title: Precise ERBB2 copy number assessment in breast cancer by means of molecular inversion probe array analysis.
abstract: HER2/ERBB2 amplification/overexpression determines the eligibility of breast cancer patients to HER2-targeted therapy. This study evaluates the agreement between ERBB2 copy number assessment by fluorescence in situ hybridization, a standard method recommended by the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP), and newly available DNA extraction-based methods. A series of n=29 formalin-fixed paraffin-embedded breast cancers were subjected to ERBB2 copy number assessment by fluorescence in situ hybridization (FISH, Vysis, Abbott). Following macrodissection of invasive breast cancer tissue and DNA extraction, ERBB2 copy number was also determined by molecular inversion probe array analysis (MIP, OncoScan, Affymetrix) and next generation sequencing combined with normalized amplicon coverage analysis (NGS/NAC, AmpliSeq, Ion Torrent). ERBB2 copy number values obtained by MIP or NGS/NAC were tightly correlated with ERBB2 copy number values obtained by conventional FISH (rs = 0.940 and rs = 0.894, P < 0.001). Using ASCO/CAP guideline-conform thresholds for categorization of breast cancers as HER2-negative, equivocal or positive, nearly perfect concordance was observed for HER2 classification by FISH and MIP (93% concordant classifications, κ = 0.87). Substantial concordance was observed for FISH and NGS/NAC (83% concordant classifications, κ = 0.62). In conclusion, MIP facilitates precise ERBB2 copy number detection and should be considered as an ancillary method for clinical HER2 testing.
authors.affiliation: Institute of Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Christgen
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: Jana L
authors.initials: JL
authors.lastname: van Luttikhuizen
authors.affiliation: Institute of Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Mieke
authors.initials: M
authors.lastname: Raap
authors.affiliation: Institute of Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Braubach
authors.affiliation: Institute of Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Schmidt
authors.affiliation: Institute of Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Danny
authors.initials: D
authors.lastname: Jonigk
authors.affiliation: Institute of Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Feuerhake
authors.affiliation: Institute of Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Lehmann
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.affiliation: Institute of Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Hans H
authors.initials: HH
authors.lastname: Kreipe
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Steinemann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D015336:Molecular Probe Techniques; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D010641:Phenotype; D011237:Predictive Value of Tests; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D015203:Reproducibility of Results
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: HER2/ERBB2; OncoScan; breast cancer; copy number profiling; next generation sequencing