TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

• DOI: 10.1007/s00401-013-1198-2
• Publication Date: 2013-10-30T15:39:57Z
• Authors: Marc Remke; Vijay Ramaswamy; John Peacock; David J. H. Shih; Christian Koelsche; Paul A. Northcott; Nadia Hill; Florence M. G. Ca...; Marcel Kool; Xin Wang; Stephen C. Mack; Mark Barszczyk; A. Sorana Morrissy; Xiaochong Wu; Sameer Agnihotri; Betty Luu; David T. W. Jones; Livia Garzia; Adrian M. Dubuc; Nataliya Zhukova; Robert Vanner; Johan M. Kros; Pim J. French; Erwin G. Van Meir; Rajeev Vibhakar; Karel Zitterbart; Jennifer A. Chan; László Bognár; Almos Klekner; Boleslaw Lach; Shin Jung; Ali G. Saad; Linda M. Liau; Steffen Albrecht; Massimo Zollo; Michael K. Cooper; Reid C. Thompson; Oliver O. Delattre; Franck Bourdeaut; François F. Doz; Miklós Garami; Peter Hauser; Carlos G. Carlotti; Timothy E. Van Meter; Luca Massimi; Daniel Fults; Scott L. Pomeroy; Toshiro Kumabe; Young Shin Ra; Jeffrey R. Leonard; Samer K. Elbabaa; Jaume Mora; Joshua B. Rubin; Yoon-Jae Cho; Roger E. McLendon; Darell D. Bigner; Charles G. Eberhart; Maryam Fouladi; Robert J. Wechsle...; Claudia C. Faria; Sidney E. Croul; Annie Huang; Eric Bouffet; Cynthia E. Hawkins; Peter B. Dirks; William A. Weiss; Ulrich Schüller; Ian F. Pollack; Stefan Rutkowski; David Meyronet; Anne Jouvet; Michelle Fèvre-Mo...; Nada Jabado; Marta Perek-Polnik; Wieslawa A. Grajk...; Seung-Ki Kim; James T. Rutka; David Malkin; Uri Tabori; Stefan M. Pfister; Andrey Korshunov; Andreas von Deimling; Michael D. Taylor
• Keywords: Adult; Male; 0301 basic medicine; Adolescent; Genotype; DNA Mutational Analysis; Clinical Neurology; SHH pathway; 610; Klinikai orvostudományok; EMC MM-03-44-06; Pathology and Forensic Medicine; Promoter Regions; Cellular and Molecular Neuroscience; 03 medical and health sciences; Genetic; SDG 3 - Good Health and Well-being; Humans; Preschool; Child; Promoter Regions, Genetic; Telomerase; Original Paper; tumorok; Brain Neoplasms; Gene Expression Profiling; Infant; Orvostudományok; onkológia; Middle Aged; Prognosis; 3. Good health; Child, Preschool; Mutation; Female; RC0254 Neoplasms. Tumors. Oncology (including Cancer) / daganatok; Adult; Medulloblastoma; SHH pathway; TERT promoter mutations; Adolescent; Adult; Brain Neoplasms; Child; Child, Preschool; DNA Mutational Analysis; Female; Gene Expression Profiling; Genotype; Humans; Infant; Male; Medulloblastoma; Middle Aged; Prognosis; Telomerase; Mutation; Promoter Regions, Genetic; 2734; Neurology (clinical); Cellular and Molecular Neuroscience; TERT promoter mutations; Medulloblastoma

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes.