Fig. 4

Mutation load is associated with the expression of genes and pathways. a Histogram of the number of tissues for which each gene was significantly associated with mutation load (Bonferroni-corrected p < 0.05). Associations were estimated for each tissue using linear models controlling for population structure and biological and technical cofactors (see the “Methods” section). b Genes whose expression was negatively (top) or positively (bottom) associated with C>T mutation load in multiple tissues are enriched in these representative GO categories (see the “Methods” section and Additional file 11: Table S8, Additional file 12: Tables S9). c Individual gene-tissue associations between C>T mutations and expression of genes involved in DNA repair or DNA mutagenesis (right panel). Blue asterisks denote significant associations using a permutation-based FDR strategy (see the “Methods” section; *FDR < 0.2, **FDR < 0.1, ***FDR < 0.05). Shown on the left panel are genes whose expression was associated with mutation load across all tissues more than expected by chance at the indicated FDR (see the “Methods” section). d COSMIC cancer signature 6 (linked to MMR deficiency; left) is significantly similar to profiles from lung samples expressing low levels of MLH1 (right). The plot in the left panel represents the frequency of C>T mutations at the indicated tri-nucleotide context for signature 6. The plot in the right panel is the log ratio of C>T mutation rates comparing the 20% of lung samples with the lowest MLH1 expression vs the 20% with the highest MLH1 expression. Cosine similarity is indicated for C>T mutation across contexts, and the p value represents the frequency of cosine similarity values that were greater than the original from permuted values—permutations were done by randomly selecting 2 groups of 20% of samples and calculating the fold-change mutation frequencies between them. e Group-level gene expression associations of the shown pathways and C>T mutations across tissues (see the “Methods” section). Heatmap columns in c and e are ordered based on a hierarchical clustering