Stratifying and Targeting Pediatric Medulloblastoma through Genomics

In this project, genomic analyses of pediatric medulloblastoma samples, obtained through the international medulloblastoma consortium, will be performed. RNA and miRNA expression profiles of 1000 samples, representing all four subgroups (Wnt, Shh, Group C, and D), will be studied to identify novel subtypes within each subgroup. The resulting subtype-specific expression profiles will support the development of reliable and robust biomarkers to more accurately and reliably classify medulloblastomas for treatment in clinical trials. For that purpose, two assays will be developed: an antibody-based immunohistochemical assay and an orthogonal nucleic acid-based hybridization assay. Additional genomic DNA analysis of the 300 high risk subgroup cases will support the discovery of subgroup specific somatic mutations in order to inform current clinical trials of targeted therapies, and to identify genes and pathways already targeted in other diseases. Such therapies could be rapidly transitioned to Phase II trials in medulloblastoma. Furthermore, the discovery of somatic mutations could be used for developing as well as validating specific biomarkers. The project team will also try to identify risk factors that predispose children to this type of cancer.

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

12 Datasets 24 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
EGAD00001000158	Subgroup-specific structural variation across 1,000 medulloblastoma genomes		23
EGAD00001000723	Relative Spatial Homogeneity of Embryonal Brain Tumors of Childhood		42
EGAD00001000818	Quiescent Sox2+ cells drive hierarchical growth and relapse in Sonic hedgehog subgroup medulloblastoma		4
EGAD00001000946	Divergent clonal selection dominates medulloblastoma at recurrence		125
EGAD00001001210	Medulloblastoma-associated DDX3 variant selectively alters the translational response to stress		28
EGAD00001001461	CBP has opposing functions during cerebellar development and is a targetable tumor suppressor at late stages of medulloblastoma initiation		30
EGAD00001001899	HDAC and PI3K Antagonists Cooperate to Inhibit Growth of MYC-driven Medulloblastoma		102
EGAD00001003907	A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases		79
EGAD00001004435	Childhood cerebellar tumours mirror conserved fetal transcriptional programs	Illumina HiSeq 2000	145
EGAD00001004958	Highly recurrent U1 snRNA mutations drive alternative splicing in HH medulloblastoma	Illumina HiSeq 2000 Illumina HiSeq 2500	234
EGAD00001006305	To further understand the biology of Sonic hedgehog medulloblastoma and its molecular subtypes, we studied 250 human Shh-MB using strand-specific RNA sequencing. We identified novel alterations within the cAMP dependent pathway and found that 18% of tumors have genetic events that directly target the abundance and/or stability of MYCN. We also discovered an extensive network of fusions in focally amplified regions, and several loss-of-function fusions in tumor suppressor genes PTCH, SUFU and NCOR1. Molecular convergence on a core of specific genes by nucleotide variants, copy number aberrations, and gene fusions highlights key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma.	Illumina HiSeq 2000 Illumina HiSeq 2500	82
EGAD00001008458	We used single-cell transcriptomics to study cells from the developing human cerebellum, and show that different molecular subgroups of medulloblastoma resemble distinct glutamatergic progenitors.	Illumina HiSeq 2000 Illumina HiSeq 2500	391

Publications	Citations
Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Northcott PA, Shih DJ, Peacock J, Garzia L, Morrissy AS, Zichner T, Stütz AM, Korshunov A, Reimand J, Schumacher SE, Beroukhim R, Ellison DW, Marshall CR, Lionel AC, Mack S, Dubuc A, Yao Y, Ramaswamy V, Luu B, Rolider A, Cavalli FM, Wang X, Remke M, Wu X, Chiu RY, Chu A, Chuah E, Corbett RD, Hoad GR, Jackman SD, Li Y, Lo A, Mungall KL, Nip KM, Qian JQ, Raymond AG, Thiessen NT, Varhol RJ, Birol I, Moore RA, Mungall AJ, Holt R, Kawauchi D, Roussel MF, Kool M, Jones DT, Witt H, Fernandez-L A, Kenney AM, Wechsler-Reya RJ, Dirks P, Aviv T, Grajkowska WA, Perek-Polnik M, Haberler CC, Delattre O, Reynaud SS, Doz FF, Pernet-Fattet SS, Cho BK, Kim SK, Wang KC, Scheurlen W, Eberhart CG, Fèvre-Montange M, Jouvet A, Pollack IF, Fan X, Muraszko KM, Gillespie GY, Di Rocco C, Massimi L, Michiels EM, Kloosterhof NK, French PJ, Kros JM, Olson JM, Ellenbogen RG, Zitterbart K, Kren L, Thompson RC, Cooper MK, Lach B, McLendon RE, Bigner DD, Fontebasso A, Albrecht S, Jabado N, Lindsey JC, Bailey S, Gupta N, Weiss WA, Bognár L, Klekner A, Van Meter TE, Kumabe T, Tominaga T, Elbabaa SK, Leonard JR, Rubin JB, Liau LM, Van Meir EG, Fouladi M, Nakamura H, Cinalli G, Garami M, Hauser P, Saad AG, Iolascon A, Jung S, Carlotti CG, Vibhakar R, Ra YS, Robinson S, Zollo M, Faria CC, Chan JA, Levy ML, Sorensen PH, Meyerson M, Pomeroy SL, Cho YJ, Bader GD, Tabori U, Hawkins CE, Bouffet E, Scherer SW, Rutka JT, Malkin D, Clifford SC, Jones SJ, Korbel JO, Pfister SM, Marra MA, Taylor MD. Nature 488: 2012 49-56	561
Quiescent sox2(+) cells drive hierarchical growth and relapse in sonic hedgehog subgroup medulloblastoma. Vanner RJ, Remke M, Gallo M, Selvadurai HJ, Coutinho F, Lee L, Kushida M, Head R, Morrissy S, Zhu X, Aviv T, Voisin V, Clarke ID, Li Y, Mungall AJ, Moore RA, Ma Y, Jones SJ, Marra MA, Malkin D, Northcott PA, Kool M, Pfister SM, Bader G, Hochedlinger K, Korshunov A, Taylor MD, Dirks PB. Cancer Cell 26: 2014 33-47	188
Divergent clonal selection dominates medulloblastoma at recurrence. Morrissy AS, Garzia L, Shih DJ, Zuyderduyn S, Huang X, Skowron P, Remke M, Cavalli FM, Ramaswamy V, Lindsay PE, Jelveh S, Donovan LK, Wang X, Luu B, Zayne K, Li Y, Mayoh C, Thiessen N, Mercier E, Mungall KL, Ma Y, Tse K, Zeng T, Shumansky K, Roth AJ, Shah S, Farooq H, Kijima N, Holgado BL, Lee JJ, Matan-Lithwick S, Liu J, Mack SC, Manno A, Michealraj KA, Nor C, Peacock J, Qin L, Reimand J, Rolider A, Thompson YY, Wu X, Pugh T, Ally A, Bilenky M, Butterfield YS, Carlsen R, Cheng Y, Chuah E, Corbett RD, Dhalla N, He A, Lee D, Li HI, Long W, Mayo M, Plettner P, Qian JQ, Schein JE, Tam A, Wong T, Birol I, Zhao Y, Faria CC, Pimentel J, Nunes S, Shalaby T, Grotzer M, Pollack IF, Hamilton RL, Li XN, Bendel AE, Fults DW, Walter AW, Kumabe T, Tominaga T, Collins VP, Cho YJ, Hoffman C, Lyden D, Wisoff JH, Garvin JH, Stearns DS, Massimi L, Schüller U, Sterba J, Zitterbart K, Puget S, Ayrault O, Dunn SE, Tirapelli DP, Carlotti CG, Wheeler H, Hallahan AR, Ingram W, MacDonald TJ, Olson JJ, Van Meir EG, Lee JY, Wang KC, Kim SK, Cho BK, Pietsch T, Fleischhack G, Tippelt S, Ra YS, Bailey S, Lindsey JC, Clifford SC, Eberhart CG, Cooper MK, Packer RJ, Massimino M, Garre ML, Bartels U, Tabori U, Hawkins CE, Dirks P, Bouffet E, Rutka JT, Wechsler-Reya RJ, Weiss WA, Collier LS, Dupuy AJ, Korshunov A, Jones DT, Kool M, Northcott PA, Pfister SM, Largaespada DA, Mungall AJ, Moore RA, Jabado N, Bader GD, Jones SJ, Malkin D, Marra MA, Taylor MD. Nature 529: 2016 351-357	197
