Mechanisms of Risk


We have some understanding of genetic factors that lead to ovarian cancer, but we would also like to understand why genetic mutations are risky. Over 95% of the GWAS SNPs identified risk factors to date appear to be associated with non-coding DNA sequence, i.e. sequence not associated with traditional “genes” (or protein coding regions). These sequences in the past were referred to as “junk DNA” but we now understand that much of it is actually carrying the instructions for what genes are turned on or off, when and in which cell types. Many of the genes responsible for cell division (and other required cancer processes) are affected via these control sequences (called enhancers and promoters) in a cell type-specific manner. Thus, risk is often carried in these cell type specific sequences.

Because enhancers and promoters are found in the regions between genes, it is just as important to define the genes that they interact with. To do these kinds of studies, we touch on several fields. One is identifying enhancer-gene interactions using genetics (as in eQTL) or physical interactions using chromatin looping assays. Another kind of study involves knocking out the enhancer using CRISPR technology and measuring the effect on local gene expression.