Variants in Practice (ViP) - Peter MacCallum Cancer Centre

The ViP (Variants in Practice) study is a clinic-based cohort of high-risk breast and ovarian cancer families.

Our goal is to offer participation in ongoing genomic research to all families undergoing assessment and genetic testing for an inherited risk of breast or ovarian cancer in a Victorian or Tasmanian Familial Cancer Centre. To date, more than 9000 individuals have consented to take part in the study.

The previous study title was ‘Common Genomic Variants and Familial Breast Cancer’.

Our Research Focus

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.

For Participants

Firstly, thank you! Your support of research into the genetic causes of breast and ovarian cancer is 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 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.

FAQs (Frequently Asked Questions)

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 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 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 numbers, 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 This email address is being protected from spambots. You need JavaScript enabled to view it. 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.

Study snapshot

9300 Australians have agreed to participate in the ViP study
95% of our participants are female, 5% are male
Participants range in age from 25 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 October 2023

Participant enrolment sites

Our team

Chief Investigator

Professor Paul James

Clinical Geneticist
Director, Parkville Familial Cancer Centre & Genomic Medicine,
Peter MacCallum Cancer Centre & Royal Melbourne Hospital

Site Principal Investigators

Professor Paul James

Clinical Geneticist
Parkville Familial Cancer Centre
Tasmanian Clinical Genetics Service

Prof Geoff Lindeman

Medical Oncologist
Parkville Familial Cancer Centre

Dr Yoland Antill

Medical Oncologist

Cabrini Family Cancer Clinic

Dr Marion Harris

Clinical Geneticist and Medical Oncologist
Director, Monash Familial Cancer Centre

Dr Ainsley Campbell

Medical Oncologist
Director, Austin Clinical Genetics Service

Prof Ingrid Winship

Clinical Geneticist
Parkville Familial Cancer Centre

Dr Patricia Banks

Medical Oncologist
Barwon Health

Several 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, byQihong Zhao, Evanny Marinovic, Dr Belle Lim, Dr Ella Thompson, Simone Rowley, Dr Deepak Subramanian and Magnus Zethoven.

Study co-investigators include: Ms Mary-Anne Young, Associate Professor Alison Trainer, Professor Clare Scott, Professor Melissa Southey. Former: Dr Sarah Sawyer, Associate Professor Tom John, Professor David Campbell, Lucinda Salmon, Dr Jo Burke, Associate Professor Gillian Mitchell and Professor 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.

Funding

Contact

Publications

Lim BWX & LiN, et al. Somatic inactivation of breast cancer predisposition genes in tumours associated with pathogenic germline variants. J Natl Cancer Inst. 2022.
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.
Meagher NS, et al. Gene-Expression profiling of mucinous ovarian tumours and comparison with upper and lower gastrointestinal tumours identifies markers associated with adverse outcomes. Clin Cancer Res. 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.
Yanes T, et al. Breast cancer polygenic risk scores: A 12-month prospective study of patient reported outcomes measures and risk management behavior. Gen in Med 2021.
Gregory G, et al. Polygenic risk in familial breast cancer: Changing the dynamics of communicating genetic risk. J Gen.Coun 2021.
Das Gupta K, et al. Communicating polygenic risk scores in the familial breast cancer clinic. Patient Educ. Couns 2021.

Subramanian DN, et al. Exome sequencing of familial high-grade serous ovarian cancer patients to discover novel predisposition genes. Nat. Commun. 2020.
Yanes T, et al. Women's responses and understanding of polygenic breast cancer risk information. Fam Cancer 2020.
Willis A, et al. Another piece of the pie: Influence of lived experience on risk perception among women who received a polygenic risk score for breast cancer risk. JOGC 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.
Yanes T, et al. Uptake of polygenic risk information among women at increased risk of breast cancer. Clinc Genet. 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.
Young MA, et al. Making Sense of SNPs: Women's Understanding and Experiences of Receiving a Personalized Profile of Their Breast Cancer Risks. J Genet Couns. 2018.
Kaur R, et al. Development and pilot testing of a leaflet informing women with breast cancer about genomic testing for polygenic risk. Familial Cancer. 2018.
Forrest LE, et al. High-risk women's risk perception after receiving personalized polygenic breast cancer risk information. J Community Genet. 2018.
Yanes T, et al. Psychosocial and behavioral impact of breast cancer risk assessed by testing for common risk variants: protocol of a prospective study. BMC Cancer. 2017.

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.