title: Translocation and deletion breakpoints in cancer genomes are associated with potential non-B DNA-forming sequences.
abstract: Gross chromosomal rearrangements (including translocations, deletions, insertions and duplications) are a hallmark of cancer genomes and often create oncogenic fusion genes. An obligate step in the generation of such gross rearrangements is the formation of DNA double-strand breaks (DSBs). Since the genomic distribution of rearrangement breakpoints is non-random, intrinsic cellular factors may predispose certain genomic regions to breakage. Notably, certain DNA sequences with the potential to fold into secondary structures [potential non-B DNA structures (PONDS); e.g. triplexes, quadruplexes, hairpin/cruciforms, Z-DNA and single-stranded looped-out structures with implications in DNA replication and transcription] can stimulate the formation of DNA DSBs. Here, we tested the postulate that these DNA sequences might be found at, or in close proximity to, rearrangement breakpoints. By analyzing the distribution of PONDS-forming sequences within ±500 bases of 19 947 translocation and 46 365 sequence-characterized deletion breakpoints in cancer genomes, we find significant association between PONDS-forming repeats and cancer breakpoints. Specifically, (AT)n, (GAA)n and (GAAA)n constitute the most frequent repeats at translocation breakpoints, whereas A-tracts occur preferentially at deletion breakpoints. Translocation breakpoints near PONDS-forming repeats also recur in different individuals and patient tumor samples. Hence, PONDS-forming sequences represent an intrinsic risk factor for genomic rearrangements in cancer genomes.
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 6767 Bertner Ave., Houston, TX 77030, USA Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, 1400 Barbara Jordan Blvd., Austin, TX 78723, USA albinobacolla@gmail.com.
authors.forename: Albino
authors.identifier: 0000-0003-0206-8423
authors.initials: A
authors.lastname: Bacolla
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 6767 Bertner Ave., Houston, TX 77030, USA.
authors.forename: John A
authors.identifier: 0000-0003-1659-2429
authors.initials: JA
authors.lastname: Tainer
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, 1400 Barbara Jordan Blvd., Austin, TX 78723, USA karen.vasquez@austin.utexas.edu.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Vasquez
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
mesh_terms: D056905:Chromosome Breakpoints; D002872:Chromosome Deletion; D058674:Chromosome Duplication / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded; D059371:DNA, B-Form / Q000235:genetics; D043542:DNA, Z-Form / Q000235:genetics; D015894:Genome, Human; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D009690:Nucleic Acid Conformation; D014178:Translocation, Genetic / Q000235:genetics*
chemical_list: D059371:DNA, B-Form; D043542:DNA, Z-Form