Mechanisms underlying maintenance of genome stability

For most mutations identified in cancers, we have no idea of their disease relevance. This is a major health issue, in particular for breast and ovarian cancer, where hereditary predispositions contribute substantially. With the current proposal, we suggest developing a transforming solution to this issue focusing on emerging putative driver genes and variants in early-onset breast and ovarian cancer. These research questions are at the very heart of the established close collaboration between my team and the clinical Centre for Genomic Medicine at the Copenhagen General Hospital. We have already set this up for the important BRCA1 and BRCA2 genes. Thus, the focus of the EMERALD project fellow will be to uncover key pathogenic factors in non-BRCA1/2 familial cancers.

Our approaches are based on our newly invented quantitative CRISPR-Cas9 technology, CRISPR-Select, which enables functional-mechanistic clarification of cancer-derived genetic variants. The new putative genetic underpinnings are discovered at the Centre for Genomic Medicine at the Copenhagen General Hospital (which includes genetic variant data from numerous international network collaborators). Thus, the PhD student will dissect; 1) the pathogenic potential of cancer-associated variants in newly identified genes (i.e. non-BRCA1/2). 2) Therapy response impact of the newly identified variants with a focus on PARP inhibition and platinum compound chemotherapy. 3) Mechanistic role for one of the identified new genes.

Transforming the approaches to VUS will have huge benefits, in particular, with expected expansion into the clinical entities that find the methodology relevant. CRISPR-SurF is at the heart of precision medicine, and it can assist doctors in decision-making and counselling options on 1) whether or not to remove the breast and ovaries from the patient and female relatives with the variant, 2) whether the patient should be treated with PARP (Poly ADP-ribose polymerase) inhibitor that is highly effective in patients with BRCA-loss or 3) whether life-long surveillance of patient should be implemented. As the methodology will develop further, we expect to precisely determine genetic variant roles for all patients where relevant, thereby expanding well beyond the familial breast and ovarian cancers.

The person should have an interest in cancer and genotype-phenotype interactions. Prior experience with CRISPR approaches would be preferred.

Interest in molecular genetics and basic cancer research would be relevant.