Georgia Chenevix-Trench

QIMR Berghofer 
Medical Research Institute

Professor Georgia Chenevix-Trench is a Senior Principal Research Fellow of the NHMRC, a Fellow of the Australian Academy of Sciences and of the Australian Academy of Health and Medical Sciences, and head of the Cancer Genetics Laboratory and the Department of Genetics and Computational Biology at the QIMR Berghofer in Brisbane.  She is the author of more than 400 peer-reviewed papers, and has been instrumental in the collection of public resources such as kConFab, the Australian consortium for research into familial breast cancer. She is the leader of the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), and a founding member of the Breast and Ovarian Cancer Association Consortia, which have identified almost 200 novel breast and ovarian cancer susceptibility loci since the advent of genome-wide association studies. 

A major focus of her current research is to work out the function of the alleles associated with cancer risk and to identify their target genes.

Drowning in our success: post-GWAS studies of breast cancer risk

Breast cancer risk is influenced by rare coding variants in susceptibility genes such as BRCA1 and many common, mainly non-coding, variants. Following the success of the iCOGS study through which the Breast Cancer Association Consortium and the Consortium of Investigators of Modifiers of BRCA1/2 identified almost 100 loci associated with risk, we have carried out another genome-wide association study (GWAS) in more than 119,000 cases (including >21,000 with estrogen receptor negative disease), 19,000 BRCA1 mutation carriers, and 101,000 controls. We identified 65 novel loci associated with overall, and 10 with ER-ve breast cancer, at p<5x10-8. The majority of candidate causal SNPs at these loci fall in distal regulatory elements, and so the challenge of functionally identifying the target genes is immense. We therefore developed INQUISIT (Integrated expression Quantitative trait and In Silico prediction of GWAS Targets) and demonstrated a strong overlap between predicted target genes and somatic driver genes in breast tumours. The allows improved pathway analyses, informed functional follow up of individual risk loci and pooled CRISPR screens of putative target genes. In addition, we have carried out transcription-wide association studies of breast cancer, and identified genes at known and novel risk loci whose predicted expression is associated with risk. In vitro assays have shown that the majority of these genes affect cell proliferation and colony formation, some of the hallmarks of cancer. Given that the likelihood of developing a successful drug is doubled if the target has a genetic basis, there is an imperative to uncover the many new breast cancer risk genes initially identified by GWAS.