Comprehensive molecular profiling identifies novel genetic drivers and subtypes underlying medulloblastoma

Current therapies for medulloblastoma (MB), a highly malignant childhood brain tumor, impose debilitating effects on the developing child, warranting the development of molecularly targeted treatments with reduced toxicities. Prior studies have failed to disclose the full spectrum of driver genes and molecular processes operative in MB or adequately explain heterogeneity among molecular subgroups. Herein, we detail the somatic landscape across 491 sequenced MBs and molecular heterogeneity amongst 1,256 epigenetically analyzed cases, identifying subgroup-specific mutational signatures, driver genes, and pathway alterations including previously unappreciated actionable therapeutic targets. Integrative approaches for assigning driver genes to subgroups explained >65-70% of Group 3 and Group 4, doubling previous knowledge. Novel subtypes underlying Group 3 and Group 4 were differentially enriched for specific driver events, including hotspot in-frame indels targeting KBTBD4 and ‘enhancer hijacking’ driving activation of PRDM6. Thus, application of integrative genomics to an unprecedented cohort of clinical samples derived from a single childhood cancer entity has disclosed a series of new cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for treating MB.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

9 Datasets 10 Publications

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001003125	WGS data of medulloblastoma tumor/control pairs.		224
EGAD00001003126	WGS data of medulloblastoma tumor/control pairs.		74
EGAD00001003127	WGS data of medulloblastoma tumor/control pairs.		482
EGAD00001003128	Exome sequencing data for medulloblastoma tumor/control pairs		35
EGAD00001003279	RNA sequencing data for 170 medulloblastoma tumor samples	Illumina HiSeq 2000	171
EGAD00010001300	Medulloblastoma expression profiling	Affymetrix expression array	146
EGAD00010001301	Medulloblastoma expression profiling	Affymetrix expression array	246
EGAD00010001319	Medulloblastoma methylation profiling	Illumina Infinium HumanMethylation450 BeadChip	345
EGAD00010001323	Medulloblastoma methylation profiling	Illumina Infinium HumanMethylation450 BeadChip	911

Publications	Citations
The whole-genome landscape of medulloblastoma subtypes. Northcott PA, Buchhalter I, Morrissy AS, Hovestadt V, Weischenfeldt J, Ehrenberger T, Gröbner S, Segura-Wang M, Zichner T, Rudneva VA, Warnatz HJ, Sidiropoulos N, Phillips AH, Schumacher S, Kleinheinz K, Waszak SM, Erkek S, Jones DTW, Worst BC, Kool M, Zapatka M, Jäger N, Chavez L, Hutter B, Bieg M, Paramasivam N, Heinold M, Gu Z, Ishaque N, Jäger-Schmidt C, Imbusch CD, Jugold A, Hübschmann D, Risch T, Amstislavskiy V, Gonzalez FGR, Weber UD, Wolf S, Robinson GW, Zhou X, Wu G, Finkelstein D, Liu Y, Cavalli FMG, Luu B, Ramaswamy V, Wu X, Koster J, Ryzhova M, Cho YJ, Pomeroy SL, Herold-Mende C, Schuhmann M, Ebinger M, Liau LM, Mora J, McLendon RE, Jabado N, Kumabe T, Chuah E, Ma Y, Moore RA, Mungall AJ, Mungall KL, Thiessen N, Tse K, Wong T, Jones SJM, Witt O, Milde T, Von Deimling A, Capper D, Korshunov A, Yaspo ML, Kriwacki R, Gajjar A, Zhang J, Beroukhim R, Fraenkel E, Korbel JO, Brors B, Schlesner M, Eils R, Marra MA, Pfister SM, Taylor MD, Lichter P. Nature 547: 2017 311-317	531
