Mutational signatures in cancer genomes alter protein sequence motifs in cellular signaling networks

Abstract Somatic mutations in cancer genomes arise from distinct, context-specific mutational processes, yet their functional consequences at the protein and network level remain incompletely understood. Here, we show that mutational processes of single-nucleotide variants (SNVs) can systematically rewire signaling networks by inducing amino acid substitutions in short linear motifs (SLiMs) that mediate interactions with kinases and other signaling proteins. By analysing 11,000 cancer genomes and 144 classes of SLiMs, we identify motif-rewiring SNVs (rwSNVs) that create or disrupt SLiMs or remove phosphorylated residues. Mutational processes of methylcytosine deamination, APOBEC activity, and ultraviolet light exposure emerge as major contributors to motif rewiring. rwSNVs are enriched in cancer driver genes and pathways, linking mutation etiology to functional consequences. rwSNVs at the BRAF V600E hotspot associated with UV-related mutagenesis are predicted to generate a phosphorylation motif recognized by PLK1 kinase. Together, these findings reveal how mutational processes shape oncogenic signaling and tumor heterogeneity.