title: A common copy-number breakpoint of ERBB2 amplification in breast cancer colocalizes with a complex block of segmental duplications.
abstract: BACKGROUND
  Segmental duplications (low-copy repeats) are the recently duplicated genomic segments in the human genome that display nearly identical (> 90%) sequences and account for about 5% of euchromatic regions. In germline, duplicated segments mediate nonallelic homologous recombination and thus cause both non-disease-causing copy-number variants and genomic disorders. To what extent duplicated segments play a role in somatic DNA rearrangements in cancer remains elusive. Duplicated segments often cluster and form genomic blocks enriched with both direct and inverted repeats (complex genomic regions). Such complex regions could be fragile and play a mechanistic role in the amplification of the ERBB2 gene in breast tumors, because repeated sequences are known to initiate gene amplification in model systems.
  
  
  METHODS
  We conducted polymerase chain reaction (PCR)-based assays for primary breast tumors and analyzed publically available array-comparative genomic hybridization data to map a common copy-number breakpoint in ERBB2-amplified primary breast tumors. We further used molecular, bioinformatics, and population-genetics approaches to define duplication contents, structural variants, and haplotypes within the common breakpoint.
  
  
  RESULTS
  We found a large (> 300-kb) block of duplicated segments that was colocalized with a common-copy number breakpoint for ERBB2 amplification. The breakpoint that potentially initiated ERBB2 amplification localized in a region 1.5 megabases (Mb) on the telomeric side of ERBB2. The region is very complex, with extensive duplications of KRTAP genes, structural variants, and, as a result, a paucity of single-nucleotide polymorphism (SNP) markers. Duplicated segments are varied in size and degree of sequence homology, indicating that duplications have occurred recurrently during genome evolution.
  
  
  CONCLUSIONS
  Amplification of the ERBB2 gene in breast tumors is potentially initiated by a complex region that has unusual genomic features and thus requires rigorous, labor-intensive investigation. The haplotypes we provide could be useful to identify the potential association between the complex region and ERBB2 amplification.
authors.forename: Michael
authors.initials: M
authors.lastname: Marotta
authors.forename: Xiongfong
authors.initials: X
authors.lastname: Chen
authors.forename: Ayako
authors.initials: A
authors.lastname: Inoshita
authors.forename: Robert
authors.initials: R
authors.lastname: Stephens
authors.forename: G Thomas
authors.initials: GT
authors.lastname: Budd
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Crowe
authors.forename: Joanne
authors.initials: J
authors.lastname: Lyons
authors.forename: Anna
authors.initials: A
authors.lastname: Kondratova
authors.forename: Raymond
authors.initials: R
authors.lastname: Tubbs
authors.forename: Hisashi
authors.initials: H
authors.lastname: Tanaka
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D056905:Chromosome Breakpoints; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D005260:Female; D005784:Gene Amplification / Q000235:genetics; D018628:Gene Dosage; D015894:Genome, Human; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D053564:Keratins, Hair-Specific / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D056916:Segmental Duplications, Genomic / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics
chemical_list: D053564:Keratins, Hair-Specific; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human