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000293955 1001_ $$aSchwalbe, Edward C$$b0
000293955 245__ $$aMolecular and clinical heterogeneity within MYC-family amplified medulloblastoma is associated with survival outcomes: A multicenter cohort study.
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000293955 500__ $$aVolume 27, Issue 1, January 2025, Pages 222–236
000293955 520__ $$aMYC/MYCN are the most frequent oncogene amplifications in medulloblastoma (MB) and its primary biomarkers of high-risk (HR) disease. However, while many patients' MYC(N)-amplified tumors are treatment-refractory, some achieve long-term survival. We therefore investigated clinicobiological heterogeneity within MYC(N)-amplified MB and determined its relevance for improved disease management.We characterized the clinical and molecular correlates of MYC- (MYC-MB; n = 64) and MYCN-amplified MBs (MYCN-MB; n = 95), drawn from >1600 diagnostic cases.Most MYC-MBs were molecular group 3 (46/58; 79% assessable) and aged ≥3 years at diagnosis (44/64 [69%]). We identified a 'canonical' very high-risk (VHR) MYC-amplified group (n = 51/62; 82%) with dismal survival irrespective of treatment (11% 5-year progression-free survival [PFS]), defined by co-occurrence with ≥1 additional established risk factor(s) (subtotal surgical-resection [STR], metastatic disease, LCA pathology), and commonly group 3/4 subgroup 2 with a high proportion of amplified cells. The majority of remaining noncanonical MYC-MBs survived (i.e. non-group 3/group 3 without other risk features; 11/62 (18%); 61% 5-year PFS). MYCN survival was primarily related to molecular group; MYCN-amplified SHH MB, and group 3/4 MB with additional risk factors, respectively defined VHR and HR groups (VHR, 39% [35/89]; 20% 5-year PFS/HR, 33% [29/89]; 46% 5-year PFS). Twenty-two out of 35 assessable MYCN-amplified SHH tumors harbored TP53 mutations; 9/12 (75%) with data were germline. MYCN-amplified group 3/4 MB with no other risk factors (28%; 25/89) had 70% 5-year PFS.MYC(N)-amplified MB displays significant clinicobiological heterogeneity. Diagnostics incorporating molecular groups, subgroups, and clinical factors enable their risk assessment. VHR 'canonical' MYC tumors are essentially incurable and SHH-MYCN-amplified MBs fare extremely poorly (20% survival at 5 years); both require urgent development of alternative treatment strategies. Conventional risk-adapted therapies are appropriate for more responsive groups, such as noncanonical MYC and non-SHH-MYCN MB.
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000293955 650_7 $$2Other$$aMYC amplification
000293955 650_7 $$2Other$$aMYCN amplification
000293955 650_7 $$2Other$$amedulloblastoma
000293955 650_7 $$2Other$$asurvival
000293955 7001_ $$aLindsey, Janet C$$b1
000293955 7001_ $$aDanilenko, Marina$$b2
000293955 7001_ $$aHill, Rebecca M$$b3
000293955 7001_ $$aCrosier, Stephen$$b4
000293955 7001_ $$aRyan, Sarra L$$b5
000293955 7001_ $$aWilliamson, Daniel$$b6
000293955 7001_ $$aCastle, Jemma$$b7
000293955 7001_ $$aHicks, Debbie$$b8
000293955 7001_ $$0P:(DE-He78)4c28e2aade5f44d8eca9dd8e97638ec8$$aKool, Marcel$$b9
000293955 7001_ $$0P:(DE-He78)0be2f86573954f87e97f8a4dbb05cb0f$$aMilde, Till$$b10$$udkfz
000293955 7001_ $$0P:(DE-He78)8d9c904a6cea14d4c99c78ba46e41f93$$aKorshunov, Andrey$$b11$$udkfz
000293955 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan M$$b12$$udkfz
000293955 7001_ $$aBailey, Simon$$b13
000293955 7001_ $$00000-0003-4893-2184$$aClifford, Steven C$$b14
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