Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumors carrying IDH1/IDH2 and TP53 mutations
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Abstract
Gliomas are the most common primary brain tumors in children and adults. We recently identified frequent alterations in chromatin remodelling pathways including recurrent mutations in H3F3A and mutations in ATRX (α-thalassemia/mental-retardation-syndrome-X-linked) in pediatric and young adult glioblastoma (GBM, WHO grade IV astrocytoma). H3F3A mutations were specific to pediatric high-grade gliomas and identified in only 3.4 % of adult GBM. Using sequencing and/or immunohistochemical analyses, we investigated ATRX alterations (mutation/loss of expression) and their association with TP53 and IDH1 or IDH2 mutations in 140 adult WHO grade II, III and IV gliomas, 17 pediatric WHO grade II and III astrocytomas and 34 pilocytic astrocytomas. In adults, ATRX aberrations were detected in 33 % of grade II and 46 % of grade III gliomas, as well as in 80 % of secondary and 7 % of primary GBMs. They were absent in the 17 grade II and III astrocytomas in children, and the 34 pilocytic astrocytomas. ATRX alterations closely overlapped with mutations in IDH1/2 (p < 0.0001) and TP53 (p < 0.0001) in samples across all WHO grades. They were prevalent in astrocytomas and oligoastrocytomas, but were absent in oligodendrogliomas (p < 0.0001). No significant association of ATRX mutation/loss of expression and alternative lengthening of telomeres was identified in our cohort. In summary, our data show that ATRX alterations are frequent in adult diffuse gliomas and are specific to astrocytic tumors carrying IDH1/2 and TP53 mutations. Combined alteration of these genes may contribute to drive the neoplastic growth in a major subset of diffuse astrocytomas in adults.
Keywords
Gliomas ATRX IDH TP53 Alternative lengthening of telomeresNotes
Acknowledgments
This work was supported by the Cole Foundation, and was funded by the Canadian Institute for Health Research (CIHR) (NJ). X.-Y.L. and A.M.F. are recipients of studentship awards from CIHR. N.J. is the recipient of a ChercheurClinicien Award from Fonds de Recherche en Santé du Québec.
Conflict of interest
The authors declare that they have no conflict of interest.
Supplementary material
References
- 1.Bassett AR, Cooper SE, Ragab A, Travers AA (2008) The chromatin remodelling factor dATRX is involved in heterochromatin formation. PLoS One 3(5):e2009Google Scholar
- 2.Baumann C, Viveiros MM, De La Fuente R (2010) Loss of maternal ATRX results in centromere instability and aneuploidy in the mammalian oocyte and pre-implantation embryo. PLoS Genet 6(9), pii:e1001137Google Scholar
- 3.Bettegowda C, Agrawal N, Jiao Y, Sausen M, Wood LD, Hruban RH, Rodriguez FJ, Cahill DP, McLendon R, Riggins G, Velculescu VE, Oba-Shinjo SM, Marie SK, Vogelstein B, Bigner D, Yan H, Papadopoulos N, Kinzler KW (2011) Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science 333(6048):1453–1455PubMedCentralCrossRefPubMedGoogle Scholar
- 4.Bourne TD, Schiff D (2010) Update on molecular findings, management and outcome in low-grade gliomas. Nat Rev Neurol 6(12):695–701CrossRefPubMedGoogle Scholar
- 5.Capper D, Weissert S, Balss J, Habel A, Meyer J, Jager D, Ackermann U, Tessmer C, Korshunov A, Zentgraf H, Hartmann C, von Deimling A (2010) Characterization of R132H mutation-specific IDH1 antibody binding in brain tumors. Brain Pathol 20(1):245–254CrossRefPubMedGoogle Scholar
- 6.Cheung NK, Zhang J, Lu C, Parker M, Bahrami A, Tickoo SK, Heguy A, Pappo AS, Federico S, Dalton J, Cheung IY, Ding L, Fulton R, Wang J, Chen X, Becksfort J, Wu J, Billups CA, Ellison D, Mardis ER, Wilson RK, Downing JR, Dyer MA (2012) Association of age at diagnosis and genetic mutations in patients with neuroblastoma. JAMA 307(10):1062–1071PubMedCentralCrossRefPubMedGoogle Scholar