HDAC and PI3K Antagonists Cooperate to Inhibit Growth of MYC-Driven Medulloblastoma. Pei Y, Liu KW, Wang J, Garancher A, Tao R, Esparza LA, Maier DL, Udaka YT, Murad N, Morrissy S, Seker-Cin H, Brabetz S, Qi L, Kogiso M, Schubert S, Olson JM, Cho YJ, Li XN, Crawford JR, Levy ML, Kool M, Pfister SM, Taylor MD, Wechsler-Reya RJ. Cancer Cell 29: 2016 311-323	161
Medulloblastoma-associated DDX3 variant selectively alters the translational response to stress. Oh S, Flynn RA, Floor SN, Purzner J, Martin L, Do BT, Schubert S, Vaka D, Morrissy S, Li Y, Kool M, Hovestadt V, Jones DT, Northcott PA, Risch T, Warnatz HJ, Yaspo ML, Adams CM, Leib RD, Breese M, Marra MA, Malkin D, Lichter P, Doudna JA, Pfister SM, Taylor MD, Chang HY, Cho YJ. Oncotarget 7: 2016 28169-28182	48
Spatial heterogeneity in medulloblastoma. Morrissy AS, Cavalli FMG, Remke M, Ramaswamy V, Shih DJH, Holgado BL, Farooq H, Donovan LK, Garzia L, Agnihotri S, Kiehna EN, Mercier E, Mayoh C, Papillon-Cavanagh S, Nikbakht H, Gayden T, Torchia J, Picard D, Merino DM, Vladoiu M, Luu B, Wu X, Daniels C, Horswell S, Thompson YY, Hovestadt V, Northcott PA, Jones DTW, Peacock J, Wang X, Wang X, Mack SC, Reimand J, Albrecht S, Fontebasso AM, Thiessen N, Li Y, Schein JE, Lee D, Carlsen R, Mayo M, Tse K, Tam A, Dhalla N, Ally A, Chuah E, Cheng Y, Plettner P, Li HI, Corbett RD, Wong T, Long W, Loukides J, Buczkowicz P, Hawkins CE, Tabori U, Rood BR, Myseros JS, Packer RJ, Korshunov A, Lichter P, Kool M, Pfister SM, Schüller U, Dirks P, Huang A, Bouffet E, Rutka JT, Bader GD, Swanton C, Ma Y, Moore RA, Mungall AJ, Majewski J, Jones SJM, Das S, Malkin D, Jabado N, Marra MA, Taylor MD. Nat Genet 49: 2017 780-788	83
Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation. Tech K, Tikunov AP, Farooq H, Morrissy AS, Meidinger J, Fish T, Green SC, Liu H, Li Y, Mungall AJ, Moore RA, Ma Y, Jones SJM, Marra MA, Vander Heiden MG, Taylor MD, Macdonald JM, Gershon TR. Cancer Res 77: 2017 3217-3230	33
Identification of GPC2 as an Oncoprotein and Candidate Immunotherapeutic Target in High-Risk Neuroblastoma. Bosse KR, Raman P, Zhu Z, Lane M, Martinez D, Heitzeneder S, Rathi KS, Kendsersky NM, Randall M, Donovan L, Morrissy S, Sussman RT, Zhelev DV, Feng Y, Wang Y, Hwang J, Lopez G, Harenza JL, Wei JS, Pawel B, Bhatti T, Santi M, Ganguly A, Khan J, Marra MA, Taylor MD, Dimitrov DS, Mackall CL, Maris JM. Cancer Cell 32: 2017 295-309.e12	107
A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases. Garzia L, Kijima N, Morrissy AS, De Antonellis P, Guerreiro-Stucklin A, Holgado BL, Wu X, Wang X, Parsons M, Zayne K, Manno A, Kuzan-Fischer C, Nor C, Donovan LK, Liu J, Qin L, Garancher A, Liu KW, Mansouri S, Luu B, Thompson YY, Ramaswamy V, Peacock J, Farooq H, Skowron P, Shih DJH, Li A, Ensan S, Robbins CS, Cybulsky M, Mitra S, Ma Y, Moore R, Mungall A, Cho YJ, Weiss WA, Chan JA, Hawkins CE, Massimino M, Jabado N, Zapotocky M, Sumerauer D, Bouffet E, Dirks P, Tabori U, Sorensen PHB, Brastianos PK, Aldape K, Jones SJM, Marra MA, Woodgett JR, Wechsler-Reya RJ, Fults DW, Taylor MD. Cell 172: 2018 1050-1062.e14	52
Proteomic analysis of Medulloblastoma reveals functional biology with translational potential. Rivero-Hinojosa S, Lau LS, Stampar M, Staal J, Zhang H, Gordish-Dressman H, Northcott PA, Pfister SM, Taylor MD, Brown KJ, Rood BR. Acta Neuropathol Commun 6: 2018 48	25
p53 Function Is Compromised by Inhibitor 2 of Phosphatase 2A in Sonic Hedgehog Medulloblastoma. Wei Y, Maximov V, Morrissy SA, Taylor MD, Pallas DC, Kenney AM. Mol Cancer Res 17: 2019 186-198	8
