Subgroup-specific structural variation across 1,000 medulloblastoma genomes.


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Subgroup-specific structural variation across 1,000 medulloblastoma genomes.
Northcott P.A., Shih D.J., Peacock J., Garzia L., Morrissy A.S., Zichner T., Stütz A.M., Korshunov A., Reimand J., Schumacher S.E., Beroukhim R., Ellison D.W., Marshall C.R., Lionel A.C., Mack S., Dubuc A., Yao Y., Ramaswamy V., Luu B., Rolider A., Cavalli F.M., Wang X., Remke M., Wu X., Chiu R.Y., Chu A., Chuah E., Corbett R.D., Hoad G.R., Jackman S.D., Li Y., Lo A., Mungall K.L., Nip K.M., Qian J.Q., Raymond A.G., Thiessen N.T., Varhol R.J., Birol I., Moore R.A., Mungall A.J., Holt R., Kawauchi D., Roussel M.F., Kool M., Jones D.T., Witt H., Fernandez-L A., Kenney A.M., Wechsler-Reya R.J., Dirks P., Aviv T., Grajkowska W.A., Perek-Polnik M., Haberler C.C., Delattre O., Reynaud S.S., Doz F.F., Pernet-Fattet S.S., Cho B.K., Kim S.K., Wang K.C., Scheurlen W., Eberhart C.G., Fèvre-Montange M., Jouvet A., Pollack I.F., Fan X., Muraszko K.M., Gillespie G.Y., Di Rocco C., Massimi L., Michiels E.M., Kloosterhof N.K., French P.J., Kros J.M., Olson J.M., Ellenbogen R.G., Zitterbart K., Kren L., Thompson R.C., Cooper M.K., Lach B., McLendon R.E., Bigner D.D., Fontebasso A., Albrecht S., Jabado N., Lindsey J.C., Bailey S., Gupta N., Weiss W.A., Bognár L., Klekner A., Van Meter T.E., Kumabe T., Tominaga T., Elbabaa S.K., Leonard J.R., Rubin J.B., Liau L.M., Van Meir E.G., Fouladi M., Nakamura H., Cinalli G., Garami M., Hauser P., Saad A.G., Iolascon A., Jung S., Carlotti C.G., Vibhakar R., Ra Y.S., Robinson S., Zollo M., Faria C.C., Chan J.A., Levy M.L., Sorensen P.H., Meyerson M., Pomeroy S.L., Cho Y.J., Bader G.D., Tabori U., Hawkins C.E., Bouffet E., Scherer S.W., Rutka J.T., Malkin D., Clifford S.C., Jones S.J., Korbel J.O., Pfister S.M., Marra M.A., Taylor M.D.
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Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov'tPublication Status: ppublish. Contributions: P.A.N. and M.D.T. co-conceived the study. P.A.N., M.A.M., and M.D.T. led the study. P.A.N. planned and executed experiments and analyses, supervised data acquisition, performed bioinformatic analyses, and extracted nucleic acids for the MAGIC cohort. D.J.H.S. led the bioinformatics and performed analyses. J.P. performed quantitative RT-PCR and Sanger sequencing of PVT1 fusions, expression profiled PVT1-encoded miRNAs, and generated schematics for PVT1 fusion genes. L.G. performed the MYC and miR-1204 knockdown experiments. A.S.M. supervised the RNA-Seq and WGS experiments and performed data analysis. T.Z., A.M.S. and J.O.K. performed the large insert paired-end sequencing and PCR verification of SNCAIP duplication samples. A.Ko. performed interphase FISH and immunohistochemistry for candidate genes. J.R. and G.D.B. led the pathway analyses and generated enrichment plots. S.E.S. and R.B. provided technical support with the GISTIC2 bioinformatic platform. D.W.E. performed interphase FISH for candidate genes. C.R.M., A.C.L. and S.W.S. performed the SNP6 genotyping analysis, provided a database of normal copy number variants, and the control dataset used to infer copy number in the tumour samples. S.M., A.D., F.M.G.C., M.K., D.T.W.J. and H.W. performed bioinformatic analyses and provided technical advice. Y.Y. sequenced CTNNB1 in the WNT tumours. V.R., D.K., M.F.R., T.A., and P.D. performed functional assays for candidate genes. B.Lu. extracted nucleic acids, managed biobanking, and maintained the patient database. S.M. and A.R. performed the drug database analysis. Xin W., Xiaochong W. and M.R. provided technical support. R.Y.B.C., A.C., E.C., R.D.C., G.R.H., S.D.J., Y.L., A.L., K.L.M., K.M.N., J.Q.Q., A.G.J.R., N.T., R.J.V., I.B., R.A.M., A.J.M., R.H. and S.J.M.J. led the RNA-Seq and WGS experiments and performed data analyses. A.F.-L and A.M.K. provided the database of SHH-responsive genes. R.J.W.-R., W.A.G., M.P.-P., C.C.H., O.D., S.S.R., F.F.D., S.S.P.-F., B.-K.C., S.-K.K., K.-C.W., W.S., C.G.E., M.F.-M., A.J., I.F.P., X.F., K.M.M., G.Y.G., C.D.R., L.M., E.M.C.M., N.K.K., P.J.F., J.M.K., J.M.O., R.G.E., K.Z., L.K., R.C.T., MKC, B.La., R.E.M., D.D.B., A.F., S.A., N.J., J.C.L., S.B., N.G., W.A.W., L.B., A.Kl., T.E.V.M., T.K., T.T., S.K.E., J.R.L., J.B.R., L.M.L., E.G.V.M., M.F., H.N., G.C., M.G., P.H., A.G.S., A.I., S.J., C.G.C., R.V., Y.S.R., S.R., M.Z., C.C.F., J.A.C., M.L.L., Y.-J.C., U.T., C.E.H., E.B., S.C.C. and S.M.P. provided the patient samples and clinical details that made the study possible. P.H.B.S., M.M., S.L.P., Y.-J.C., U.T., C.E.H., E.B., S.W.S., J.T.R., D.M., S.C.C., S.J.M.J., J.O.K., S.M.P. and M.A.M. provided valuable input regarding study design, data analysis, and interpretation of results. P.A.N., D.J.H.S., J.P., L.G., A.S.M., M.A.M. and M.D.T. wrote the manuscript. M.A.M. and M.D.T. provided financial and technical infrastructure and oversaw the study. M.A.M. and M.D.T. are joint senior authors and project co-leaders.
Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.
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18/08/2012 9:49
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20/08/2019 15:28
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