- 7.Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455(7216):1061–1068Google Scholar
- 8.Elsasser SJ, Allis CD, Lewis PW (2011) Cancer. New epigenetic drivers of cancers. Science 331(6021):1145–1146CrossRefPubMedGoogle Scholar
- 9.Emelyanov AV, Konev AY, Vershilova E, Fyodorov DV (2010) Protein complex of drosophila ATRX/XNP and HP1a is required for the formation of pericentric beta-heterochromatin in vivo. J Biol Chem 285(20):15027–15037PubMedCentralCrossRefPubMedGoogle Scholar
- 10.Faury D, Nantel A, Dunn SE, Guiot MC, Haque T, Hauser P, Garami M, Bognar L, Hanzely Z, Liberski PP, Lopez-Aguilar E, Valera ET, Tone LG, Carret AS, Del Maestro RF, Gleave M, Montes JL, Pietsch T, Albrecht S, Jabado N (2007) Molecular profiling identifies prognostic subgroups of pediatric glioblastoma and shows increased YB-1 expression in tumors. J Clin Oncol 25(10):1196–1208CrossRefPubMedGoogle Scholar
- 11.Gibbons R (2006) Alpha thalassaemia-mental retardation, X linked. Orphanet J Rare Dis 1:15PubMedCentralCrossRefPubMedGoogle Scholar
- 12.Gibbons RJ, Pellagatti A, Garrick D, Wood WG, Malik N, Ayyub H, Langford C, Boultwood J, Wainscoat JS, Higgs DR (2003) Identification of acquired somatic mutations in the gene encoding chromatin-remodeling factor ATRX in the alpha-thalassemia myelodysplasia syndrome (ATMDS). Nat Genet 34(4):446–449CrossRefPubMedGoogle Scholar
- 13.Gibbons RJ, Picketts DJ, Villard L, Higgs DR (1995) Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome). Cell 80(6):837–845CrossRefPubMedGoogle Scholar
- 14.Gibbons RJ, Wada T, Fisher CA, Malik N, Mitson MJ, Steensma DP, Fryer A, Goudie DR, Krantz ID, Traeger-Synodinos J (2008) Mutations in the chromatin-associated protein ATRX. Hum Mutat 29(6):796–802CrossRefPubMedGoogle Scholar
- 15.Gravendeel LA, Kouwenhoven MC, Gevaert O, de Rooi JJ, Stubbs AP, Duijm JE, Daemen A, Bleeker FE, Bralten LB, Kloosterhof NK, De Moor B, Eilers PH, van der Spek PJ, Kros JM, Sillevis Smitt PA, van den Bent MJ, French PJ (2009) Intrinsic gene expression profiles of gliomas are a better predictor of survival than histology. Cancer Res 69(23):9065–9072CrossRefPubMedGoogle Scholar
- 16.Heaphy CM, de Wilde RF, Jiao Y, Klein AP, Edil BH, Shi C, Bettegowda C, Rodriguez FJ, Eberhart CG, Hebbar S, Offerhaus GJ, McLendon R, Rasheed BA, He Y, Yan H, Bigner DD, Oba-Shinjo SM, Marie SK, Riggins GJ, Kinzler KW, Vogelstein B, Hruban RH, Maitra A, Papadopoulos N, Meeker AK (2011) Altered telomeres in tumors with ATRX and DAXX mutations. Science 333(6041):425PubMedCentralCrossRefPubMedGoogle Scholar
- 17.Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, Schulick RD, Tang LH, Wolfgang CL, Choti MA, Velculescu VE, Diaz LA Jr, Vogelstein B, Kinzler KW, Hruban RH, Papadopoulos N (2011) DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331(6021):1199–1203PubMedCentralCrossRefPubMedGoogle Scholar
- 18.Jones DT, Gronych J, Lichter P, Witt O, Pfister SM (2011) MAPK pathway activation in pilocytic astrocytoma. Cell Mol Life Sci 69(11):1799–1811PubMedCentralCrossRefPubMedGoogle Scholar
- 19.Khuong-Quang DA, Buczkowicz P, Rakopoulos P, Liu XY, Fontebasso AM, Bouffet E, Bartels U, Albrecht S, Schwartzentruber J, Letourneau L, Bourgey M, Bourque G, Montpetit A, Bourret G, Lepage P, Fleming A, Lichter P, Kool M, von Deimling A, Sturm D, Korshunov A, Faury D, Jones DT, Majewski J, Pfister SM, Jabado N, Hawkins C (2012) K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta neuropathol [Epub ahead of print]Google Scholar
- 20.Kieran MW, Walker D, Frappaz D, Prados M (2010) Brain tumors: from childhood through adolescence into adulthood. J Clin Oncol 28(32):4783–4789CrossRefPubMedGoogle Scholar
