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

Daniel G Piqué,Cristina Montagna,Jessica C Mar,John M Greally

doi:10.1038/s41416-019-0387-8

Daniel G Piqué, Cristina Montagna + Show 2 more

Open Access

https://doi.org/10.1038/s41416-019-0387-8

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Abstract

BackgroundOncogenes 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.MethodsHere, 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.ResultsIntronic 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.ConclusionsOncomix 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.

Highlights

Oncogenes promote the development of therapeutic targets against subsets of cancers
We show that breast tumours that overexpress chromobox 2 (CBX2) highly express genes that belong to cell cycle-related pathways
This result is consistent with a prior study, which showed that over 500 differentially expressed genes between CBX2 knockdown and wildtype prostate cancers (PrCa) cells were enriched in proliferation-related processes.[21]

Summary

Introduction

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. 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. 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. The availability of genome-wide gene expression data from matched tumour and adjacent normal tissue of large patient populations provides a valuable resource for developing new approaches for identifying oncogenes that are likely to have pivotal roles in important clinical outcomes such as chemoresistance. These studies recognise the limitations of the unimodal assumption made by many statistical tests and have taken advantage of the inherent heterogeneity in gene expression profiles to discover new subtypes

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Conclusion