Ian Campbell

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.

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.

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.

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.

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.