TERT promoter than those with the wild-type TERT promoter. TERT promoter mutations were strongly associated with high-risk clinicopathologic characteristics and outcome. An adverse event (relapse, death) occurred in 16 of 68 (24%) patients, 12 with solitary fibrous tumors with TERT promoter mutations and 4 with the wild-type TERT promoter. TERT promoter mutations were strongly associated with older age (P=0.006), larger tumor size (P=0.000002), higher risk classifications (P=2.9 × 10-9), and a worse event-free survival (P=0.0082). Thus, TERT promoter mutations in solitary fibrous tumor influence gene expression and are associated with adverse patient outcome. Integrating TERT promoter mutational status with existing multivariable risk-prediction models might improve risk prediction in patients with solitary fibrous tumor.
authors: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors: Armita
authors: A
authors: Bahrami
authors: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors: Seungjae
authors: S
authors: Lee
authors: Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
authors: Inga-Marie
authors: IM
authors: Schaefer
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors: Jennifer M
authors: JM
authors: Boland
authors: Trumbull Laboratories, Germantown, TN, USA.
authors: Kurt T
authors: KT
authors: Patton
authors: Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors: Stanley
authors: S
authors: Pounds
authors: Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
authors: Christopher D
authors: CD
authors: Fletcher
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D054364:Solitary Fibrous Tumors / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D019098:Telomerase / Q000235:genetics*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C509186:TERT protein, human; D019098:Telomerase