TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Marc Remke, Vijay Ramaswamy, John Peacock, David J.H. Shih, Christian Koelsche, Paul A. Northcott, Nadia Hill, Florence M.G. Cavalli, 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 & 63 others 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. Wechsler-Reya, 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-Montange, Nada Jabado, Marta Perek-Polnik, Wieslawa A. Grajkowska, Seung Ki Kim, James T. Rutka, David Malkin, Uri Tabori, Stefan M. Pfister, Andrey Korshunov, Andreas Von Deimling, Michael D. Taylor

Research output: Contribution to journalArticle

81 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)917-929
Number of pages13
JournalActa Neuropathologica
Volume126
Issue number6
DOIs
StatePublished - Oct 31 2013
Externally publishedYes

Fingerprint

Medulloblastoma
Telomerase
Mutation
Neoplasms
Demography
Monosomy
Chromosome Deletion
Genomics
Point Mutation
Cytogenetics

Keywords

  • Adult
  • Medulloblastoma
  • SHH pathway
  • TERT promoter mutations

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Remke, M., Ramaswamy, V., Peacock, J., Shih, D. J. H., Koelsche, C., Northcott, P. A., ... Taylor, M. D. (2013). TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma. Acta Neuropathologica, 126(6), 917-929. https://doi.org/10.1007/s00401-013-1198-2

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma. / Remke, Marc; Ramaswamy, Vijay; Peacock, John; Shih, David J.H.; Koelsche, Christian; Northcott, Paul A.; Hill, Nadia; Cavalli, Florence M.G.; Kool, Marcel; Wang, Xin; Mack, Stephen C.; Barszczyk, Mark; Morrissy, A. Sorana; Wu, Xiaochong; Agnihotri, Sameer; Luu, Betty; Jones, David T.W.; Garzia, Livia; Dubuc, Adrian M.; Zhukova, Nataliya; Vanner, Robert; Kros, Johan M.; French, Pim J.; Van Meir, Erwin G.; Vibhakar, Rajeev; Zitterbart, Karel; Chan, Jennifer A.; Bognár, László; Klekner, Almos; Lach, Boleslaw; Jung, Shin; Saad, Ali G.; Liau, Linda M.; Albrecht, Steffen; Zollo, Massimo; Cooper, Michael K.; Thompson, Reid C.; Delattre, Oliver O.; Bourdeaut, Franck; Doz, François F.; Garami, Miklós; Hauser, Peter; Carlotti, Carlos G.; Van Meter, Timothy E.; Massimi, Luca; Fults, Daniel; Pomeroy, Scott L.; Kumabe, Toshiro; Ra, Young Shin; Leonard, Jeffrey R.; Elbabaa, Samer K.; Mora, Jaume; Rubin, Joshua B.; Cho, Yoon-Jae; McLendon, Roger E.; Bigner, Darell D.; Eberhart, Charles G.; Fouladi, Maryam; Wechsler-Reya, Robert J.; Faria, Claudia C.; Croul, Sidney E.; Huang, Annie; Bouffet, Eric; Hawkins, Cynthia E.; Dirks, Peter B.; Weiss, William A.; Schüller, Ulrich; Pollack, Ian F.; Rutkowski, Stefan; Meyronet, David; Jouvet, Anne; Fèvre-Montange, Michelle; Jabado, Nada; Perek-Polnik, Marta; Grajkowska, Wieslawa A.; Kim, Seung Ki; Rutka, James T.; Malkin, David; Tabori, Uri; Pfister, Stefan M.; Korshunov, Andrey; Von Deimling, Andreas; Taylor, Michael D.

In: Acta Neuropathologica, Vol. 126, No. 6, 31.10.2013, p. 917-929.

