Fig. 3

Cancer-critical genes with frequent frameshift mutations. a Mutation frequency of cancer-critical genes with most frequent indels affecting the reading frame, splice sites, or stop codons. CRTC1 (mutation frequency 42%), BCL9 (30%), JAK1 (24%), and PTCH1 (24%) were identified as novel frequently mutated genes. b Mutation validation analyses in MSI+ CRCs in independent patient series. c The JAK1 frameshift indels were found in four hotspot amino acid positions (GenBank accession NP_002218; 1154 amino acids). The number of mutations detected in each patient series and mutation hotspot is shown, confirming frequent mutations upstream of the JAK1 kinase domain (JH1). The patient series analyzed are indicated (top left) using the same color code as in b. All four homopolymers of length ≥6 in JAK1 are indicated below the protein. Protein domains are indicated by color; SH2 Src Homology 2, FERM (F, 4.1 protein; E, ezrin; R, radixin; M, moesin), JH1 kinase domain, JH2 pseudokinase domain. d Gene signatures of five processes previously found to be associated with innate resistance to anti-PD-1 treatment in melanomas were over-expressed in MSI+ CRCs with versus without JAK1 mutations in both Norwegian series I and TCGA. e Six of the tumors in Norwegian series I with JAK1 indels were available for clonality analyses. All these tumors had at least one JAK1 indel (asterisk) scored as truncal, and all JAK1 mutations were heterozygous. Each plot represents one sample and separate tumor clones, identified as mutation clusters with different variant allele frequencies, are indicated with different colors