SNPs (Single Nucleotide Polymorphisms) and genomic testing
One of the major projects for the study has been an investigation into the way that common genetic variation (of the type we all have) can play a role in the inherited risk of breast and ovarian cancer. This work has built on the findings of very large studies in Australia and internationally that identified minor variations in our genetic makeup (known as Single Nucleotide Polymorphisms or SNPs) that each have a very small influence on a person’s cancer risk. We now know that when the effect of all these common variants is added together (known as a polygenic risk score), the effect can end up being quite significant, and can explain an important proportion of the breast cancers that occur in families that have been assessed in a Familial Cancer Clinic.
We, and many other research groups, are working hard to understand more about common genetic variants so that this kind of testing (genomic testing) can be brought into clinical practice. We want to know more about exactly what it means when someone has a high number of these risk SNPs; what is their lifetime risk of developing cancer and, more importantly, what strategies might they use to reduce that risk? We would like to understand whether there are specific features that are more likely to be associated with this kind of genetic variation, such as the age of diagnosis or specific cancer sub-types. We also need to know exactly which variants (SNPs) should be included in a test – when this study began in 2012 there were only 22 known breast cancer SNPs, now there are more than 300 breast and 30 ovarian cancer SNPs. Lastly, we want to understand the best way to introduce this testing into clinical practice. To investigate this, we have undertaken psychosocial studies looking at participants’ and health professionals’ experience of receiving (and giving) this genetic information.
Discovering novel rare variants
Another important part of the ViP study is the effort to identify new rare genetic changes (variants) that result in a high (or moderate) risk of breast or ovarian cancer, as well as evaluating changes that have been reported by other research groups but are not yet well understood. This is currently a major focus of the study and additional funding has been secured that allows us to continue our investigation into breast cancer predisposition genes but also to really ramp up the investigations into ovarian cancer predisposition genes; a much-needed area of research. We do this using several different methods, from targeted testing of a panel of genes or even all the genes (whole exome sequencing) using germline DNA, to tumour sequencing and segregation analysis in families. We analyse this genetic information in combination with the relevant medical data such as personal and/or family history of cancer including age of diagnosis, specific cancer sub-type and treatment outcomes. So far, we’ve contributed to the understanding of the PALB2 risk gene and more recently, we found that the RAD51C gene, which is known to moderately increase the risk of ovarian cancer, is also associated with a specific sub-type of breast cancer. Our findings have also shown that we need to be careful when interpreting genetic information because there are genes that have been reported by other research groups as being cancer risk genes that our data suggests is not the case. Recently our analysis has identified several potential new cancer risk genes and we are working on gathering more information about these genes.
Combining rare variant and genomic testing results
Recent investigations have examined what happens when you look at a person’s common variant (polygenic risk score) results in combination with the results of testing for rare high and moderate risk gene changes such as BRCA1, BRCA2, PALB2, CHEK2 and RAD51C. We have some exciting preliminary results that suggest that testing carriers of the moderate risk genes for common variants may improve our ability to accurately estimate an individual’s lifetime risk of developing cancer, which is important for determining the most appropriate risk management strategies for that individual. These results have led to us being awarded funding for the PRiMo trial
Collaborations
In all research, but particularly when investigating rare gene changes, discovery is often accelerated when research groups collaborate, and we do so wherever possible. For example, we are involved in BRA-STRAP (led by Southey Lab, University of Melbourne), an Australian study aiming to provide accurate local risk estimates for the recently described breast cancer predisposition genes. We have collaborated with groups aiming to understand specific genes such as PALB2 (led by Dr Marc Tischkowitz, University of Cambridge), ATM (led by Jorge Reis-Filho, Memorial Sloan Kettering), NTHL1 (led by Kuiper Lab, Radboud University Medical Center in Nijmegen), BAP1 (led by Sebastian Walpole, QIMR) and TP53 (led by Spurdle lab, QIMR).
We are also a member of the Breast Cancer Association Consortium (BCAC) led by Cambridge University. We plan to contribute to the upcoming Confluence project (NIH) that aims to uncover more information about breast cancer genetics through large genome wide association studies.