Top

Published in:

01-12-2013 | Editorial

Promoting a new brain tumor mutation: TERT promoter mutations in CNS tumors

Authors: Zachary J. Reitman, Christopher J. Pirozzi, Hai Yan

Published in: Acta Neuropathologica | Issue 6/2013

Excerpt

Genomic research has recently linked two fundamental observations about the molecular biology of cancer. The first of these pivotal observations is that cancer is essentially a genetic disease, with tumor cells driven to grow inappropriately by acquired genetic alterations that deregulate cellular molecular machinery. The second observation is that ~85 % of tumors contain upregulated activity of the ribonucleoprotein complex telomerase, which is thought to help tumor cells avoid senescence and achieve immortality by replenishing the telomere cap on the tips of chromatin. For many cancers, it remained unclear how telomerase activity came to be upregulated in the first place, with no obvious genetic cause to explain why telomerase activity was inappropriately “switched on”. Now, recent work has uncovered what may very well be the genetic basis for telomerase activation in many human cancers, particularly CNS tumors. This work, including discoveries reported in three articles and one letter in this issue of Acta Neuropathologica, centers around recurrent point mutations in the promoter of the telomerase reverse transcriptase gene (TERT). …

Arita H, Narita Y, Fukushima S, Tateishi K, Matsushita Y, Yoshida A, Miyakita Y, Ohno M, Collins VP, Kawahara N, Shibui S, Ichimura K (2013) Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss. Acta Neuropathol 126(2):267–276. doi:10.1007/s00401-013-1141-6 PubMedCrossRef

Arita H, Narita Y, Takami H, Fukushima S, Matsushita Y, Yoshida A, Miyakita Y, Ohno M, Shibui S, Ichimura K (2013) TERT promoter mutations rather than methylation are the main mechanism for TERT upregulation in adult gliomas. Acta Neuropathol. doi:10.1007/s00401-013-1203-9

Castelo-Branco P, Choufani S, Mack S, Gallagher D, Zhang C, Lipman T, Zhukova N, Walker EJ, Martin D, Merino D, Wasserman JD, Elizabeth C, Alon N, Zhang L, Hovestadt V, Kool M, Jones DT, Zadeh G, Croul S, Hawkins C, Hitzler J, Wang JC, Baruchel S, Dirks PB, Malkin D, Pfister S, Taylor MD, Weksberg R, Tabori U (2013) Methylation of the TERT promoter and risk stratification of childhood brain tumours: an integrative genomic and molecular study. Lancet Oncol 14(6):534–542. doi:10.1016/s1470-2045(13)70110-4 PubMedCrossRef

Henson JD, Hannay JA, McCarthy SW, Royds JA, Yeager TR, Robinson RA, Wharton SB, Jellinek DA, Arbuckle SM, Yoo J, Robinson BG, Learoyd DL, Stalley PD, Bonar SF, Yu D, Pollock RE, Reddel RR (2005) A robust assay for alternative lengthening of telomeres in tumors shows the significance of alternative lengthening of telomeres in sarcomas and astrocytomas. Clin Cancer Res 11(1):217–225PubMed

Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A, Gast A, Kadel S, Moll I, Nagore E, Hemminki K, Schadendorf D, Kumar R (2013) TERT promoter mutations in familial and sporadic melanoma. Science 339(6122):959–961. doi:10.1126/science.1230062 PubMedCrossRef

Hu J, Hwang SS, Liesa M, Gan B, Sahin E, Jaskelioff M, Ding Z, Ying H, Boutin AT, Zhang H, Johnson S, Ivanova E, Kost-Alimova M, Protopopov A, Wang YA, Shirihai OS, Chin L, DePinho RA (2012) Antitelomerase therapy provokes ALT and mitochondrial adaptive mechanisms in cancer. Cell 148(4):651–663. doi:10.1016/j.cell.2011.12.028 PubMedCrossRef

Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA (2013) Highly recurrent TERT promoter mutations in human melanoma. Science 339(6122):957–959. doi:10.1126/science.1229259 PubMedCrossRef

