Fig 1.
Recurrent JAK frameshift alterations in solid tumors.
(A-C) Incidence of mutations by amino acid (only positions with >2 tumors mutated shown) in (A) JAK1, (B) JAK2, and (C) JAK3. (D) The frequency of JAK1/2/3 frameshift mutations in different tumor types, scc other = squamous cell carcinoma of the eye, penis, trachea, vagina, vulva, or unknown primary. (E) Number of JAK1 frameshifts observed in the three most common hotspots by disease type. (F) Pie chart classifying JAK1 alterations by the number of JAK1 copies mutated. (G, H) Box and whiskers plots of JAK1 expression in endometrial (G) tumors from TCGA, expression measure is scaled estimate and (H) CCLE cell lines, expression measure is log2 of transcripts per million (TPM). The red line defines the median, box defines the quartiles and the whiskers define the 10th and 90th percentiles. The notch in the box provides a 95% confidence interval around the median. (*** = P < 10−4, Mann-Whitney U test).
Fig 2.
Association of JAK1 frameshifts with MSI and high tumor mutational burden.
(A) Frequency of JAK1 frameshifts by tumor type stratified by MSS/MSI-H status. Error bars show standard error. (*** = P < 10−4, Fisher’s exact test) (B-E) Box and whiskers plots of mutations per Mb in (B) endometrial, (C) prostate, (D) CRC, and (E) gastric cancers. The red line defines the median, box defines the quartiles and the whiskers define the 10th and 90th percentiles. The notch in the box provides a 95% confidence interval around the median (*** = P < 10−4, Mann-Whitney U test). (F) Frequency of JAK1 frameshifts by tumor type stratified by MSS/MSI-L/MSI-H status (*** = P < 10−4, * = P < 0.05, Fisher’s exact test). (G) Frequency of JAK1 frameshifts in MSI-H tumors from the FMI and TCGA cohorts (* = P < 0.05, Fisher’s exact test). (H-J) Box and whiskers plots of coding mutations per exome in (H) endometrial, (I) stomach, and (J) colon adenocarcinomas (* = P < 0.05, *** = P < 10−4, Mann-Whitney U test).
Table 1.
GSEA of JAK1 frameshift+ and wild-type UCEC.
Fig 3.
Sample level gene expression changes in MSI-H UCEC samples with a JAK1 frameshift.
(A) Heatmap of MSI-H, UCEC tumors (columns). Marker rows: 1) Samples with a JAK1 frameshift are denoted in green. 2) IFN Response, after JAK1 frameshift samples are ordered by IFN Response. 3) Log10 of JAK1 expression. 4) JAK1 frameshift (FS) MAF. Gene expression was scaled by Z scoring and the order of genes (rows) is determined by the signal to noise metric for GSEA analysis (t). Negative t indicated decreased expression in JAK1 frameshift samples. Only genes in the HALLMARK IFN GAMMA RESPONSE are shown. (B) Histogram of IFN Gamma Response in arbitrary units (AU). (C) Scatter plot of samples for JAK1 expression and IFN Gamma Response. Pearson’s r and associated P values are shown. (D) Scatter plot of samples for JAK1 expression and JAK1 FS MAF. Pearson’s r and associated P values are shown. (E) Scatter plot of JAK1 frameshift samples for JAK1 FS MAF and IFN Gamma Response. Pearson’s r and associated P value is shown.
Table 2.
GSEA of JAK1 frameshift+ and wild-type CCLE endometrial cell lines.
Fig 4.
GSEA results in UCEC and CCLE.
Heatmap showing the maximum enrichment score (ES) for (A) Hallmark or (B) Immune gene sets in UCEC and CCLE for significantly altered gene sets. Negative ES indicates expression is decreased in JAK1 frameshift samples. White star indicates gene set is significantly altered in that disease type (FWER P < 0.05).
Table 3.
GSEA of MSI WT vs. JAK1 frameshift STAD.
Fig 5.
Sample level gene expression changes in MSI-H STAD samples with a JAK1 frameshift.
(A) Heatmap of MSI-H, STAD tumors (columns). Marker rows: 1) Samples with a JAK1 frameshift are denoted in green. 2) IFN Response, after JAK1 frameshift samples are ordered by IFN Response. 3) Log10 of JAK1 expression. 4) JAK1 frameshift (FS) MAF. Gene expression was scaled by Z scoring and the order of genes (rows) is determined by the signal to noise metric for GSEA analysis (t). Negative t indicated decreased expression in JAK1 frameshift samples. Only genes in the HALLMARK IFN GAMMA RESPONSE are shown. (B) Histogram of IFN Gamma Response in arbitrary units (AU). (C) Scatter plot of samples for JAK1 expression and IFN Gamma Response. Pearson’s r and associated P values are shown. (D) Scatter plot of samples for JAK1 expression and JAK1 FS MAF. Pearson’s r and associated P values are shown. (E) Scatter plot of JAK1 frameshift samples for JAK1 FS MAF and IFN Gamma Response. Pearson’s r and associated P value is shown.
Fig 6.
Comparison of GSEA results for UCEC and STAD.
Heatmap showing the maximum enrichment score (ES) for (A) Hallmark or (B) Immune gene sets in UCEC and STAD for significantly altered gene sets. Negative ES indicates expression is decreased in JAK1 frameshift samples. White star indicates gene set is significantly altered in that disease type (FWER P < 0.05).