DR-179 The impact of non-coding/regulatory mutations on cancer susceptibility and response to targeted therapies.

In terms of the research on genetic predisposition to cancers, recent advances in DNA sequencing technologies are facilitating the discovery of more and more genetic ‘variants’ that predispose to cancer. However, thwarting these efforts is that fact that the majority of these inherited ‘germline variants’ are located in the ‘non-coding’ regions of the human genome. This project is focused finding new germline (inherited) and somatic DNA mutations affecting the extended gene loci of known cancer predisposition genes, e.g. BRCA1, BRCA2 and ATM and also genes encoding members of the PI3K/AKT signalling and DNA damaging response pathways. We want to determine if these genetic variants predict which people are predisposed to cancer and which patients will respond to a group of drugs that target either the PI3K/AKT signalling or the DNA damage response pathways. A key step towards achieving this goal will be to access large datasets of cancer patient tumour DNA sequencing. We will identify from these datasets the non-coding or ‘regulatory’ mutations that exist in in the gene loci of cancer susceptibility and PI3K/AKT signalling or DNA damage response pathway genes. Once this is done, we will functionally characterise the most promising variants/mutations and use this knowledge to best predict those patients most likely to be predisposed to cancer and also those who we will predict to most likely respond to the targeted therapies.

Alexander Eustace Dublin City University Ireland