Extended Data Fig. 5: Mutational signature analysis of primary and secondary hypermutated cohort (n = 111).
From: Mechanisms and therapeutic implications of hypermutation in gliomas
a, Mutational signature analysis of newly diagnosed hypermutated gliomas in the DFCI-Profile dataset (n = 24). b, Mutational signature analysis of secondary hypermutated gliomas (samples in which hypermutation was detected in the recurrent tumour) in the DFCI-Profile dataset (n = 58). The novel COSMIC Signature 11-related signature (S2) was associated with 1p/19q co-deletion and lack of prior radiation therapy (66.7% of samples with high S2 versus 26.2% of samples with high S1 signature, Fisher P = 0.016). c, Mutational signature analysis of hypermutated gliomas from the MSKCC-IMPACT dataset (n = 29). d, Mutational signature analysis in de novo (hypermutated at first diagnosis, n = 26, left) and post-treatment hypermutated gliomas (hypermutation in a recurrent tumour, n = 59, right). Percentage of samples exhibiting the most common mutational signatures and their hypothesized causes are displayed. MMR, C6, C14, C15, C26; age-related, C1; POLE, C10, C14. Chi-squared test. e, Mutational signatures identified in individual de novo hypermutated gliomas (hypermutated at first diagnosis, n = 26, left) and post-treatment hypermutated gliomas (hypermutation in a recurrent tumour, n = 59, right). f, Mutational signature analysis of MMR variants in hypermutated gliomas from the DFCI-Profile and MSKCC-IMPACT datasets (n = 114). Ninety variants of the MMR genes MSH2, MSH6, MLH1, and PMS2 were merged into two groups (de novo, n = 18; post-treatment, n = 72) according to the type of sample in which they were found and analysed for mutational signatures using a regression model (Rosenthal et al.52). In each sample, only the MMR variant with the highest VAF was included, to limit the inclusion of possible passenger variants. For signature discovery in both cohorts (a–c), variants were analysed using the non-negative matrix factorization (NMF) method and correlated with known COSMIC mutational signatures14 using Pearson correlation.
