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Spatial Genome Organization as a Framework for Somatic Alterations in Human Cancer

By Kadir C. Akdemir, Yilong Li, Roel G. Verhaak, Rameen Beroukhim, Peter Cambell, Lynda Chin, P. Andrew Futreal, on behalf of the PCAWG-Structural Variation Working Group

Posted 22 Aug 2017
bioRxiv DOI: 10.1101/179176 (published DOI: 10.1038/s41588-019-0564-y)

Genomic material within the nucleus is folded into successive layers in order to package and organize the long string of linear DNA. This hierarchical level of folding is closely associated with transcriptional regulation and DNA replication. Recent chromosome conformation studies have revealed that mammalian chromosomes are structured into tissue-invariant topologically associating domains (TADs) where the DNA within a given domain interacts more frequently together than with regions in other domains. Genes within the same TADs represent similar expression and histone-modification profiles. Therefore, regions separating different TADs (boundaries) have important roles in reinforcing the stability of these domain-wide features. Indeed, TAD boundary disruptions in human genetic disorders or human cancers lead to misregulation of certain genes, due to de novo enhancer exposure to promoters. Here, to understand effects and distributions of somatic structural variations across TADs, we utilized single nucleotide variations and genomic rearrangements from 2658 high-coverage whole genome sequencing data across various cancer types with paired normal samples. Our analysis revealed that deletions between repressed and active TADs result in up-regulation of genes on the repressed end of the deletions, whereas active domain genes remain unaffected. Interestingly, we further identified a strong correlation between the mutational distributions in human cancers and the spatial organization of the genome. Transcriptionally active TADs contain less mutation burden compared to inactive TADs, as a result regional mutation rates are drastically different around the boundaries delineating epigenetically distinct domains. However, mutation rates remain similar around the boundaries for samples with the DNA mismatch repair deficiency. Taken together, our analyses reveal new insights about genome architecture, aberrant gene expression and mutational distributions in human cancers.

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