The transcriptional landscape of Shh medulloblastoma.
Patryk SkowronHamza FarooqFlorence M G CavalliA Sorana MorrissyMichelle LyLiam D HendrikseEvan Y WangHaig Hugo Vrej DjambazianHelen ZhuKaren L MungallQuang M TrinhTina ZhengShizhong DaiAna S Guerreiro StucklinMaria C VladoiuVernon FongBorja L HolgadoCarolina NorXiaochong WuDiala Abd-RabboPierre BérubéYu Chang WangBetty LuuRaul A SuarezAvesta RastanAaron H GillmorJohn J Y LeeXiao Yun ZhangCraig DanielsPeter B DirksDavid MalkinEric BouffetUri TaboriJames LoukidesFrançois P DozFranck BourdeautOlivier O DelattreJulien Masliah-PlanchonOlivier AyraultSeung-Ki KimDavid MeyronetWieslawa A GrajkowskaCarlos G CarlottiCarmen de TorresJaume MoraCharles G EberhartErwin G Van MeirToshihiro KumabePim J FrenchJohan M KrosNada JabadoBoleslaw LachIan F PollackRonald L HamiltonAmulya A Nageswara RaoCaterina GianniniJames M OlsonLászló BognárAlmos KleknerKarel ZitterbartJoanna J PhillipsReid C ThompsonMichael K CooperJoshua B RubinLinda M LiauMiklós GaramiPeter HauserKay Ka Wai LiHo-Keung NgWai Sang PoonG Yancey GillespieJennifer A ChanShin JungRoger E McLendonEric M ThompsonDavid ZagzagRajeev VibhakarYoung Shin RaMaria Luisa GarreUlrich SchüllerTomoko ShofudaClaudia C FariaEnrique López-AguilarGelareh ZadehChi-Chung HuiVijay RamsawamiSwneke D BaileySteven J M JonesAndrew J MungallRichard A MooreJohn A CalarcoLincoln D SteinGary D BaiderJüri ReimandJiannis RagoussisWilliam A WeissMarco A MarraHiromichi SuzukiMichael D TaylorPublished in: Nature communications (2021)
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.