TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

• Authors: REMKE Marc; RAMASWAMY Vijaj; PEACOCK John; SHIH David J.H.; KOELSCHE C.; NORTHCOTT Paul A.; HILL Nadia; CAVALLI Florence M.G.; KOOL Marcel; WANG Xin; MACK Stephen C.; BARSZCZYK Mark; MORRISSY Sorana A.; WU Xiaochong; AGNIHOTRI Sameer; LUU Betty; JONES David T.W.; GARZIA Livia; DUBUC Adrian M.; ZHUKOVA Nataliya; VANNER Robert; KROS Johan Max; FRENCH Pim J.; VAN MEIR Erwin G.; VIBHAKAR Rajeev; ZITTERBART Karel; CHAN Jennifer A.; BOGNÁR László; KLEKNER Álmos P.; LACH Bolesław; JUNG Shin; SAAD Ali G.; LIAU Linda M.; ALBRECHT Steffen; ZOLLO Massimo; COOPER Michael K.; THOMPSON Reid C.; DELATTRE Olivier O.; BOURDEAUT Franck; DOZ François F.; GARAMI Miklós; HAUSER Péter; CARLOTTI Carlos G.; VAN METER Timothy E.; MASSIMI Luca; FULTS Daniel; POMEROY Scott L.; KUMABE Toshiro; RA Youngshin; LEONARD Jeffrey Russell; ELBABAA Samer K.; MORA Jaume; RUBIN Joshua B.; CHO Yoonjae; MCLENDON Roger E.; BIGNER Darell D.; EBERHART Charles G.; FOULADI Maryam; WECHSLER-REYA Robert J.; FARIA Claudia C.; CROUL Sidney E.; HUANG Annie; BOUFFET Éric; HAWKINS Cynthia E.; DIRKS Peter B.; WEISS William A.; SCHÜLLER Ulrich; POLLACK Ian F.; RUTKOWSKI Stefan; MEYRONET David; JOUVET Anne; FEVRE-MONTANGE Michelle F.; JABADO Nada; PEREK-POLNIK Marta; GRAJKOWSKA Wiesława A.; KIM Seungki-Ki; RUTKA James T.; MALKIN David F.; TABORI Uri; PFISTER Stefan Michael; KORSHUNOV Andrey G.; DEIMLING Andreas von; TAYLOR Michael D.
• Year of publication: 2013
• Type: Article in Periodical
• Magazine / Source: Acta Neuropathologica
• MU Faculty or unit: Faculty of Medicine
• Web: http://download.springer.com/static/pdf/422/art%253A10.1007%252Fs00401-013-1198-2.pdf?auth66=1388904723_bf87a0f47053680330d08a9281ebbab5&ext=.pdf
• Doi: http://dx.doi.org/10.1007/s00401-013-1198-2
• Field: Oncology and hematology
• Keywords: TERT promoter mutations; SHH pathway
• Description: Abstract 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.