A novel approach to modelling transcriptional heterogeneity identifies the oncogene candidate CBX2 in invasive breast carcinoma

Abstract

Background: Oncogenes promote the development of therapeutic targets against subsets of cancers. Only several hundred oncogenes have been identified, primarily via mutation-based approaches, in the human genome. Transcriptional overexpression is a less-explored mechanism through which oncogenes can arise. Methods: Here, a new statistical approach, termed oncomix, which captures transcriptional heterogeneity in tumour and adjacent normal (i.e., tumour-free) mRNA expression profiles, was developed to identify oncogene candidates that were overexpressed in a subset of breast tumours. Results: 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 prior analytical approaches. CBX2 overexpression in breast tumours was associated with the upregulation of genes involved in cell cycle progression and with poorer 5-year survival. The predicted function of CBX2 was confirmed in vitro, providing the first experimental evidence that CBX2 promotes breast cancer cell growth. Conclusions: Oncomix is a novel approach that captures transcriptional heterogeneity between tumour and adjacent normal tissue, and that has the potential to uncover therapeutic targets that benefit subsets of cancer patients. CBX2 is an oncogene candidate that should be further explored as a potential drug target for aggressive types of breast cancer.