title: Oncogene amplification in male breast cancer: analysis by multiplex ligation-dependent probe amplification.
abstract: Gene amplification is an important mechanism for oncogene activation, a crucial step in carcinogenesis. Compared to female breast cancer, little is known on the genetic makeup of male breast cancer, because large series are lacking. Copy number changes of 21 breast cancer related genes were studied in 110 male breast cancers using multiplex ligation-dependent probe amplification. A ratio of >1.3 was regarded indicative for gene copy number gain and a ratio >2.0 for gene amplification. Data were correlated with clinicopathological features, prognosis and 17 genes were compared with a group of female breast cancers. Gene copy number gain of CCND1, TRAF4, CDC6 and MTDH was seen in >40 % of the male breast cancer cases, with also frequent amplification. The number of genes with copy number gain and several single genes were associated with high grade, but only CCND1 amplification was an independent predictor of adverse survival in Cox regression (p = 0.015; hazard ratio 3.0). In unsupervised hierarchical clustering a distinctive group of male breast cancer with poor prognosis (p = 0.009; hazard ratio 3.4) was identified, characterized by frequent CCND1, MTDH, CDC6, ADAM9, TRAF4 and MYC copy number gain. Compared to female breast cancers, EGFR (p = 0.005) and CCND1 (p = 0.041) copy number gain was more often seen in male breast cancer, while copy number gain of EMSY (p = 0.004) and CPD (p = 0.001) and amplification in general was less frequent. In conclusion, several female breast cancer genes also seem to be important in male breast carcinogenesis. However, there are also clear differences in copy number changes between male and female breast cancers, pointing toward differences in carcinogenesis between male and female breast cancer and emphasizing the importance of identifying biomarkers and therapeutic agents based on research in male breast cancer. In addition CCND1 amplification seems to be an independent prognosticator in male breast cancer.
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Kornegoor
authors.forename: Cathy B
authors.initials: CB
authors.lastname: Moelans
authors.forename: Anoek H J
authors.initials: AH
authors.lastname: Verschuur-Maes
authors.forename: Marieke C H
authors.initials: MC
authors.lastname: Hogenes
authors.forename: Peter C
authors.initials: PC
authors.lastname: de Bruin
authors.forename: Joost J
authors.initials: JJ
authors.lastname: Oudejans
authors.forename: Luigi
authors.initials: L
authors.lastname: Marchionni
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D018567:Breast Neoplasms, Male / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D056915:DNA Copy Number Variations; D005784:Gene Amplification; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D009857:Oncogenes; D016601:RNA-Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D053449:TNF Receptor-Associated Factor 4 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D019938:Cyclin D1; D008565:Membrane Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D053449:TNF Receptor-Associated Factor 4; C530104:CCND1 protein, human; C103706:CDC6 protein, human; C483039:MTDH protein, human; C506367:TRAF4 protein, human; C508053:ERBB2 protein, human