Previous study title: Common Genomic Variants and Familial Breast Cancer
The ViP study is part of the global research effort to understand how differences in our genetics contribute to the risk of cancer in individuals and families.
SNPs 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 of these common variants are 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 kind of 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 a number of different methods, from targeted testing of a panel of genes or even all of 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.
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 BCAC, a global breast cancer association consortium led by Cambridge University, and 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.
Firstly, thank you! Your support of research into the genetic causes of breast and ovarian cancer is greatly appreciated and without you the ViP study would not be possible.
You may have enrolled in the study when it began in 2012, or you may have only just recently agreed to participate. Regardless, this webpage is to provide you with information about the study, and you can check back here in the future if you would like to follow our progress.
- 9000 Australians have agreed to participate in the ViP study
- 95% of our participants are female, 5% are male
- Participants range in age from 23 to 100 years
- 75% of participants have had a diagnosis of breast cancer
- 8% of participants have had a diagnosis of ovarian cancer
- So far, we have analysed more than 8000 DNA samples and 800 tumour samples
- We have contributed to more than 24 academic publications and presented our findings at more than 25 national and international conferences
*as of Sept 2022
Will you tell me my individual results?
Because the type of analysis and testing we do in this study is for research purposes, the information that we find is usually not in a form that is currently interpretable (this means that there is uncertainty about what the information means and whether or not it is relevant). Our aim is to analyse the information to try and understand it better.
Occasionally though, we do get results that we understand may be important for the health of particular participants and their family members. When this happens, we contact those participants and let them know that these results are available (if they want to receive them).
As a participant in the ViP study, will I be asked to do anything else?
When you signed the consent form agreeing to take part in the study, you gave us permission to collect information relating to your medical history of cancer and/or family history of cancer, collect your DNA sample for research genetic testing and access your stored tumour sample (if you have had a diagnosis of cancer). You do not have to do anything else to participate in this study. However, as a participant of the ViP study, you may occasionally be asked if you would like to participate in an additional related research study. At that time, we would tell you all about the additional study and you can decide if you want to be involved in that study too.
How long will the ViP study go for?
Since the study began we have contributed significantly to improving our understanding of the inherited causes of breast and ovarian cancer, and we’ve been helping to integrate research findings into clinical care. But, there is still a lot that we don’t know, and so we are applying for more funding to allow the ViP study to continue beyond 2022.
Do you want to know about changes to my contact details or medical history?
Yes. If you have moved house or changed phone number, we would be grateful if you would let us know. Also, we are doing our bit to protect the environment by changing from postal contact to text message and email where we can. If you would like to provide your mobile number and/or email address, send us an email at [email protected] and we will add it to our records.
We know that when you, or someone in your family, is diagnosed with a new cancer there is a lot to do and think about, but we would be grateful if at some stage you could let us know about the new diagnosis so that we can update our records.
Austin Clinical Genetics Service, Austin Health
Barwon Regional Familial Cancer Clinic, Royal Melbourne Hospital & Barwon Health
Cabrini Family Cancer Clinic, Cabrini Health
Monash Familial Cancer Centre, Monash Health
Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre & Royal Melbourne Hospital
Tasmanian Clinical Genetics Service
- Li N, et al. The contribution of large genomic rearrangements in PALB2 to familial breast cancer: Implications for genetic testing. J Med Genet. 2022.
- Lim B, et al. Integration of tumour sequencing and case-control data to assess pathogenicity of RAD51C missense variants in familial breast cancer. NPJ Breast Cancer. 2022.
- Li N, et al. Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study. NPJ Breast Cancer. 2021.
- Li N, et al. Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects. NPJ Breast Cancer. 2021.
- Subramanian DN, et al. Exome sequencing of familial high-grade serous ovarian cancer patients to discover novel predisposition genes. Nat. Commun. 2020.
- Yang X, et al. Cancer risks associated with germline PALB2 pathogenic variants: An international study of 524 families. J Clin Oncol. 2019.
- Li N, et al. Combined tumor sequencing and case/control analyses of RAD51C in breast cancer. J Natl Cancer Inst. 2019.
- Grolleman JE, et al. Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype. Cancer Cell. 2019.
- Li N, et al. Evaluating the breast cancer predisposition role of rare variants in genes associated with low-penetrance breast cancer risk SNPs. Breast Cancer Res. 2018.
- Li N, et al. Mutations in RECQL are not associated with breast cancer risk in an Australian population. Nat Genet. 2018.
- Lee JEA, et al. Molecular analysis of PALB2-associated breast cancers. J Pathol. 2018.
- Weigelt B, et al. The Landscape of Somatic Genetic Alterations in Breast Cancers From ATM Germline Mutation Carriers. J Natl Cancer Inst. 2018.
- Thompson ER, et al. Panel Testing for Familial Breast Cancer: Calibrating the Tension Between Research and Clinical Care. J Clin Oncol. 2016.
- Li N, et al. Reevaluation of RINT1 as a breast cancer predisposition gene. Breast Cancer Res Treat. 2016.
- Easton DF, et al. No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing. J Med Genet. 2016.
- Thompson ER, et al. Prevalence of PALB2 mutations in Australian familial breast cancer cases and controls. Breast Cancer Res. 2015.
- Thompson ER, et al. Reevaluation of the BRCA2 truncating allele c.9976A > T (p.Lys3326Ter) in a familial breast cancer context. Sci Rep. 2015.
- Antoniou AC, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014.
- Teo ZL, et al. Tumour morphology predicts PALB2 germline mutation status. Br J Cancer. 2013.
- Teo ZL, et al. The incidence of PALB2 c.3113G>A in women with a strong family history of breast and ovarian cancer attending familial cancer centres in Australia. Familial Cancer. 2013.
- Thompson ER, et al. Analysis of RAD51D in Ovarian Cancer Patients and Families with a History of Ovarian or Breast Cancer. PLoS One. 2013.
- Hilbers FS, et al. Rare variants in XRCC2 as breast cancer susceptibility alleles. J Med Genet. 2012.
- Sawyer S, et al. A Role for Common Genomic Variants in the Assessment of Familial Breast Cancer. J Clin Oncol. 2012.
- Thompson E, et al. Analysis of RAD51C germline mutations in high-risk breast and ovarian cancer families and hospital-based ovarian cancer patients. Human Mutation. 2012.
Site Principal Investigators
A number of study activities are undertaken by the Campbell Laboratory at Peter MacCallum Cancer Centre under the direction of ViP investigators Prof Ian Campbell and Dr Na Li, in particular by Dr Belle Lim, Dr Ella Thompson, Simone Rowley, Dr Deepak Subramanian and Magnus Zethoven.
Study co-investigators include: Ms Mary-Anne Young, A/Prof Alison Trainer, Prof Clare Scott, Prof Melissa Southey. Former: Dr Sarah Sawyer, A/Prof Tom John, Prof David Campbell, Lucinda Salmon, Dr Jo Burke, A/Prof Gillian Mitchell and Prof Martin Delatycki.
This study is supported by a team of study coordinators and research assistants* at the Parkville Familial Cancer Centre, and the genetic counsellors, clinicians, data managers and administration teams at each of the study sites, in particular by Denisse Garza (Tasmanian Clinical Genetics Service), Rhiana Spinoso (Austin Health), Courtney Smyth (Monash Health), Dr Lynne Mckay (Cabrini Health), Alexandra Lewis, Katrina Monohan, Anastasia Lewis and Shelby Taylor (Parkville Familial Cancer Centre). In addition, the Diagnostic Pathology Laboratory and the kConFab study team at Peter MacCallum Cancer Centre provide laboratory support.
*Current: Simone McInerny, Theresa Wang & Natasha Alexander. Former: Norah Grewal, Lyon Mascarenhas, Samantha Kleverlaan, Mia Friedman, James Morgan, Rebecca Driessen, Kate Riley and Vesna Stanovic.
National Health & Medical Research Council
National Breast Cancer Foundation
Victorian Cancer Agency
Victorian Comprehensive Cancer Centre