Extra-mitochondrial prosurvival BCL-2 proteins regulate gene transcription by inhibiting the SUFU tumour suppressor. Wu X, Zhang LS, Toombs J, Kuo YC, Piazza JT, Tuladhar R, Barrett Q, Fan CW, Zhang X, Walensky LD, Kool M, Cheng SY, Brekken R, Opferman JT, Green DR, Moldoveanu T, Lum L. Nat Cell Biol 19: 2017 1226-1236	27
Proteomics, Post-translational Modifications, and Integrative Analyses Reveal Molecular Heterogeneity within Medulloblastoma Subgroups. Archer TC, Ehrenberger T, Mundt F, Gold MP, Krug K, Mah CK, Mahoney EL, Daniel CJ, LeNail A, Ramamoorthy D, Mertins P, Mani DR, Zhang H, Gillette MA, Clauser K, Noble M, Tang LC, Pierre-François J, Silterra J, Jensen J, Tamayo P, Korshunov A, Pfister SM, Kool M, Northcott PA, Sears RC, Lipton JO, Carr SA, Mesirov JP, Pomeroy SL, Fraenkel E. Cancer Cell 34: 2018 396-410.e8	92
Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma. Suzuki H, Kumar SA, Shuai S, Diaz-Navarro A, Gutierrez-Fernandez A, De Antonellis P, Cavalli FMG, Juraschka K, Farooq H, Shibahara I, Vladoiu MC, Zhang J, Abeysundara N, Przelicki D, Skowron P, Gauer N, Luu B, Daniels C, Wu X, Forget A, Momin A, Wang J, Dong W, Kim SK, Grajkowska WA, Jouvet A, Fèvre-Montange M, Garrè ML, Nageswara Rao AA, Giannini C, Kros JM, French PJ, Jabado N, Ng HK, Poon WS, Eberhart CG, Pollack IF, Olson JM, Weiss WA, Kumabe T, López-Aguilar E, Lach B, Massimino M, Van Meir EG, Rubin JB, Vibhakar R, Chambless LB, Kijima N, Klekner A, Bognár L, Chan JA, Faria CC, Ragoussis J, Pfister SM, Goldenberg A, Wechsler-Reya RJ, Bailey SD, Garzia L, Morrissy AS, Marra MA, Huang X, Malkin D, Ayrault O, Ramaswamy V, Puente XS, Calarco JA, Stein L, Taylor MD. Nature 574: 2019 707-711	90
The transcriptional landscape of Shh medulloblastoma. Skowron P, Farooq H, Cavalli FMG, Morrissy AS, Ly M, Hendrikse LD, Wang EY, Djambazian H, Zhu H, Mungall KL, Trinh QM, Zheng T, Dai S, Stucklin ASG, Vladoiu MC, Fong V, Holgado BL, Nor C, Wu X, Abd-Rabbo D, Bérubé P, Wang YC, Luu B, Suarez RA, Rastan A, Gillmor AH, Lee JJY, Zhang XY, Daniels C, Dirks P, Malkin D, Bouffet E, Tabori U, Loukides J, Doz FP, Bourdeaut F, Delattre OO, Masliah-Planchon J, Ayrault O, Kim SK, Meyronet D, Grajkowska WA, Carlotti CG, de Torres C, Mora J, Eberhart CG, Van Meir EG, Kumabe T, French PJ, Kros JM, Jabado N, Lach B, Pollack IF, Hamilton RL, Rao AAN, Giannini C, Olson JM, Bognár L, Klekner A, Zitterbart K, Phillips JJ, Thompson RC, Cooper MK, Rubin JB, Liau LM, Garami M, Hauser P, Li KKW, Ng HK, Poon WS, Yancey Gillespie G, Chan JA, Jung S, McLendon RE, Thompson EM, Zagzag D, Vibhakar R, Ra YS, Garre ML, Schüller U, Shofuda T, Faria CC, López-Aguilar E, Zadeh G, Hui CC, Ramaswamy V, Bailey SD, Jones SJ, Mungall AJ, Moore RA, Calarco JA, Stein LD, Bader GD, Reimand J, Ragoussis J, Weiss WA, Marra MA, Suzuki H, Taylor MD. Nat Commun 12: 2021 1749	37
