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 B, 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. [Cancer Res 2008;68(22):9532-40]

Recurrent epimutations activate gene body promoters in primary glioblastoma

“…GREAT enrichments for hypomethylated DMRs from individual GBMs were diverse, with relatively few commonalities between these tumors with shared GBM histology but differing molecular subtype. A highly significant hypomethylation enrichment, common to four of five individual GBMs and also significant in recurring hypomethylated DMRs, was for an ;3.4-Mb region of chromosome 5p15 that contains 26 genes and is recurrently amplified in breast cancer (Supplemental Table S3; Nikolsky et al 2008). This region is not amplified in our five GBMs, but encompasses a large number of hypomethylated DMRs including a recurrent hypomethylated DMR in the gene body of TERT, encoding telomerase reverse transcriptase which plays a critical role in telomere length and tumorigenesis.…”

“…Functional enrichment analysis by GREAT found that individual and recurring hypomethylated DMRs significantly enriched for a gene set corresponding to recurrent 5p15 genomic amplification in breast cancer (Nikolsky et al 2008), and numerous hypomethylated DMRs are found in this region (Fig. 6A).…”

CLK2 Is an Oncogenic Kinase and Splicing Regulator in Breast Cancer

“…SNP array data analysis and shRNA screen SNP array data (22) were analyzed to define ARI (aberration amplitude and recurrence index) and AFI (aberration focality index) scores essentially as described (23). ARI is a measure of the copy number gain and the recurrence of such copy numbers across the samples.…”

Gene expression profiling of human breast tissue samples using SAGE-Seq

“…Network and pathway analysis using METACORE was performed essentially as previously described (Nikolsky et al 2008). Specific details are in the Supplemental Methods.…”