Fig. 3: SSVs associated with disruption of TADs and translocated enhancers.

a Box plots of expression for TERT, MYB, and NF1 by alteration class (“amp.” or high-level gene amplification, approximating copy levels more than 2× greater than that of wild-type; gain, approximating 1–2 additional copies; SNV, activating promoter mutations in the case of TERT and inactivating mutation by indel/nonsense/nonstop in the case of NF1; SV breakpoint within gene body or within 100 kb of gene start; or none of the above, i.e., “unaligned”). P values by t-test using log2-transformed data. Box plots represent 5% (lower whisker), 25% (lower box), 50% (median), 75% (upper box), and 95% (upper whisker). b For tumors with SSV breakpoint within 100 kb of TERT or MYB, respectively, allele-specific patterns associated with increased expression. P values by binomial test using cis-X⁵². c As compared to all SSVs, fractions of SSVs involving topologically associated domain (TAD) disruption and altered gene expression (defined as FDR < 10% for the gene by distance metric method⁴ using 1 Mb region window, with corrections for tumor type and CNA, and expression > 0.4 SD or < −4 SD from median for the case harboring the breakpoint). P values by chi-squared test. d Percentages of SSV breakpoint associations involving the translocation of an enhancer within 0.5 Mb of the SSV breakpoint in proximity to the gene (and closer than any enhancer within 1 Mb of the unaltered gene), as tabulated for the entire set of SSV breakpoint associations with breakpoint mate on the distal side from the gene, as well as for the subsets of SSV breakpoint associations involving altered gene expression (defined as for b). P values by chi-squared test. e By gene and by histologic type, the number of SV breakpoint associations involving the translocation of an enhancer, which involved 103 genes and 140 tumors. f Depiction of the TERT locus (left) and MYB locus (right) and associated TADs and SSVs. Top: TADs as Hi-C-based contact maps, with gray shading indicating locus interactions (darker, stronger interactions). Bottom: gene expression levels of TERT and MYB corresponding to SSV breakpoints located in the genomic region. SSV breakpoints are annotated as TAD-preserving (i.e., both breakpoints fall within the same TAD) or TAD-disrupting. Dotted lines denote breakpoints within the same sample and solid lines denote common SV event.