- 21.Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114(2):97–109PubMedCentralCrossRefPubMedGoogle Scholar
- 22.Molenaar JJ, Koster J, Zwijnenburg DA, van Sluis P, Valentijn LJ, van der Ploeg I, Hamdi M, van Nes J, Westerman BA, van Arkel J, Ebus ME, Haneveld F, Lakeman A, Schild L, Molenaar P, Stroeken P, van Noesel MM, Ora I, Santo EE, Caron HN, Westerhout EM, Versteeg R (2012) Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature 483(7391):589–593CrossRefPubMedGoogle Scholar
- 23.Ohgaki H, Kleihues P (2011) Genetic profile of astrocytic and oligodendroglial gliomas. Brain Tumor Pathol 28(3):177–183CrossRefPubMedGoogle Scholar
- 24.Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321(5897):1807–1812PubMedCentralCrossRefPubMedGoogle Scholar
- 25.Paugh BS, Qu C, Jones C, Liu Z, Adamowicz-Brice M, Zhang J, Bax DA, Coyle B, Barrow J, Hargrave D, Lowe J, Gajjar A, Zhao W, Broniscer A, Ellison DW, Grundy RG, Baker SJ (2010) Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol 28(18):3061–3068PubMedCentralCrossRefPubMedGoogle Scholar
- 26.Pollack IF, Hamilton RL, Sobol RW, Nikiforova MN, Lyons-Weiler MA, Laframboise WA, Burger PC, Brat DJ, Rosenblum MK, Holmes EJ, Zhou T, Jakacki RI (2010) IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children’s Oncology Group. Childs Nerv Syst 27(1):87–94PubMedCentralCrossRefPubMedGoogle Scholar
- 27.Qu HQ, Jacob K, Fatet S, Ge B, Barnett D, Delattre O, Faury D, Montpetit A, Solomon L, Hauser P, Garami M, Bognar L, Hansely Z, Mio R, Farmer JP, Albrecht S, Polychronakos C, Hawkins C, Jabado N (2010) Genome-wide profiling using single-nucleotide polymorphism arrays identifies novel chromosomal imbalances in pediatric glioblastomas. Neuro Oncol 12(2):153–163PubMedCentralCrossRefPubMedGoogle Scholar
- 28.Schneiderman JI, Sakai A, Goldstein S, Ahmad K (2009) The XNP remodeler targets dynamic chromatin in Drosophila. Proc Natl Acad Sci USA 106(34):14472–14477PubMedCentralCrossRefPubMedGoogle Scholar
- 29.Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, Sturm D, Fontebasso AM, Quang DA, Tonjes M, Hovestadt V, Albrecht S, Kool M, Nantel A, Konermann C, Lindroth A, Jager N, Rausch T, Ryzhova M, Korbel JO, Hielscher T, Hauser P, Garami M, Klekner A, Bognar L, Ebinger M, Schuhmann MU, Scheurlen W, Pekrun A, Fruhwald MC, Roggendorf W, Kramm C, Durken M, Atkinson J, Lepage P, Montpetit A, Zakrzewska M, Zakrzewski K, Liberski PP, Dong Z, Siegel P, Kulozik AE, Zapatka M, Guha A, Malkin D, Felsberg J, Reifenberger G, von Deimling A, Ichimura K, Collins VP, Witt H, Milde T, Witt O, Zhang C, Castelo-Branco P, Lichter P, Faury D, Tabori U, Plass C, Majewski J, Pfister SM, Jabado N (2012) Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482(7384):226–231CrossRefPubMedGoogle Scholar
- 30.Tabori U, Baskin B, Shago M, Alon N, Taylor MD, Ray PN, Bouffet E, Malkin D, Hawkins C (2010) Universal poor survival in children with medulloblastoma harboring somatic TP53 mutations. J Clin Oncol 28(8):1345–1350CrossRefPubMedGoogle Scholar
- 31.Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G, Lawrence M, O’Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM, Hayes DN (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17(1):98–110PubMedCentralCrossRefPubMedGoogle Scholar
- 32.Wu G, Broniscer A, McEachron TA, Lu C, Paugh BS, Becksfort J, Qu C, Ding L, Huether R, Parker M, Zhang J, Gajjar A, Dyer MA, Mullighan CG, Gilbertson RJ, Mardis ER, Wilson RK, Downing JR, Ellison DW, Baker SJ (2012) Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 44(3):251–253Google Scholar
- 33.Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360(8):765–773PubMedCentralCrossRefPubMedGoogle Scholar
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