Publication details

The transcriptional landscape of Shh medulloblastoma

Authors

SKOWRON P. FAROOQ H. CAVALLI F. M. G. MORRISSY A. S. LY M. HENDRIKSE L. D. WANG E. Y. DJAMBAZIAN H. ZHU H. MUNGALL K. L. TRINH Q. M. ZHENG T. N. DAI S. Z. STUCKLIN A. S. G. VLADOIU M. C. FONG V. HOLGADO B. L. NOR C. WU X. C. ABD-RABBO D. BERUBE P. WANG Y. C. LUU B. SUAREZ R. A. RASTAN A. GILLMOR A. H. LEE J. J. Y. ZHANG X. Y. DANIELS C. DIRKS P. MALKIN D. BOUFFET E. TABORI U. LOUKIDES J. DOZ F. P. BOURDEAUT F. DELATTRE O. O. MASLIAH-PLANCHON J. AYRAULT O. KIM S. K. MEYRONET D. GRAJKOWSKA W. A. CARLOTTI C. G. DE TORRES C. MORA J. EBERHART C. G. VAN MEIR E. G. KUMABE T. FRENCH P. J. KROS J. M. JABADO N. LACH B. POLLACK I. F. HAMILTON R. L. RAO A. A. N. GIANNINI C. OLSON J. M. BOGNAR L. KLEKNER A. ZITTERBART Karel PHILLIPS J. J. THOMPSON R. C. COOPER M. K. RUBIN J. B. LIAU L. M. GARAMI M. HAUSER P. LI K. K. W. NG H. K. POON W. S. GILLESPIE G. Y. CHAN J. A. JUNG S. MCLENDON R. E. THOMPSON E. M. ZAGZAG D. VIBHAKAR R. RA Y. S. GARRE M. L. SCHULLER U. SHOFUDA T. FARIA C. C. LOPEZ-AGUILAR E. ZADEH G. HUI C. C. RAMASWAMY V. BAILEY S. D. JONES S. J. MUNGALL A. J. MOORE R. A. CALARCO J. A. STEIN L. D. BADER G. D. REIMAND J. RAGOUSSIS J. WEISS W. A. MARRA M. A. SUZUKI H. TAYLOR MD

Year of publication 2021
Type Article in Periodical
Magazine / Source Nature Communications
MU Faculty or unit

Faculty of Medicine

Citation
Web https://www.nature.com/articles/s41467-021-21883-0
Doi http://dx.doi.org/10.1038/s41467-021-21883-0
Keywords Shh medulloblastoma; transcriptional landscape
Description Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention. Sonic Hedgehog medulloblastoma (Shh-MB) comprises four subtypes each with distinct clinical traits. Here the authors characterize the genome, transcriptome, and methylome of Shh-MB subtypes, revealing a complex fusion landscape and the molecular convergence of MYCN and cAMP signaling pathways.

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