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.
Bibliographical noteFunding Information:
M.D.T. is supported by the NIH (R01CA148699 and R01CA159859), The Pediatric Brain Tumour Foundation, The Terry Fox Research Institute, The Canadian Institutes of Health Research, The Cure Search Foundation, b.r.a.i.n.child, Meagan’s Walk, SWIFTY Foundation, The Brain Tumour Charity, Genome Canada, Genome BC, Genome Quebec, the Ontario Research Fund, Worldwide Cancer Research, V-Foundation for Cancer Research, and the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. M.D.T. is also supported by a Canadian Cancer Society Research Institute Impact grant, a Cancer Research UK‘ Brain Tumour Award, and by a Stand Up To Cancer (SU2C) St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113) and SU2C Canada Cancer Stem Cell Dream Team Research Funding (SU2C-AACR-DT-19-15) provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, with supplementary support from the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. Stand Up to Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. M.D.T. is also supported by the Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children and the University of Toronto. F.M.G.C. is supported by the Stephen Buttrum Brain Tumor Research Fellowship, granted by the Brain Tumor Foundation of Canada. A.S. M. is supported by the Cancer Research Society Scholarships for the Next Generation of Scientists. P.S is supported by Sickkids Restracomp Ph.D. scholarship, and by funding provided by the Government of Ontario. The authors would like to thank Jim Loukides (Manager, Brain Tumour Biobank at SickKids) and recognize the Labatt Brain Tumour Research Centre and The Michael and Amira Dan Brain Tumour Bank Network. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health. Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI\Leidos Biomedical Research, Inc. subcontracts to the National Disease Research Interchange (10XS170), GTEx Project March 5, 2014 version Page 5 of 8 Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to The Broad Institute, Inc. Biorepository operations were funded through a Leidos Biomedical Research, Inc. subcontract to Van Andel Research Institute (10ST1035). Additional data repository and project management were provided by Leidos Biomedical Research, Inc. (HHSN261200800001E). This work was supported by NRNB (U.S. National Institutes of Health, National Center for Research Resources grant number P41 GM103504). A.K. was supported by the 2017-1.2.1-NKP-2017-00002 National Brain Research Program NAP 2.0 of Hungary. Computations were partially performed on the NIG supercomputer at ROIS National Institute of Genetics and on the Niagara supercomputer at the SciNet HPC Consortium. SciNet is funded by the Canada Foundation for Innovation under the auspices of Compute Canada; the Government of Ontario; the Ontario Research Fund-Research Excellence; and the University of Toronto.
© 2021, The Author(s).