title: The activating TERT promoter mutation C228T is recurrent in subsets of adrenal tumors.
abstract: The telomerase reverse transcriptase gene (TERT) encodes the reverse transcriptase component of the telomerase complex, which is essential for telomere stabilization and cell immortalization. Recent studies have demonstrated a transcriptional activation role for the TERT promoter mutations C228T and C250T in many human cancers, as well as a role in aggressive disease with potential clinical applications. Although telomerase activation is known in adrenal tumors, the underlying mechanisms are not established. We assessed C228T and C250T TERT mutations by direct Sanger sequencing in tumors of the adrenal gland, and further evaluated potential associations with clinical parameters and telomerase activation. A total of 199 tumors were evaluated, including 34 adrenocortical carcinomas (ACC), 47 adrenocortical adenomas (ACA), 105 pheochromocytomas (PCC; ten malignant and 95 benign), and 13 abdominal paragangliomas (PGL; nine malignant and four benign). TERT expression levels were determined by quantitative RT-PCR. The C228T mutation was detected in 4/34 ACCs (12%), but not in any ACA (P=0.028). C228T was also observed in one benign PCC and in one metastatic PGL. The C250T mutation was not observed in any case. In the ACC and PGL groups, TERT mutation-positive cases exhibited TERT expression, indicating telomerase activation; however, since expression was also revealed in TERT WT cases, this could denote additional mechanisms of TERT activation. To conclude, the TERT promoter mutation C228T is a recurrent event associated with TERT expression in ACCs, but rarely occurs in PGL and PCC. The involvement of the TERT gene in ACC represents a novel mutated gene in this entity.
authors.affiliation: Department of Medicine-Solna, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden Yale Endocrine Neoplasia Laboratory, Yale School of Medicine, 333 Cedar Street, FMB130A, PO Box 208062, New Haven, Connecticut 06520, USA Department of Surgery, Yale School of Medicine, New Haven, Connecticut, USA Departments of Oncology-Pathology Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital CCK, SE-171 76 Stockholm, Sweden Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Tiantian
authors.initials: T
authors.lastname: Liu
authors.forename: Taylor C
authors.initials: TC
authors.lastname: Brown
authors.forename: C Christofer
authors.initials: CC
authors.lastname: Juhlin
authors.forename: Adam
authors.initials: A
authors.lastname: Andreasson
authors.forename: Na
authors.initials: N
authors.lastname: Wang
authors.forename: Martin
authors.initials: M
authors.lastname: Bäckdahl
authors.forename: James M
authors.initials: JM
authors.lastname: Healy
authors.forename: Manju L
authors.initials: ML
authors.lastname: Prasad
authors.forename: Reju
authors.initials: R
authors.lastname: Korah
authors.forename: Tobias
authors.initials: T
authors.lastname: Carling
authors.forename: Dawei
authors.initials: D
authors.lastname: Xu
authors.forename: Catharina
authors.initials: C
authors.lastname: Larsson
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018246:Adrenocortical Adenoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D010235:Paraganglioma / Q000235:genetics / Q000401:mortality / Q000473:pathology; D010673:Pheochromocytoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D019098:Telomerase / Q000235:genetics*; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; C509186:TERT protein, human; D019098:Telomerase
keywords: TERT; adrenocortical tumor; endocrine; mutation; pheochromocytoma; telomerase