title: Genome-wide functional synergy between amplified and mutated genes in human breast cancer.
abstract: A single cancer cell contains large numbers of genetic alterations that in combination create the malignant phenotype. However, whether amplified and mutated genes form functional and physical interaction networks that could explain the selection for cells with combined alterations is unknown. To investigate this issue, we characterized copy number alterations in 191 breast tumors using dense single nucleotide polymorphism arrays and identified 1,747 genes with copy number gain organized into 30 amplicons. Amplicons were distributed unequally throughout the genome. Each amplicon had distinct enrichment pattern in pathways, networks, and molecular functions, but genes within individual amplicons did not form coherent functional units. Genes in amplicons included all major tumorigenic pathways and were highly enriched in breast cancer-causative genes. In contrast, 1,188 genes with somatic mutations in breast cancer were distributed randomly over the genome, did not represent a functionally cohesive gene set, and were relatively less enriched in breast cancer marker genes. Mutated and gained genes did not show statistically significant overlap but were highly synergistic in populating key tumorigenic pathways including transforming growth factor beta, WNT, fibroblast growth factor, and PIP3 signaling. In general, mutated genes were more frequently upstream of gained genes in transcription regulation signaling than vice versa, suggesting that mutated genes are mainly regulators, whereas gained genes are mostly regulated. ESR1 was the major transcription factor regulating amplified but not mutated genes. Our results support the hypothesis that multiple genetic events, including copy number gains and somatic mutations, are necessary for establishing the malignant cell phenotype.
authors.affiliation: GeneGo, Inc., St. Joseph, Michigan, USA.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Nikolsky
authors.forename: Evgeny
authors.initials: E
authors.lastname: Sviridov
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.forename: Damir
authors.initials: D
authors.lastname: Dosymbekov
authors.forename: Vadim
authors.initials: V
authors.lastname: Ustyansky
authors.forename: Valery
authors.initials: V
authors.lastname: Kaznacheev
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Dezso
authors.forename: Laura
authors.initials: L
authors.lastname: Mulvey
authors.forename: Laura E
authors.initials: LE
authors.lastname: Macconaill
authors.forename: Wendy
authors.initials: W
authors.lastname: Winckler
authors.forename: Tatiana
authors.initials: T
authors.lastname: Serebryiskaya
authors.forename: Tatiana
authors.initials: T
authors.lastname: Nikolskaya
authors.forename: Kornelia
authors.initials: K
authors.lastname: Polyak
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D016758:Genes, jun; D006801:Humans; D009154:Mutation; D020543:Proteome
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D020543:Proteome