title: Comprehensive DNA Methylation and Extensive Mutation Analyses of HER2-Positive Breast Cancer.
abstract: OBJECTIVE
  Resistance to trastuzumab is a problem that remains to be solved in HER2-positive breast cancer. We aimed to characterize profiles of genetic and epigenetic alterations in cancer-related pathways in HER2-positive breast cancers, using biopsy tissue samples obtained from patients enrolled in a prospective neoadjuvant clinical trial.
  
  
  METHODS
  HER2-positive breast cancer tissue samples were collected and processed with the PAXgene Tissue System. A total of 24 breast cancers were analyzed. Genetic alterations of 409 cancer-related genes were analyzed by a bench-top next-generation sequencer. DNA methylation statuses were analyzed by a bead array with 485,512 probes.
  
  
  RESULTS
  The WNT pathway was potentially activated by aberrant methylation of its negative regulators, such as DKK3 and SFRP1, in 9 breast cancers. The AKT/mTOR pathway was activated by mutations of PIK3CA in 5 breast cancers. The Notch pathway was potentially activated by mutations of NOTCH1 and NOTCH2 in 4 breast cancers. The p53 pathway was inactivated by mutations of TP53 in 13 breast cancers and potentially by aberrant methylation of its downstream genes in 10 breast cancers. Cell adhesion was affected by mutations of CDH1 in 1 breast cancer.
  
  
  CONCLUSIONS
  Genes involved in cancer-related pathways were frequently affected not only by genetic but also by epigenetic alterations in HER2-positive breast cancer.
authors.affiliation: Department of Medical Oncology, Musashino Red Cross Hospital, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Mukai
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamashita
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fujii
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Ushijima
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D019175:DNA Methylation; D004252:DNA Mutational Analysis / Q000379:methods*; D019008:Drug Resistance, Neoplasm; D057890:Epigenomics / Q000379:methods; D005260:Female; D005784:Gene Amplification; D006801:Humans; D020935:MAP Kinase Signaling System; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D060449:Wnt Signaling Pathway; D055815:Young Adult
chemical_list: D009363:Neoplasm Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human