Ian Campbell lab

Genetic mosaicism is the presence of mutations in a subset of somatic cells, that are not inherited in the germline genome. Using next generation sequencing technologies, genetic mosaicism can be detected in blood as a consequence sub-populations of peripheral blood lymphocytes (PBLs) that have acquired a somatic mutation.

There is strong evidence linking genetic mosaicism with risk of hematologic malignancies, but the level of evidence supporting an association with solid malignancies varies considerably. We hypothesize that genetic, environmental and lifestyle factors that increase the risk of cancer) will be reflected in the burden of mosaic mutations in PBL DNA and this biomarker can be used to improve cancer risk prediction detection. We are conducing deep whole exome sequencing of more than 3000 cases and controls to identify mosaic mutations and provide definitive data to confirm or refute the potential of mosaic mutations as a biomarker for cancer risk prediction.

Key personnel leading the study:  Ian Campbell, Lisa Deveux, Paul James.

The prognosis and psychological outcomes for women diagnosed with a breast cancer (BC) under the age of 45 years are poor compared with later onset BC (7% of cases but 15% of deaths). These young women, many of whom are mothers of young children and/or are pregnant at time of BC diagnosis, bear a disproportionality high impact compared to women diagnosed with later onset BC.  Discovery of the germline and somatic genetic causes of many BC sub-groups has opened new avenues for effective screening and treatment, but such information is lacking for early onset breast cancers (EOBC). We hypothesis that EOBC differ biologically from other BCs and possess unique therapeutic vulnerabilities that can be exploited to develop effective but less toxic personalised treatments. We will use our unique cohort of cancer biospecimens to characterise the hereditary and somatic events that underlie the poor prognosis of EOBC and PABC as a means of linking this to modern molecular therapeutics. 

Key personnel leading the study:  Ian Campbell, Lily Owen.

Understanding the genetic causes of breast cancer (BC) has opened new avenues for effective screening, cancer prevention and improved management - but is currently limited to the small number of women with a monogenic hereditary breast cancer (HBC) gene abnormality in a high-risk gene such as BRCA1. Compelling research data has identified hundreds of common, single nucleotide polymorphisms (SNPs) identified through BC genome-wide association studies (GWAS) that are each associated with a minor risk of BC but when summarised in a polygenic risk score (PRS) explain up to 41% of the heritable risk of BC.  The mechanism through which these SNPs collectively modify BC risk is unknown but we hypothesise this will occur through only a small number of unifying molecular pathways. We will use a library of rare patient derived materials and induce pluripotent stem cell technology to characterise these biological functions that underlie the extremes of BC polygenic risk as a means to connect PRS with the biological processes that now underpin prevention, targeted treatment decisions and outcomes in BC.

Key personnel leading the study:  Ian Campbell, Paul James, Evanny Marinovic Ashleigh Monson (PhD student)

Pathogenic coding region mutations in BRCA1, BRCA2 and PALB2 are major contributors to hereditary breast cancer (HBC) but collectively explain less than a quarter of the families. We are exploring the possibility that a substantial component of the uncovered risk of breast cancer is due to alternative mechanisms of inactivation of known HBC genes, including rare variants in intronic and promoter regions and inherited epigenetic promoter hypermethylation. This study is underpinned by the unparalleled clinical, biospecimen and sequencing data of the principal investigators' BEACCON study which comprises the world’s largest dataset of full gene and promoter sequence of BRCA1, BRCA2 and PALB2 in over 6,000 BC patients clinically evaluated as having a high likelihood of a hereditary cause, but without evidence of conventional exonic mutation. 

Key personnel leading the study:  Ian Campbell, Paul James, Qihong Zhao (PhD student).

Breast and ovarian cancers have a major heritable component but since the discovery of BRCA1 and BRCA2 no equivalent high penetrance predisposition genes have been found. Our pioneering whole exome sequencing revealed that the remaining heritability must be due to numerous genes each responsible for only a small proportion of families and future studies needed to be highly powered to uncover such genes. We are exploiting our unique cohorts and clinical resources to integrate whole genome germline and tumour sequencing data, including identification of “second hit” somatic inactivation events and characteristic mutational signatures to identify and validate novel cancer predisposition genes.  

Key personnel leading the study:  Deepak Subramanian, Qihong Zhao (PhD student) Ian Campbell, Paul James.

Following diagnosis of breast cancer (BC), identification of germline mutations in hereditary breast cancer (HBC) genes can have profound benefits in terms of immediate treatment decisions and managing future cancer risk for both the affected woman and their family members. In addition, sequencing of the BC can reveal clinically relevant insights into effective treatments beyond those revealed by germline sequencing. We are conducting a trial (the MAGIC study) that is performing whole genome sequencing of matched germline and tumour at time of diagnosis for all newly diagnosed cases of invasive female BC at the Victorian Comprehensive Cancer Centre. Germline information on actionable HBOC gene mutations will be provided to the treating clinician to directly inform clinical management in the ~8% of patients where an actionable mutation is identified.  In the long term, the germline and tumour sequencing data from MAGIC participants will be linked with treatment and clinical outcome data to identify new prognostic and predictive markers.

Key personnel leading the study:  Lisa Devereux, Ian Campbell, Paul James (Dilanka De Silva (PhD student)

Low Grade Serous Ovarian Carcinoma (LGSOC) is a morphologically and molecularly distinct subtype of epithelial ovarian cancer, accounting for ~5% of all serous carcinomas. These cancers have a protracted clinical course, and are largely unresponsive to standard chemotherapy regimens with an overall recurrent response rate of 3.7%. The development better therapeutics is hampered by the fact that little is known about the molecular drivers of LGSOC.  We are applying multi-omics analysis to piece together the unmapped genomic puzzle of LGSOC to reveal new therapeutic targets. 

Key personnel leading the study:  Dane Cheasley, Kathleen Pishas, Ian Campbell.

In patients with LGSOC who relapse the overall chemotherapy response rate is very poor and highlights the need for new therapeutic approaches for this group of women with particularly poor outcome.

To discover new treatment regimens, we are undertaking the largest global discovery of synergistic drug combinations in LGSOC which includes high-throughput drug screening of 6710 single agents from FDA approved, kinase and epigenetic drug libraries in 20 patient-derived LGSOC cell lines representing all LGSOC molecular subtypes. This work has the capacity to significantly change the survival landscape for LGSOC patients and reduce the burden of ovarian cancer within the community.

Key personnel leading the study:  Dane Cheasely, Kathleen Pishas, Kaylene Simpson.