title: Prognostic relevance of gene amplifications and coamplifications in breast cancer.
abstract: Multiple different oncogenes have been described previously to be amplified in breast cancer including HER2, EGFR, MYC, CCND1, and MDM2. Gene amplification results in oncogene overexpression but may also serve as an indicator of genomic instability. As such, presence of one or several gene amplifications may have prognostic significance. To assess the prognostic importance of amplifications and coamplifications of HER2, EGFR, MYC, CCND1, and MDM2 in breast cancer, we analyzed a breast cancer tissue microarray containing samples from 2197 cancers with follow-up information. Fluorescence in situ hybridizations revealed amplifications of CCND1 in 20.1%, HER2 in 17.3%, MDM2 in 5.7%, MYC in 5.3%, and EGFR in 0.8% of the tumors. All gene amplifications were significantly associated with high grade. HER2 (P < 0.001) and MYC amplification (P < 0.001) were also linked to shortened survival. In case of HER2, this was independent of grade, pT, and pN categories. MYC amplification was almost 3 times more frequent in medullary cancer (15.9%), than in the histologic subtype with the second highest frequency (ductal; 5.6%; P = 0.0046). HER2 and MYC amplification were associated with estrogen receptor/progesterone receptor negativity (P < 0.001) whereas CCND1 amplification was linked to estrogen receptor/progesterone receptor positivity (P < 0.001). Coamplifications were more prevalent than expected based on the individual frequencies. Coamplifications of one or several other oncogenes occurred in 29.6% of CCND1, 43% of HER2, 55.7% of MDM2, 65% of MYC, and 72.8% of EGFR-amplified cancers. HER2/MYC-coamplified cancers had a worse prognosis than tumors with only one of these amplifications. Furthermore, a gradual decrease of survival was observed with increasing number of amplifications. In conclusion, these data support a major prognostic impact of genomic instability as determined by a broad gene amplification survey in breast cancer.
authors.affiliation: King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Khawla
authors.initials: K
authors.lastname: Al-Kuraya
authors.forename: Peter
authors.initials: P
authors.lastname: Schraml
authors.forename: Joachim
authors.initials: J
authors.lastname: Torhorst
authors.forename: Coya
authors.initials: C
authors.lastname: Tapia
authors.forename: Boriana
authors.initials: B
authors.lastname: Zaharieva
authors.forename: Hedvika
authors.initials: H
authors.lastname: Novotny
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Spichtin
authors.forename: Robert
authors.initials: R
authors.lastname: Maurer
authors.forename: Martina
authors.initials: M
authors.lastname: Mirlacher
authors.forename: Ossi
authors.initials: O
authors.lastname: Köchli
authors.forename: Markus
authors.initials: M
authors.lastname: Zuber
authors.forename: Holger
authors.initials: H
authors.lastname: Dieterich
authors.forename: Friedrich
authors.initials: F
authors.lastname: Mross
authors.forename: Kim
authors.initials: K
authors.lastname: Wilber
authors.forename: Ronald
authors.initials: R
authors.lastname: Simon
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics; D005784:Gene Amplification; D018628:Gene Dosage; D018773:Genes, erbB-1; D018734:Genes, erbB-2; D016259:Genes, myc; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2
chemical_list: D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019938:Cyclin D1; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2