title: Impact of DNA amplification on gene expression patterns in breast cancer.
abstract: Genetic changes underlie tumor progression and may lead to cancer-specific expression of critical genes. Over 1100 publications have described the use of comparative genomic hybridization (CGH) to analyze the pattern of copy number alterations in cancer, but very few of the genes affected are known. Here, we performed high-resolution CGH analysis on cDNA microarrays in breast cancer and directly compared copy number and mRNA expression levels of 13,824 genes to quantitate the impact of genomic changes on gene expression. We identified and mapped the boundaries of 24 independent amplicons, ranging in size from 0.2 to 12 Mb. Throughout the genome, both high- and low-level copy number changes had a substantial impact on gene expression, with 44% of the highly amplified genes showing overexpression and 10.5% of the highly overexpressed genes being amplified. Statistical analysis with random permutation tests identified 270 genes whose expression levels across 14 samples were systematically attributable to gene amplification. These included most previously described amplified genes in breast cancer and many novel targets for genomic alterations, including the HOXB7 gene, the presence of which in a novel amplicon at 17q21.3 was validated in 10.2% of primary breast cancers and associated with poor patient prognosis. In conclusion, CGH on cDNA microarrays revealed hundreds of novel genes whose overexpression is attributable to gene amplification. These genes may provide insights to the clonal evolution and progression of breast cancer and highlight promising therapeutic targets.
authors.affiliation: Howard Hughes Medical Institute-NIH Research Scholar, Bethesda, Maryland 20892, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hyman
authors.forename: Päivikki
authors.initials: P
authors.lastname: Kauraniemi
authors.forename: Sampsa
authors.initials: S
authors.lastname: Hautaniemi
authors.forename: Maija
authors.initials: M
authors.lastname: Wolf
authors.forename: Spyro
authors.initials: S
authors.lastname: Mousses
authors.forename: Ester
authors.initials: E
authors.lastname: Rozenblum
authors.forename: Markus
authors.initials: M
authors.lastname: Ringnér
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.forename: Outi
authors.initials: O
authors.lastname: Monni
authors.forename: Abdel
authors.initials: A
authors.lastname: Elkahloun
authors.forename: Olli-P
authors.initials: OP
authors.lastname: Kallioniemi
authors.forename: Anne
authors.initials: A
authors.lastname: Kallioniemi
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D004273:DNA, Neoplasm / Q000235:genetics; D005784:Gene Amplification; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D004273:DNA, Neoplasm; D012333:RNA, Messenger