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000169868 0247_ $$2doi$$a10.1093/neuonc/noab178
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000169868 037__ $$aDKFZ-2021-01602
000169868 041__ $$aEnglish
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000169868 1001_ $$aRichardson, Stacey$$b0
000169868 245__ $$aEmergence and maintenance of actionable genetic drivers at medulloblastoma relapse.
000169868 260__ $$aOxford$$bOxford Univ. Press$$c2022
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000169868 500__ $$a2022 Jan 5;24(1):153-165
000169868 520__ $$a<5% of medulloblastoma patients survive following failure of contemporary radiation-based therapies. Understanding the molecular drivers of medulloblastoma relapse (rMB) will be essential to improve outcomes. Initial genome-wide investigations suggested significant genetic divergence of the relapsed disease.We undertook large-scale integrated characterization of the molecular features of rMB - molecular subgroup, novel subtypes, copy number variation (CNV) and driver gene mutation. 119 rMBs were assessed in comparison with their paired diagnostic samples (n=107), alongside an independent reference cohort sampled at diagnosis (n=282). rMB events were investigated for association with outcome post-relapse in clinically-annotated patients (n=54).Significant genetic evolution occurred over disease-course; 40% of putative rMB drivers emerged at relapse and differed significantly between molecular subgroups. MBSHH Non-infant displayed significantly more chromosomal CNVs at relapse (TP53 mutation-associated). Relapsed MBGroup4 demonstrated the greatest genetic divergence, enriched for targetable (e.g. CDK amplifications) and novel (e.g. USH2A mutations) events. Importantly, many hallmark features of medulloblastoma were stable over time; novel subtypes (>90% of tumors) and established genetic drivers (e.g. SHH/WNT/P53 mutations; 60% of rMB events) were maintained from diagnosis. Critically, acquired and maintained rMB events converged on targetable pathways which were significantly enriched at relapse (e.g. DNA damage-signaling) and specific events (e.g. 3p loss) predicted survival post-relapse.rMB is defined by the emergence of novel events and pathways, in concert with selective maintenance of established genetic drivers. Together, these define the actionable genetic landscape of rMB and provide a basis for improved clinical management and development of stratified therapeutics, across disease-course.
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000169868 650_7 $$2Other$$aDrivers
000169868 650_7 $$2Other$$aGenomics
000169868 650_7 $$2Other$$aMedulloblastoma
000169868 650_7 $$2Other$$aRelapse
000169868 650_7 $$2Other$$aSubgroups
000169868 7001_ $$aHill, Rebecca M$$b1
000169868 7001_ $$aKui, Christopher$$b2
000169868 7001_ $$aLindsey, Janet C$$b3
000169868 7001_ $$aGrabovksa, Yura$$b4
000169868 7001_ $$aKeeling, Claire$$b5
000169868 7001_ $$aPease, Louise$$b6
000169868 7001_ $$aBashton, Matthew$$b7
000169868 7001_ $$aCrosier, Stephen$$b8
000169868 7001_ $$aVinci, Maria$$b9
000169868 7001_ $$aAndré, Nicolas$$b10
000169868 7001_ $$00000-0002-3604-887X$$aFigarella-Branger, Dominique$$b11
000169868 7001_ $$aHansford, Jordan R$$b12
000169868 7001_ $$aLastowska, Maria$$b13
000169868 7001_ $$aZakrzewski, Krzysztof$$b14
000169868 7001_ $$aJorgensen, Mette$$b15
000169868 7001_ $$aPickles, Jessica C$$b16
000169868 7001_ $$aTaylor, Michael D$$b17
000169868 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan M$$b18$$udkfz
000169868 7001_ $$00000-0003-2785-333X$$aWharton, Stephen B$$b19
000169868 7001_ $$aPizer, Barry$$b20
000169868 7001_ $$aMichalski, Antony$$b21
000169868 7001_ $$aJoshi, Abhijit$$b22
000169868 7001_ $$aJacques, Thomas S$$b23
000169868 7001_ $$aHicks, Debbie$$b24
000169868 7001_ $$aSchwalbe, Edward C$$b25
000169868 7001_ $$aWilliamson, Daniel$$b26
000169868 7001_ $$00000-0002-6557-895X$$aRamaswamy, Vijay$$b27
000169868 7001_ $$aBailey, Simon$$b28
000169868 7001_ $$aClifford, Steven C$$b29
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