Jiao Y, Killela PJ, Reitman ZJ, Rasheed AB, Heaphy CM, de Wilde RF, Rodriguez FJ, Rosemberg S, Oba-Shinjo SM, Nagahashi Marie SK, Bettegowda C, Agrawal N, Lipp E, Pirozzi C, Lopez G, He Y, Friedman H, Friedman AH, Riggins GJ, Holdhoff M, Burger P, McLendon R, Bigner DD, Vogelstein B, Meeker AK, Kinzler KW, Papadopoulos N, Diaz LA, Yan H (2012) Frequent ATRX, CIC, and FUBP1 mutations refine the classification of malignant gliomas. Oncotarget 3(7):709–722PubMed

Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA Jr, Friedman AH, Friedman H, Gallia GL, Giovanella BC, Grollman AP, He TC, He Y, Hruban RH, Jallo GI, Mandahl N, Meeker AK, Mertens F, Netto GJ, Rasheed BA, Riggins GJ, Rosenquist TA, Schiffman M, Shih Ie M, Theodorescu D, Torbenson MS, Velculescu VE, Wang TL, Wentzensen N, Wood LD, Zhang M, McLendon RE, Bigner DD, Kinzler KW, Vogelstein B, Papadopoulos N, Yan H (2013) TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci USA 110(15):6021–6026. doi:10.1073/pnas.1303607110 PubMedCrossRef

10.

Koelsche C, Sahm F, Capper D, Reuss D, Sturm D, Jones DT, Kool M, Northcott PA, Wiestler B, Bohmer K, Meyer J, Mawrin C, Hartmann C, Mittelbronn M, Platten M, Brokinkel B, Seiz M, Herold-Mende C, Unterberg A, Schittenhelm J, Weller M, Pfister S, Wick W, Korshunov A, von Deimling A (2013) Distribution of TERT promoter mutations in pediatric and adult tumors of the nervous system. Acta Neuropathol. doi:10.1007/s00401-013-1195-5

11.

Langford LA, Piatyszek MA, Xu R, Schold SC Jr, Shay JW (1995) Telomerase activity in human brain tumours. Lancet 346(8985):1267–1268PubMedCrossRef

12.

Marian CO, Cho SK, McEllin BM, Maher EA, Hatanpaa KJ, Madden CJ, Mickey BE, Wright WE, Shay JW, Bachoo RM (2010) The telomerase antagonist, imetelstat, efficiently targets glioblastoma tumor-initiating cells leading to decreased proliferation and tumor growth. Clin Cancer Res 16(1):154–163. doi:10.1158/1078-0432.ccr-09-2850 PubMedCrossRef

13.

Nonoguchi N, Ohta T, Oh JE, Kim YH, Kleihues P, Ohgaki H (2013) TERT promoter mutations in primary and secondary glioblastomas. Acta Neuropathol. doi:10.1007/s00401-013-1163-0 PubMed

14.

Remke M, Ramaswamy V, Peacock J, Shih DJ, Koelsche C, Northcott PA, Hill N, Cavalli FM, Kool M, Wang X, Mack SC, Barszczyk M, Morrissy AS, Wu X, Agnihotri S, Luu B, Jones DT, Garzia L, Dubuc AM, Zhukova N, Vanner R, Kros JM, French PJ, Van Meir EG, Vibhakar R, Zitterbart K, Chan JA, Bognar 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 YJ, 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, Schuller U, Pollack IF, Rutkowski S, Meyronet D, Jouvet A, Fevre-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 Neuropathol. doi:10.1007/s00401-013-1198-2

Title: Promoting a new brain tumor mutation: TERT promoter mutations in CNS tumors
Authors: Zachary J. Reitman
Christopher J. Pirozzi
Hai Yan
Publication date: 01-12-2013
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 6/2013
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-013-1207-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Promoting a new brain tumor mutation: TERT promoter mutations in CNS tumors

Excerpt

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Excerpt

Please log in to get access to this content

Other articles of this Issue 6/2013

Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins

Distribution of TERT promoter mutations in pediatric and adult tumors of the nervous system

LRRK2 phosphorylates novel tau epitopes and promotes tauopathy

TERT promoter mutations in primary and secondary glioblastomas

Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma