Extended Data Fig. 6: Characteristics of MMR molecular variants in hypermutated gliomas.
From: Mechanisms and therapeutic implications of hypermutation in gliomas
a, b, Proportion of TMBhigh versus TMBlow samples with mutations in selected DNA repair genes and glioma drivers (a) and in the MMR pathway (MSH2, MSH6, MLH1 and PMS2) (b) in the merged DFCI-Profile/MSKCC-IMPACT dataset (n = 2,173). Permutation test; ****P < 10−5, **P < 10−2, *P < 0.05. c, CCFs of MMR gene mutations in post-treatment hypermutated gliomas versus other hypermutated cancers in the FMI dataset. Horizontal line, median. Two-sided Wilcoxon rank-sum test with Benjamini–Hochberg correction. d, VAF distribution of mutations in post-treatment hypermutated gliomas, non-glioma MMR-deficient cancers (diverse histologies) and other non-glioma hypermutated samples (diverse histologies) from the TCGA and MSKCC-IMPACT datasets. Each dot represents a mutation found in an individual sample (represented vertically). MMR mutations are depicted in red. Left, hypermutated samples from the pan-TCGA dataset; right, hypermutated samples from the MSKCC-IMPACT dataset. e, Integrated view of mutational signatures and MMR gene mutations and protein expression in hypermutated gliomas (n = 114). Tumours with the mutational hotspot MSH6(T1219I) (11.9% of post-treatment hypermutated gliomas) are highlighted. f, Mutation diagram of MSH2, MSH6, MLH1, and PMS2 mutations found in hypermutated gliomas from the DFCI-Profile and MSKCC-IMPACT datasets (n = 114). The hotspot MSH6 missense variant p.T1219I was found in nine samples. g, Hotspot MSH6 p.T1219I variant mapped to the bacterial MutS 3D structure (PDB 5YK4). h, Representative immunohistochemistry (IHC) images of the MMR proteins MSH2, MSH6, MLH1 and PMS2 in a hypermutated glioblastoma with MSH6(T1219I) mutation. Three independent samples were stained. Scale bar, 100 μm.
