Cancer often originates from gene overexpression; accordingly, many tumor cells contain chromosomes with duplicated segments, resulting in amplified activity of the various genes contained within the affected region. These ‘recurrent chromosomal amplifications’ can incorporate many genes, making it difficult to zoom in on a particular cancer-causing culprit. However, new work from a team at A*STAR’s Genome Institute of Singapore, led by long-time collaborators Bing Lim and Lance Miller has demonstrated a powerful, multi-dimensional strategy for revealing these genes.
Years of cancer research have generated massive amounts of gene expression data—an informational gold mine awaiting proper analysis. “Dr Miller had spent considerable effort thinking about how to make good use of the vast database out there, with transcriptome profiles of all types of cancer samples completed by many labs at many centers,” says Lim. Their group developed a method called ‘triangulating oncogenes through clinico-genomic intersects’, dubbed ‘TRIAGE’, which identifies likely sites of multi-gene amplification sites based on expression levels, then analyzes these regions to identify genes potentially associated with aggressive or metastatic cancer. “The idea was that a significant correlative link between genes and poor clinical survival would increase the probability that these genes are involved in some function critical for cancer cell survival,” explains Lim.
Analysis of data from over 700 breast cancer patients revealed half a dozen potentially important chromosomal amplification sites. Within one of these, on the short arm of chromosome 8, TRIAGE identified the RCP gene as having a highly significant association with breast cancer onset and progression, although no such role had previously been assigned to this gene.
The RCP protein appears to be involved in a number of cellular signaling pathways—a common hallmark of oncogenes—and is highly expressed in late-stage and metastatic tumors (Fig. 1). Tissue culture experiments showed that RCP overexpression boosts the proliferation and invasive behavior of breast cancer cells; on the other hand, breast tumors implanted in mice exhibited greatly reduced growth and metastasis when RCP activity was selectively reduced.
“Narrowing down the gene list from thousands to one gene is a reminder of the power of our current tools for genomic studies,” notes Lim. He is also optimistic about the potential to achieve similar revelations in future research, as he and Miller continue to explore the potential of RCP as a clinical indicator and target. “Given the power of the TRIAGE algorithm in this study, we will be very interested in applying it to other cancers,” says Lim.
The A*STAR-affiliated authors in this highlight are from the Genome Institute of Singapore.