Childhood cerebellar tumours mirror conserved fetal transcriptional programs. Vladoiu MC, El-Hamamy I, Donovan LK, Farooq H, Holgado BL, Sundaravadanam Y, Ramaswamy V, Hendrikse LD, Kumar S, Mack SC, Lee JJY, Fong V, Juraschka K, Przelicki D, Michealraj A, Skowron P, Luu B, Suzuki H, Morrissy AS, Cavalli FMG, Garzia L, Daniels C, Wu X, Qazi MA, Singh SK, Chan JA, Marra MA, Malkin D, Dirks P, Heisler L, Pugh T, Ng K, Notta F, Thompson EM, Kleinman CL, Joyner AL, Jabado N, Stein L, Taylor MD. Nature 572: 2019 67-73	195
Upregulation of the chromatin remodeler HELLS is mediated by YAP1 in Sonic Hedgehog Medulloblastoma. Robinson MH, Maximov V, Lallani S, Farooq H, Taylor MD, Read RD, Kenney AM. Sci Rep 9: 2019 13611	13
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	101
Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma. Garancher A, Suzuki H, Haricharan S, Chau LQ, Masihi MB, Rusert JM, Norris PS, Carrette F, Romero MM, Morrissy SA, Skowron P, Cavalli FMG, Farooq H, Ramaswamy V, Jones SJM, Moore RA, Mungall AJ, Ma Y, Thiessen N, Li Y, Morcavallo A, Qi L, Kogiso M, Du Y, Baxter P, Henderson JJ, Crawford JR, Levy ML, Olson JM, Cho YJ, Deshpande AJ, Li XN, Chesler L, Marra MA, Wajant H, Becher OJ, Bradley LM, Ware CF, Taylor MD, Wechsler-Reya RJ. Nat Neurosci 23: 2020 842-853	32
A transcriptome-based classifier to determine molecular subtypes in medulloblastoma. Rathi KS, Arif S, Koptyra M, Naqvi AS, Taylor DM, Storm PB, Resnick AC, Rokita JL, Raman P. PLoS Comput Biol 16: 2020 e1008263	6
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	43
Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse. Richardson S, Hill RM, Kui C, Lindsey JC, Grabovksa Y, Keeling C, Pease L, Bashton M, Crosier S, Vinci M, André N, Figarella-Branger D, Hansford JR, Lastowska M, Zakrzewski K, Jorgensen M, Pickles JC, Taylor MD, Pfister SM, Wharton SB, Pizer B, Michalski A, Joshi A, Jacques TS, Hicks D, Schwalbe EC, Williamson D, Ramaswamy V, Bailey S, Clifford SC. Neuro Oncol 24: 2022 153-165	23
Subgroup and subtype-specific outcomes in adult medulloblastoma. Coltin H, Sundaresan L, Smith KS, Skowron P, Massimi L, Eberhart CG, Schreck KC, Gupta N, Weiss WA, Tirapelli D, Carlotti C, Li KKW, Ryzhova M, Golanov A, Zheludkova O, Absalyamova O, Okonechnikov K, Stichel D, von Deimling A, Giannini C, Raskin S, Van Meir EG, Chan JA, Fults D, Chambless LB, Kim SK, Vasiljevic A, Faure-Conter C, Vibhakar R, Jung S, Leary S, Mora J, McLendon RE, Pollack IF, Hauser P, Grajkowska WA, Rubin JB, van Veelen MC, French PJ, Kros JM, Liau LM, Pfister SM, Kool M, Kijima N, Taylor MD, Packer RJ, Northcott PA, Korshunov A, Ramaswamy V. Acta Neuropathol 142: 2021 859-871	29
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	46
The LIN28B-let-7-PBK pathway is essential for group 3 medulloblastoma tumor growth and survival. Shahab SW, Roggeveen CM, Sun J, Kunhiraman H, McSwain LF, Juraschka K, Kumar SA, Saulnier O, Taylor MD, Schniederjan M, Schnepp RW, MacDonald TJ, Kenney AM. Mol Oncol 17: 2023 1784-1802	4
MYC up-regulation confers vulnerability to dual inhibition of CDK12 and CDK13 in high-risk Group 3 medulloblastoma. Pitolli C, Marini A, Guerra M, Pieraccioli M, Marabitti V, Palluzzi F, Giacò L, Tamburrini G, Cecconi F, Nazio F, Sette C, Pagliarini V. J Exp Clin Cancer Res 42: 2023 214	2
Heterogeneity and tumoral origin of medulloblastoma in the single-cell era. Sheng H, Li H, Zeng H, Zhang B, Lu Y, Liu X, Xu Z, Zhang J, Zhang L. Oncogene 43: 2024 839-850	1
A group 3 medulloblastoma stem cell program is maintained by OTX2-mediated alternative splicing. Saulnier O, Zagozewski J, Liang L, Hendrikse LD, Layug P, Gordon V, Aldinger KA, Haldipur P, Borlase S, Coudière-Morrison L, Cai T, Martell E, Gonzales NM, Palidwor G, Porter CJ, Richard S, Sharif T, Millen KJ, Doble BW, Taylor MD, Werbowetski-Ogilvie TE. Nat Cell Biol 26: 2024 1233-1246	0