Research output: Contribution to journalArticle

Remke, M, Ramaswamy, V, Peacock, J, Shih, DJH, Koelsche, C, Northcott, PA, Hill, N, Cavalli, FMG, Kool, M, Wang, X, Mack, SC, Barszczyk, M, Morrissy, AS, Wu, X, Agnihotri, S, Luu, B, Jones, DTW, Garzia, L, Dubuc, AM, Zhukova, N, Vanner, R, Kros, JM, French, PJ, Van Meir, EG, Vibhakar, R, Zitterbart, K, Chan, JA, Bognár, L, Klekner, A, Lach, B, Jung, S, Saad, AG, Liau, LM, Albrecht, S, Zollo, M, Cooper, MK, Thompson, RC, Delattre, OO, Bourdeaut, F, Doz, FF, Garami, M, Hauser, P, Carlotti, CG, Van Meter, TE, Massimi, L, Fults, D, Pomeroy, SL, Kumabe, T, Ra, YS, Leonard, JR, Elbabaa, SK, Mora, J, Rubin, JB, Cho, Y-J, McLendon, RE, Bigner, DD, Eberhart, CG, Fouladi, M, Wechsler-Reya, RJ, Faria, CC, Croul, SE, Huang, A, Bouffet, E, Hawkins, CE, Dirks, PB, Weiss, WA, Schüller, U, Pollack, IF, Rutkowski, S, Meyronet, D, Jouvet, A, Fèvre-Montange, M, Jabado, N, Perek-Polnik, M, Grajkowska, WA, Kim, SK, Rutka, JT, Malkin, D, Tabori, U, Pfister, SM, Korshunov, A, Von Deimling, A & Taylor, MD 2013, 'TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma', Acta Neuropathologica, vol. 126, no. 6, pp. 917-929. https://doi.org/10.1007/s00401-013-1198-2
Remke M, Ramaswamy V, Peacock J, Shih DJH, Koelsche C, Northcott PA et al. TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma. Acta Neuropathologica. 2013 Oct 31;126(6):917-929. https://doi.org/10.1007/s00401-013-1198-2
Remke, Marc ; Ramaswamy, Vijay ; Peacock, John ; Shih, David J.H. ; Koelsche, Christian ; Northcott, Paul A. ; Hill, Nadia ; Cavalli, Florence M.G. ; Kool, Marcel ; Wang, Xin ; Mack, Stephen C. ; Barszczyk, Mark ; Morrissy, A. Sorana ; Wu, Xiaochong ; Agnihotri, Sameer ; Luu, Betty ; Jones, David T.W. ; Garzia, Livia ; Dubuc, Adrian M. ; Zhukova, Nataliya ; Vanner, Robert ; Kros, Johan M. ; French, Pim J. ; Van Meir, Erwin G. ; Vibhakar, Rajeev ; Zitterbart, Karel ; Chan, Jennifer A. ; Bognár, László ; Klekner, Almos ; Lach, Boleslaw ; Jung, Shin ; Saad, Ali G. ; Liau, Linda M. ; Albrecht, Steffen ; Zollo, Massimo ; Cooper, Michael K. ; Thompson, Reid C. ; Delattre, Oliver O. ; Bourdeaut, Franck ; Doz, François F. ; Garami, Miklós ; Hauser, Peter ; Carlotti, Carlos G. ; Van Meter, Timothy E. ; Massimi, Luca ; Fults, Daniel ; Pomeroy, Scott L. ; Kumabe, Toshiro ; Ra, Young Shin ; Leonard, Jeffrey R. ; Elbabaa, Samer K. ; Mora, Jaume ; Rubin, Joshua B. ; Cho, Yoon-Jae ; McLendon, Roger E. ; Bigner, Darell D. ; Eberhart, Charles G. ; Fouladi, Maryam ; Wechsler-Reya, Robert J. ; Faria, Claudia C. ; Croul, Sidney E. ; Huang, Annie ; Bouffet, Eric ; Hawkins, Cynthia E. ; Dirks, Peter B. ; Weiss, William A. ; Schüller, Ulrich ; Pollack, Ian F. ; Rutkowski, Stefan ; Meyronet, David ; Jouvet, Anne ; Fèvre-Montange, Michelle ; Jabado, Nada ; Perek-Polnik, Marta ; Grajkowska, Wieslawa A. ; Kim, Seung Ki ; Rutka, James T. ; Malkin, David ; Tabori, Uri ; Pfister, Stefan M. ; Korshunov, Andrey ; Von Deimling, Andreas ; Taylor, Michael D. / TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma. In: Acta Neuropathologica. 2013 ; Vol. 126, No. 6. pp. 917-929.
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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.",
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T1 - TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

AU - Remke, Marc

AU - Ramaswamy, Vijay

AU - Peacock, John

AU - Shih, David J.H.

AU - Koelsche, Christian

AU - Northcott, Paul A.

AU - Hill, Nadia

AU - Cavalli, Florence M.G.

AU - Kool, Marcel

AU - Wang, Xin

AU - Mack, Stephen C.

AU - Barszczyk, Mark

AU - Morrissy, A. Sorana

AU - Wu, Xiaochong

AU - Agnihotri, Sameer

AU - Luu, Betty

AU - Jones, David T.W.

AU - Garzia, Livia

AU - Dubuc, Adrian M.

AU - Zhukova, Nataliya

AU - Vanner, Robert

AU - Kros, Johan M.

AU - French, Pim J.

AU - Van Meir, Erwin G.

AU - Vibhakar, Rajeev

AU - Zitterbart, Karel

AU - Chan, Jennifer A.

AU - Bognár, László

AU - Klekner, Almos

AU - Lach, Boleslaw

AU - Jung, Shin

AU - Saad, Ali G.

AU - Liau, Linda M.

AU - Albrecht, Steffen

AU - Zollo, Massimo

AU - Cooper, Michael K.

AU - Thompson, Reid C.

AU - Delattre, Oliver O.

AU - Bourdeaut, Franck

AU - Doz, François F.

AU - Garami, Miklós

AU - Hauser, Peter

AU - Carlotti, Carlos G.

AU - Van Meter, Timothy E.

AU - Massimi, Luca

AU - Fults, Daniel

AU - Pomeroy, Scott L.

AU - Kumabe, Toshiro

AU - Ra, Young Shin

AU - Leonard, Jeffrey R.

AU - Elbabaa, Samer K.

AU - Mora, Jaume

AU - Rubin, Joshua B.

AU - Cho, Yoon-Jae

AU - McLendon, Roger E.

AU - Bigner, Darell D.

AU - Eberhart, Charles G.

AU - Fouladi, Maryam

AU - Wechsler-Reya, Robert J.

AU - Faria, Claudia C.

AU - Croul, Sidney E.

AU - Huang, Annie

AU - Bouffet, Eric

AU - Hawkins, Cynthia E.

AU - Dirks, Peter B.

AU - Weiss, William A.

AU - Schüller, Ulrich

AU - Pollack, Ian F.

AU - Rutkowski, Stefan

AU - Meyronet, David

AU - Jouvet, Anne

AU - Fèvre-Montange, Michelle

AU - Jabado, Nada

AU - Perek-Polnik, Marta

AU - Grajkowska, Wieslawa A.

AU - Kim, Seung Ki

AU - Rutka, James T.

AU - Malkin, David

AU - Tabori, Uri

AU - Pfister, Stefan M.

AU - Korshunov, Andrey

AU - Von Deimling, Andreas

AU - Taylor, Michael D.

PY - 2013/10/31

Y1 - 2013/10/31

N2 - 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.

AB - 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.

KW - Adult

KW - Medulloblastoma

KW - SHH pathway

KW - TERT promoter mutations

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