Technology

The OncoMark Process

The OncoMasTR technology was originally developed by researchers in Trinity College Dublin (TCD) in collaboration with Prof. William Gallagher of University College Dublin (UCD) (who is also founder and Chief Scientific Officer of OncoMark). The central hypothesis of the work was to identify upstream ‘drivers’ of breast cancer progression, rather than ‘passenger’ genes, which other breast cancer gene signatures had identified. Upstream drivers represent a more accurate and reliable indicator of tumour progression.

 

Background

Several multigene prognostic signatures, which identify the risk of women with early stage, LN-negative breast cancer of developing a recurrence after surgical resection, have been developed in recent years[1],[2].  Many of these have been adopted in the clinic and have proven useful in terms of stratifying patients into lower and higher recurrence risk groups. However, since there was little overlap in the genes represented in these signatures, it was hypothesized that identifying and measuring gene expression of the upstream Master Transcriptional Regulators (MTRs) that are associated with poor prognosis in breast cancer would allow the development of more accurate tests to help inform on best treatment options. 

Approach

A bioinformatic approach called ARACNe [3],[4] was used to predict the upstream MTRs of two independent breast cancer prognosis gene signatures. ARACNe uses networks constructed from gene expression datasets to infer direct transcriptional interactions. A panel of Master Transcriptional Regulators (MTRs), commonly associated with poor prognosis in existing tests and that shared a common role in cell proliferation, was identified.

It was sought to include a further marker in the panel to indicate if tumours had bypassed the cellular senescence checkpoint and to determine whether this could help further refine breast cancer treatment options. Accordingly, it was established that certain expression levels of CDKN2A mRNA (the gene which encodes p16INK4A) were associated with recurrence of breast cancer.

In this way, a mechanistically anchored panel of genes was identified comprising up to 10 MTRs and CDKN2A. These were brought forward for the development of the OncoMasTR test.

 

Development of the OncoMasTR test

Through our network of clinical and scientific collaborators, we successfully combined the mRNA expression levels of prognosis-linked MTRs with those of CDKN2A into a scoring system which underpins the OncoMasTR test [5]. The test was subjected to a series of analysis in microarray databases, challenged to provide additional clinically useful data over standard clinical variables before testing the accuracy of the test in patient samples. 

The results revealed that the OncoMasTR test was capable of classifying patients as low risk with more accuracy compared to the existing tests in the market thereby supporting the ongoing technical, clinical and commercial translation of the test.

 

Future Developments

OncoMark continue to apply this methodology to identify novel signatures for prognosis and prediction in many other cancers including Bladder, Prostate, Multiple Myeloma, Lung and Colorectal cancers. See Pipeline »


[1] Duffy MJ et al. Eur J Cancer, 2017; 75, 284-295 

[2] Stein RC et al. Health Technol Assess, 2016; 20(10), xxiii-xxix 

[3] Margolin AA et al. Nat Protoc, 2006; 1, 662-671 

[4] Carro MS et al. Nature, 2010; 463, 318-325 

[5] Lanigan F et al. FEBS J., 2015; 282(18), 3455-3473