The Role of Synergistic Responses in Tumorigenesis

Source: McMurray et al. (2008). Synergistic response to oncogenic mutations defines gene class critical to cancer phenotype. Nature 453: 1112-1116.

First of all, a couple of my friends have started a similar blog on parasitology (http://parasitediary.wordpress.com/); for those of you who are working in this field, I think they'll be thrilled if you visit their blog, leave comments or even better contribute.

Now back to our own post... well, tumorigenesis is a hot topic with many papers being published in very good journals solely based on a subject profiling. This paper, however, very well deserves its publication in Nature. The authors start with the notion that genes with synergistic effects across tumorigenic mutations should play a key role in the emergence of the transformed state and throughout the paper they provide evidence in support of their hypothesis. First, they profile the gene expressions in p53, ras, and p53/ras cell lines. Then, they focus on the genes in the double mutant with a fold-change larger than the sum of fold changes in the single mutants (i.e. synergistic genes). Note that these fold-changes can be both positive and negative; thus, we include both positive and negative synergism. An initial look at these genes shows a diversity of roles in signaling, transcription, apoptosis and adhesion that are generally deregulated in the available cancer gene-expression datasets.

To show that these genes are important in tumorigenesis, they restore the normal expression levels of 24 synergistic and 14 non-synergistic genes, one by one, in the double mutant background. For this, they employ retro-virus mediated re-expression or shRNA-dependent knockdown. They show that in 14/24 cases, for the synergistic genes, there is a significant reduction in tumorigenesis upon restoring normal expression levels; whereas, only 1/14 non-synergistic genes shows such level of effect.

To summarize, this paper makes the case for synergistic genes to be foci of transformation; thus, excellent genes for studying or therapeutic targeting.