Identification of novel breast cancer predisposition genes to improve risk assessment and management of familial breast cancer

Mutations in BRCA1 and BRCA2 and other known predisposition genes explain less than half of all families with a history of breast cancer. Identification of the remaining breast cancer predisposing genes would greatly improve risk assessment and management of these individuals and their families.

Our data and experience in this field shows that germline mutations in any individual gene are likely to be very rare and consequently very challenging to validate. Together with our international collaborators in an international familial breast exome sequencing consortium (COMPLEXO) we have applied next generation sequencing to identify potential predisposing genes from ~1,000 individuals with a personal and family history of breast cancer. We validated up to 1,400 of these candidate genes in a further 6,000 BRCA1/2-negative breast cancer-affected women and 6,000 cancer-free controls from and Australian population and identified a subset of over 30 genes where germline mutations appear to be significantly over-represented among breast cancer families. We also show that in some individuals there is a significant enrichment of rare mutations in multiple genes suggesting that for a proportion of families risk may be due to a “mutation burden” effect.

The aim of this project is to study in detail a subset of these candidate genes to provide multiple lines of evidence supporting their involvement in breast cancer predisposition. These studies will include validation in an additional 10,000 cases and 10,000 controls from multiple independent cohorts from our international collaborators, segregation analysis in families carry mutations and assessing for any correlation of mutation status with mutational signatures in breast cancers carrying germline mutations.

This work will provide robust data on new breast cancer genes that will be of great importance to clinicians managing families at risk for hereditary breast cancer and more broadly to understand the molecular genetics of breast cancer susceptibility which may have implications for treatment of both sporadic and familial forms of the disease.

The major focus of the Campbell Laboratory is the identification of genes involved in the predisposition, initiation and progression of breast and ovarian cancer. Key research studies include:
1) Identifying genes involved in breast, ovarian and colorectal cancer predisposition through next generation sequencing.
2) Conducting genome-wide copy number analysis of breast ductal carcinoma in situ and atypical ductal hyperplasia to identify markers of disease progression.
3) Conducting next generation sequencing and functional screens to identify driver genes of ovarian tumourigenesis.
4) Integrating genomic analyses to identify genes involved in breast and ovarian carcinogenesis.
5) Understanding interval breast cancer biology and mammographic density through LifePool.

https://www.petermac.org/research/labs/ian-campbell

Peter MacCallum Cancer Centre, Melbourne Australia
Peter MacCallum Cancer Centre is Australia’s only public hospital solely dedicated to cancer, and home to the largest cancer research group in Australia. Cancer is a complex set of diseases, and modern cancer research institutes such as Peter Mac conduct research covering a diversity of topics that range from laboratory-based studies into the fundamental mechanisms of cell growth, translational studies that seek more accurate cancer diagnosis, clinical trials with novel treatments, and research aimed to improve supportive care.
All students engaged in postgraduate studies at Peter Mac are enrolled in the Comprehensive Cancer PhD (CCPhD) program, regardless of which university they are enrolled through. The program is managed by the Sir Peter MacCallum Department of Oncology (The University of Melbourne), based at Peter Mac.

Tapping into the depth and breadth of knowledge and experience offered by the ten partners of the Victorian Comprehensive Cancer Centre (VCCC) alliance, the University of Melbourne’s Comprehensive Cancer PhD Program provides a unique opportunity for multidisciplinary cancer-related PhD candidates to experience clinical and research activities across the alliance.

The Comprehensive Cancer PhD program builds on established conventional training for cancer research students providing a coordinated program of skills, research and career training in addition to usual PhD activities. The program is designed to complement existing PhD activities and provides opportunities to develop professional skills that will help candidates to fulfil their career ambitions.
https://www.petermac.org/education/comprehensive-cancer-phd-program