Identification of ITPR1 as a Hub Gene of Group 3 Medulloblastoma and Coregulated Genes with Potential Prognostic Values. das Chagas PF, de Sousa GR, Veronez LC, Martins-da-Silva A, Corrêa CAP, Cruzeiro GAV, Nagano LFP, Queiroz RGP, Marie SKN, Brandalise SR, Scrideli CA, Tone LG, Valera ET. J Mol Neurosci 72: 2022 633-641	5
Failure of human rhombic lip differentiation underlies medulloblastoma formation. Hendrikse LD, Haldipur P, Saulnier O, Millman J, Sjoboen AH, Erickson AW, Ong W, Gordon V, Coudière-Morrison L, Mercier AL, Shokouhian M, Suárez RA, Ly M, Borlase S, Scott DS, Vladoiu MC, Farooq H, Sirbu O, Nakashima T, Nambu S, Funakoshi Y, Bahcheli A, Diaz-Mejia JJ, Golser J, Bach K, Phuong-Bao T, Skowron P, Wang EY, Kumar SA, Balin P, Visvanathan A, Lee JJY, Ayoub R, Chen X, Chen X, Mungall KL, Luu B, Bérubé P, Wang YC, Pfister SM, Kim SK, Delattre O, Bourdeaut F, Doz F, Masliah-Planchon J, Grajkowska WA, Loukides J, Dirks P, Fèvre-Montange M, Jouvet A, French PJ, Kros JM, Zitterbart K, Bailey SD, Eberhart CG, Rao AAN, Giannini C, Olson JM, Garami M, Hauser P, Phillips JJ, Ra YS, de Torres C, Mora J, Li KKW, Ng HK, Poon WS, Pollack IF, López-Aguilar E, Gillespie GY, Van Meter TE, Shofuda T, Vibhakar R, Thompson RC, Cooper MK, Rubin JB, Kumabe T, Jung S, Lach B, Iolascon A, Ferrucci V, de Antonellis P, Zollo M, Cinalli G, Robinson S, Stearns DS, Van Meir EG, Porrati P, Finocchiaro G, Massimino M, Carlotti CG, Faria CC, Roussel MF, Boop F, Chan JA, Aldinger KA, Razavi F, Silvestri E, McLendon RE, Thompson EM, Ansari M, Garre ML, Chico F, Eguía P, Pérezpeña M, Morrissy AS, Cavalli FMG, Wu X, Daniels C, Rich JN, Jones SJM, Moore RA, Marra MA, Huang X, Reimand J, Sorensen PH, Wechsler-Reya RJ, Weiss WA, Pugh TJ, Garzia L, Kleinman CL, Stein LD, Jabado N, Malkin D, Ayrault O, Golden JA, Ellison DW, Doble B, Ramaswamy V, Werbowetski-Ogilvie TE, Suzuki H, Millen KJ, Taylor MD. Nature 609: 2022 1021-1028	33
Linked-read based analysis of the medulloblastoma genome. Zwaig M, Johnston MJ, Lee JJY, Farooq H, Gallo M, Jabado N, Taylor MD, Ragoussis J. Front Oncol 13: 2023 1221611	0
Compartments in medulloblastoma with extensive nodularity are connected through differentiation along the granular precursor lineage. Ghasemi DR, Okonechnikov K, Rademacher A, Tirier S, Maass KK, Schumacher H, Joshi P, Gold MP, Sundheimer J, Statz B, Rifaioglu AS, Bauer K, Schumacher S, Bortolomeazzi M, Giangaspero F, Ernst KJ, Clifford SC, Saez-Rodriguez J, Jones DTW, Kawauchi D, Fraenkel E, Mallm JP, Rippe K, Korshunov A, Pfister SM, Pajtler KW. Nat Commun 15: 2024 269	1
Childhood cancer mutagenesis caused by transposase-derived PGBD5. Yamada M, Keller RR, Gutierrez RL, Cameron D, Suzuki H, Sanghrajka R, Vaynshteyn J, Gerwin J, Maura F, Hooper W, Shah M, Robine N, Demarest P, Bayin NS, Zapater LJ, Reed C, Hébert S, Masilionis I, Chaligne R, Socci ND, Taylor MD, Kleinman CL, Joyner AL, Raju GP, Kentsis A. Sci Adv 10: 2024 eadn4649	0