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July 11, 2018

Cancer-Linked Rearrangements Pepper Genome’s Regulatory Regions

  • When cancer is studied at the genomic level, certain variations tend to receive a lot of attention, chiefly the variations affecting protein-coding genes, which include variations such as point mutations and copy number alterations. Yet variations that affect non-protein–coding parts of the genome matter, too. But how much do they matter?

    The question has persisted, even while genomic information has been piling up in data repositories. Now, by sifting through some of this information, scientists based at Baylor College of Medicine have found that structural variations are strewn throughout the cancer genome’s regulatory regions, that is, in DNA sequences that sit beside genes and regulate gene expression.

    These scientists, led by Chad Creighton, Ph.D., associate professor of medicine, Baylor College of Medicine, compiled a comprehensive catalog of somatic rearrangements and their associated transcriptional patterns. Details of this work appeared July 10 in the journal Cell Reports, in an article titled, “A Pan-Cancer Compendium of Genes Deregulated by Somatic Genomic Rearrangement across More Than 1,400 Cases.”

    “By integrative analysis of whole-genome sequencing and gene expression data from 1,448 cancers involving 18 histopathological types in The Cancer Genome Atlas, we identified hundreds of genes for which the nearby presence (within 100 kb) of a somatic structural variant (SV) breakpoint is associated with altered expression,” wrote the article’s authors. “While genomic rearrangements are associated with widespread copy-number alteration (CNA) patterns, approximately 1,100 genes show SV-associated deregulation independent of CNA.”

    The Baylor team found that deregulated genes included overexpressed cancer driver genes (such as TERT, ERBB2, CDK12, CDK4) and underexpressed tumor suppressors (such as TP53, RB1, PTEN, STK11. The team also found SVs associated with the disruption of topologically associated domains, enhancer hijacking, or fusion transcripts are implicated in gene upregulation.

    "We found that structural rearrangements can occur within protein-coding genes and alter the protein's function," says Dr. Creighton. "Rearrangements also can occur within the regulatory regions, and although they do not affect the protein-coding genes themselves, they can dramatically alter their expression. For instance, structural rearrangements can turn off tumor suppressor genes, such as p53 and PTEN, or turn on oncogenes such as TERT, which promotes cancer growth.

    "We knew of individual genes that are deregulated by structural rearrangement of regulatory regions, but it was surprising to see this as a more widespread phenomenon than we had expected. I don't think this has been looked at as deeply before, so this adds to the current body of knowledge. Our next step is to conduct whole genome sequencing at a higher resolution to find even more cancer-associated genes that are affected by this mechanism."

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