title: Somatic Copy Number Alterations at Oncogenic Loci Show Diverse Correlations with Gene Expression.
abstract: Somatic copy number alterations (SCNAs) affecting oncogenic drivers have a firmly established role in promoting cancer. However, no agreed-upon standard exists for calling locus-specific amplifications and deletions in each patient sample. Here, we report the correlative analysis of copy number amplitude and length with gene expression across 6,109 samples from The Cancer Genome Atlas (TCGA) dataset across 16 cancer types. Using specificity, sensitivity, and precision-based scores, we assigned optimized amplitude and length cutoffs for nine recurrent SCNAs affecting known oncogenic drivers, using mRNA expression as a functional readout. These cutoffs captured the majority of SCNA-driven, highly-expression-altered samples. The majority of oncogenes required only amplitude cutoffs, as high amplitude samples were almost invariably focal; however, CDKN2A and PTEN uniquely required both amplitude and length cutoffs as primary predictors. For PTEN, these extended to downstream AKT activation. In contrast, SCNA genes located peri-telomerically or in fragile sites showed poor expression-copy number correlations. Overall, our analyses identify optimized amplitude and length cutoffs as efficient predictors of gene expression changes for specific oncogenic SCNAs, yet warn against one-size-fits-all interpretations across all loci. Our results have implications for cancer data analyses and the clinic, where copy number and mutation data are increasingly used to personalize cancer therapy.
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030.|Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030.
authors.forename: Jason
authors.initials: J
authors.lastname: Roszik
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030.
authors.forename: Chang-Jiun
authors.initials: CJ
authors.lastname: Wu
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030.
authors.forename: Alan E
authors.initials: AE
authors.lastname: Siroy
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030.|Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030.|Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030.|Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Woodman
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030.
authors.forename: Lawrence N
authors.initials: LN
authors.lastname: Kwong
mesh_terms: D063646:Carcinogenesis / Q000235:genetics*; D056915:DNA Copy Number Variations; D030541:Databases, Genetic; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D009857:Oncogenes; D012372:ROC Curve; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D025521:Tumor Suppressor Proteins