Panel A shows a Circos plot with red and blue dots representing transposon insertions in the plus and minus strands, respectively. Black lines indicate common insertion sites (CIS), and the outer rim lists the genes associated with these CIS. Red lines in the center connect insertions that significantly co-occur in tumors. Panel B displays a heatmap of RNA-seq data, showing relative expression levels of the 25 most up-regulated and 25 most down-regulated CIS-genes in NEPC versus non-NEPC mouse SB tumors. The heatmap is color-coded to indicate expression levels, with annotations for phenotype, genotype, metastasis, and expression. Panel C features lollipop plots for selected CIS-genes, indicating transposon insertion sites with colors and shapes representing exonic versus intronic locations and NEPC versus non-NEPC tumor status. Panel D is a box plot comparing the number of fusion events in non-NEPC and NEPC mouse SB tumors, with P-values calculated using the Wilcoxon rank-sum test. Panel E is a flowchart outlining the analytical process for identifying CIS-genes as candidate mechanistic determinants of NEPC. Panel F presents a visual representation of the top 15 CIS-genes inferred to regulate NEPC, with connections to their target genes.
Identification of CIS genes as candidate mechanistic determinants of NEPC. (A) Circos plot of CIS genes identified using the TAPDANCE algorithm. Transposon insertions in the plus (red dots) and minus (blue dots) strands are individually annotated, with corresponding CIS (black lines) and the genes associated with those CIS (CIS genes, outer rim). Red lines in the center of the Circos plot connect insertions that significantly co-occur in tumors (i.e., CIS). Data are from analyses of 74 independent genomic DNA samples from the NPp53-SB(+) mice. (B) RNA-seq heatmap showing relative expression levels of the 25 most up-regulated and 25 most down-regulated CIS genes in NEPC versus non-NEPC mouse SB tumors. (C) Lollipop plots showing transposon insertion sites for selected CIS genes. TSS (orange arrows) indicate transcriptional orientation. Insertion colors indicate exonic (green/red) versus intronic (blue/purple) location and sense versus antisense strand orientation. Shape indicates NEPC (circle) versus non-NEPC (square) tumor status. Border thickness indicates samples with matched RNA-seq data. (D) The number of fusion events in non-NEPC and NEPC mouse SB tumors, as indicated. P values were calculated using the Wilcoxon rank-sum test. (E) CIS genes were prioritized as candidate mechanistic determinants using cross-species integration of genomic and transcriptomic data from mouse SB tumors with transcriptomic data from human patient cohorts as described in the text. (F) Visual representation of the top 15 CIS genes that are candidate modulators of NEPC (top) and the MRs they are inferred to regulate NEPC (bottom). See also Figs. S3 and S4; and Tables 2, S6, and S7.