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000307431 1001_ $$00000-0003-4844-261X$$aFernandez, Nicholas R$$b0
000307431 245__ $$aPatterns of hypermutation shape tumorigenesis and immunotherapy response in mismatch-repair-deficient glioma.
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000307431 520__ $$aPrimary mismatch-repair-deficient high-grade gliomas (priMMRD-HGG) are lethal tumors characterized by hypermutation, resistance to chemoradiation and variable response to immunotherapy. To investigate the mechanisms governing the emergence of driver mutations and their impact on gliomagenesis and patient outcomes, we analyzed genomic and clinical data from 162 priMMRD-HGG. Here we identified three subgroups defined by secondary driver mutations in replicative DNA polymerases or IDH1. These subgroups converge on glioma drivers through distinct combinations of genomic instability-generating mechanisms, displaying an inverse correlation between point mutations and copy number alterations. MMRD signatures drive the emergence of specific mutations in TP53 and IDH1, notably excluding common pediatric glioma drivers. Global hypomethylation stratifies priMMRD-HGG into a unique methylation cluster. DNA-polymerasemut priMMRD-HGG exhibit ultrahypermutation, an immune-hot microenvironment and immunotherapy responsiveness, whereas IDH1mut priMMRD-HGG are immune-cold and immunotherapy resistant. MMRD-driven gliomagenesis defines the role of nonrandom mutagenesis patterns in cancer development, providing frameworks for targeted and immune-therapeutics.
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000307431 7001_ $$aChang, Yuan$$b1
000307431 7001_ $$00000-0002-3879-9757$$aNunes, Nuno M$$b2
000307431 7001_ $$aDimayacyac, Jose R$$b3
000307431 7001_ $$aLevine, Adrian$$b4
000307431 7001_ $$aRingel, Amit$$b5
000307431 7001_ $$aNegm, Logine$$b6
000307431 7001_ $$00000-0003-3612-3515$$aErcan, Ayse Bahar$$b7
000307431 7001_ $$00000-0003-1387-4009$$aHess, Julian M$$b8
000307431 7001_ $$0P:(DE-He78)d22bc86a498d1be5f5e75a7d5d0647e3$$aAhmad, Olfat$$b9$$udkfz
000307431 7001_ $$00009-0001-4908-3551$$aLee, Caitlin$$b10
000307431 7001_ $$aStengs, Lucie$$b11
000307431 7001_ $$aBianchi, Vanessa$$b12
000307431 7001_ $$aEdwards, Melissa$$b13
000307431 7001_ $$aDoherty, Sheradan$$b14
000307431 7001_ $$aChung, Jiil$$b15
000307431 7001_ $$aNobre, Liana$$b16
000307431 7001_ $$00000-0002-4146-1511$$aBennett, Julie$$b17
000307431 7001_ $$00000-0003-3288-2047$$aDodgshun, Andrew J$$b18
000307431 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David$$b19$$udkfz
000307431 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan$$b20$$udkfz
000307431 7001_ $$aVillani, Anita$$b21
000307431 7001_ $$00000-0001-5752-9763$$aMalkin, David$$b22
000307431 7001_ $$00000-0002-6557-895X$$aRamaswamy, Vijay$$b23
000307431 7001_ $$aHuang, Annie$$b24
000307431 7001_ $$aBouffet, Eric$$b25
000307431 7001_ $$00000-0002-7503-5799$$aAronson, Melyssa$$b26
000307431 7001_ $$00000-0001-5718-6465$$aDirks, Peter B$$b27
000307431 7001_ $$00000-0002-0368-5370$$aShlien, Adam$$b28
000307431 7001_ $$00000-0002-0936-0753$$aGetz, Gad$$b29
000307431 7001_ $$aMaruvka, Yosef E$$b30
000307431 7001_ $$aErtl-Wagner, Birgit$$b31
000307431 7001_ $$00000-0003-2618-4402$$aHawkins, Cynthia$$b32
000307431 7001_ $$00000-0001-7653-9529$$aDas, Anirban$$b33
000307431 7001_ $$00000-0002-5019-2683$$aTabori, Uri$$b34
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