Oncogenes promote the development of and serve as therapeutic targets against subsets of cancers. Here, a new statistical approach that captures transcriptional heterogeneity in tumor-normal mRNA expression profiles was developed to identify oncogene candidates that were overexpressed in a subset of breast tumors. Intronic DNA methylation was strongly associated with the overexpression of Chromobox 2 (CBX2), an oncogene candidate that was identified using our method but not through existing analytical approaches. CBX2 overexpression in breast tumors was associated with the upregulation of genes involved in cell cycle progression and is associated with poor 5-year survival. The predicted function of CBX2 was confirmed in vitro providing the first experimental evidence that CBX2 promotes breast cancer cell growth. Modeling mRNA expression heterogeneity in tumors is a novel powerful approach with the potential to uncover therapeutic targets that benefit subsets of cancer patients.
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