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:
- Identifying genes involved in breast, ovarian and colorectal cancer predisposition through next generation sequencing.
- Conducting genome-wide copy number analysis of breast ductal carcinoma in situ and atypical ductal hyperplasia to identify markers of disease progression.
- Conducting next generation sequencing and functional screens to identify driver genes of ovarian tumourigenesis.
- Integrating genomic analyses to identify genes involved in breast and ovarian carcinogenesis.
- Understanding interval breast cancer biology and mammographic density through LifePool.
Population-based genetic testing for high-risk breast and ovarian cancer predisposition genes
Inherited mutations in the genes BRCA1 and BRCA2 confer a very high risk of breast and ovarian cancer. Importantly, once carriers are identified, effective strategies are available that can dramatically reduce the risk of cancer and overall mortality. However, most carriers of mutations are only identified after they develop cancer. We are conducting a world-leading genetic screen among a healthy Western population to identify breast/ovarian cancer predisposition genes before the participants develop cancer. Population-based screening could significantly reduce the incidence of these diseases and this project could provide a template to extend screening for genes that predispose to other major cancer types.
Personalised Risk Evaluation in breast Ductal Carcinoma in situ (PRECISION)
Ductal carcinoma in situ (DCIS) accounts for 20-25% of breast cancer and is a growing health problem with great variation in treatment and outcome. After local excision, about 25% of DCIS will recur. There are no robust markers of recurrence risk for tailoring treatment to optimise patient outcome and minimise treatment toxicity. Thus, clinical management of DCIS is challenging and many women are over-treated while others might benefit from more intense therapy or monitoring. We aim to develop a clinical test for personalised DCIS recurrence risk, using gene copy number, immunohistochemistry and gene expression assays. This study will leverage unique local and international DCIS cohorts that have extensive clinical annotation and follow-up data. A similar study for benign breast lesions (atypical ductal hyperplasia and papillomas) is also being undertaken.
Improving early detection and management of women at risk of developing interval breast cancer
Breast cancers diagnosed after a negative mammogram but prior to the next scheduled screening are termed “interval cancers”, and comprise 25-30% of breast cancers diagnosed in women undergoing population-based mammography screening. Women diagnosed with an interval cancer have a worse prognosis compared to screen-detected cancer and is a key limitation of the effectiveness of population-based mammographic screening. We are firstly investigating inherited features of interval cancers that can be used to prospectively identify women at risk of developing an interval cancer, so that modification of screening can reduce the interval cancer rate and reveal new treatment options. Secondly, we are investigating the somatic genetics of interval cancers in order to understand their aggressive nature.
Resolution of the missing heritability of breast and ovarian cancer
The genetic cause of the majority of multiple-case breast and/or ovarian cancer families remains unresolved. Identifying the genetic causes in these families can provide significant opportunities for the prevention of primary and secondary cancer. Together with our collaborators in an international familial breast cancer exome sequencing consortium (COMPLEXO), we are investigating novel predisposing genes identified through whole-exome sequence analysis of germline DNA from affected relatives from >900 high-risk breast cancer families who have previously tested negative for all known breast cancer genes (BRCAx families). We are also undertaking exome sequencing of ovarian cancer families. Our recent work strongly suggests that numerous moderate penetrance genes remain to be discovered, with each gene individually accounting for only a small fraction of families. We are conducting large validation studies of the strongest candidate genes in thousands of cases and controls, from multiple independent cohorts from Australia and our international collaborators. Further validation will include family- and tumour-based analyses, as well as an exploration of a novel "mutation burden" predisposition mechanism.
Genomic characterisation of rare ovarian epithelial carcinoma subtypes
While the genomic profiles of high-grade serous carcinomas have been extensively studied, little is known about the low-grade serous and mucinous subtypes. We are undertaking integrated genomics and functional analyses of these rare and chemo-resistant carcinomas to understand the molecular pathways that may lead to novel therapeutic strategies.
Thompson ER, Rowley SM, Li N, McInerny S, Devereux L, Wong-Brown MW, Trainer AH, Mitchell G, Scott RJ, James PA, Campbell IG (2016). Panel Testing for Familial Breast Cancer: Calibrating the Tension Between Research and Clinical Care. J Clin Oncol. 34(13):1455-9.
Thompson ER, Doyle MA, Ryland GL, Rowley SM, Choong DY, Tothill RW, Thorne H; kConFab, Barnes DR, Li J, Ellul J, Philip GK, Antill YC, James PA, Trainer AH, Mitchell G, Campbell IG (2012). Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles. PLoS Genet. 8(9):e1002894.
Thompson ER, Boyle SE, Johnson J, Ryland GL, Sawyer S, Choong DY, kConFab, Chenevix-Trench G, Trainer AH, Lindeman GJ, Mitchell G, James PA, Campbell IG (2012). Analysis of RAD51C germline mutations in high-risk breast and ovarian cancer families and ovarian cancer patients. Hum Mutat. 33(1):95-9.
Gorringe KL, Hunter SM, Pang JM, Opeskin K, Hill P, Rowley SM, Choong DY, Thompson ER, Dobrovic A, Fox SB, Mann GB, Campbell IG (2015). Copy number analysis of ductal carcinoma in situ with and without recurrence. Mod Pathol. 28(9):1174-84.
Hunter SM, Anglesio MS, Ryland GL, Sharma R, Chiew YE, Rowley SM, Doyle MA, Li J, Gilks CB, Moss P, Allan PE, Stephens AN, Huntsman DG, deFazio A, Bowtell DD, Australian Ovarian Cancer Study Group, Gorringe KL, Campbell IG (2015). Molecular profiling of low grade serous ovarian tumours identifies novel candidate driver genes. Oncotarget. 6(35):37663-77.
Ryland GL, Hunter SM, Doyle MA, Caramia F, Li J, Rowley SM, Christie M, Allan PE, Stephens AN, Bowtell DD, Australian Ovarian Cancer Study Group, Campbell IG, Gorringe KL (2015). Mutational landscape of mucinous ovarian carcinoma and its neoplastic precursors. Genome Med. 7(1):87.
Ryland GL, Hunter SM, Doyle MA, Rowley SM, Christie M, Allan PE, Bowtell DD; Australian Ovarian Cancer Study Group, Gorringe KL, Campbell IG (2013). RNF43 is a tumour suppressor gene mutated in mucinous tumours of the ovary. J Pathol. 229(3):469-76.