The impact of genetic heterogeneity on synthetic lethality in cancer

WT Scheme: Sir Henry Wellcome Postdoctoral Fellowship

Synthetic lethal interaction occurs when the function of one gene only becomes essential for viability in the presence of a mutation in another gene. In cancer treatment this phenomenon can be exploited to selectively kill tumour cells that have specific genetic mutations. Although this approach holds great promise for the development of therapeutics, little is understood about how additional genetic differences between individuals might impact on its use. In particular a gene predicted to be essential in a tumour cell with a particular mutation might, in reality, not be essential due to the presence of additional compensatory mutations in other genes.

I intend to investigate this phenomenon using cancer cell lines to understand what factors might 'disrupt' a synthetic lethal interaction (make it non-essential) and to identify whether certain interactions are more robust (less likely to be disrupted by other mutations) than others.

I will do this using experimental approaches (artificially disrupting a particular synthetic lethal interaction), data integration approaches (studying all of the known synthetic lethal interactions associated with a particular gene), and computational approaches (using a model of the cell to predict synthetic lethal interactions in different individuals).

Award Date
30 June 2014
Award Value
Principal Investigator
Dr Colm Ryan
Host Institution
University College Dublin
SFI-HRB-Wellcome Biomedical Partnership