title: Palindromic amplification of the ERBB2 oncogene in primary HER2-positive breast tumors.
abstract: Oncogene amplification confers a growth advantage to tumor cells for clonal expansion. There are several, recurrently amplified oncogenes throughout the human genome. However, it remains unclear whether this recurrent amplification is solely a manifestation of increased fitness resulting from random amplification mechanisms, or if a genomic locus-specific amplification mechanism plays a role. Here we show that the ERBB2 oncogene at 17q12 is susceptible to palindromic gene amplification, a mechanism characterized by the inverted (palindromic) duplication of genomic segments, in HER2-positive breast tumors. We applied two genomic approaches to investigate amplification mechanisms: sequencing of DNA libraries enriched with tumor-derived palindromic DNA (Genome-wide Analysis of Palindrome Formation) and whole genome sequencing (WGS). We observed significant enrichment of palindromic DNA within amplified ERBB2 genomic segments. Palindromic DNA was particularly enriched at amplification peaks and at boundaries between amplified and normal copy-number regions. Thus, palindromic gene amplification shaped the amplified ERBB2 locus. The enrichment of palindromic DNA throughout the amplified segments leads us to propose that the ERBB2 locus is amplified through the mechanism that repeatedly generates palindromic DNA, such as Breakage-Fusion-Bridge cycles. The genomic architecture surrounding ERBB2 in the normal genome, such as segmental duplications, could promote the locus-specific mechanism.
authors.affiliation: Lerner Research Institute and Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Marotta
authors.affiliation: Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Onodera
authors.affiliation: Department of Surgery, Cedars-Sinai Medical Center, West Hollywood, CA, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Johnson
authors.affiliation: Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: G Thomas
authors.initials: GT
authors.lastname: Budd
authors.affiliation: Lerner Research Institute and Cleveland Clinic, Cleveland, OH, USA.|Department of Surgery, Cedars-Sinai Medical Center, West Hollywood, CA, USA.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Surgery, Cedars-Sinai Medical Center, West Hollywood, CA, USA.
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Cui
authors.affiliation: Department of Surgery, Cedars-Sinai Medical Center, West Hollywood, CA, USA.
authors.forename: Armando E
authors.initials: AE
authors.lastname: Giuliano
authors.affiliation: Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Niida
authors.affiliation: Lerner Research Institute and Cleveland Clinic, Cleveland, OH, USA.|Department of Surgery, Cedars-Sinai Medical Center, West Hollywood, CA, USA.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Tanaka
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D005784:Gene Amplification; D006801:Humans; D055029:Inverted Repeat Sequences; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human