A5 SDHB Genomics: Using multi-omics to dissect a rare cancer of the sympathetic nervous system | Associate Prof Richard Tothill

ASSOCIATE PROFESSOR RICHARD TOTHILL
Group Lead - Rare Disease Oncogenomics
University of Melbourne

Phaeochromocytoma (PC) and paraganglioma (PG) are rare and heritable tumours that arise from sympathetic and parasympathetic tissues. These tumours are remarkable for their genetic heterogeneity with more than 20 driver genes implicated and with diverse phenotypes. Prediction of metastatic progression and a cure for patients with metastatic disease remains a deficiency in current clinical management. Patients with germline mutations in succinate dehydrogenase B (SDHB) are known to be at higher risk of developing metastatic disease; however, the precise determinants of metastatic progression remain poorly understood, even among the SDHB mutation carriers.

The A5 SDHB Genomics Study seeks to identify changes in the genes of tumour cells that regulate their behaviour, to understand what initiates the process of metastasis and to identify new therapeutic targets for precision treatments. Patient samples and clinical data have been accrued from 12 institutions across 6 countries. A genome-wide multi-omics analysis has been applied to almost one hundred benign and metastatic patient samples. Platforms have included whole-genome DNA sequencing, bulk total RNA-seq (large and small fractions), DNA methylation (methylation arrays) as well as 10x genomics single nuclei (sn) RNA and snATAC-seq in a subset of samples. Results from the data will be presented highlighting recurrent gene lesions and mutational signatures in PCPG as well using single cell platforms to dissected transcriptional patterns in different cell types in a genotype dependent manner.

Associate Professor Richard Tothill is head of the Rare Disease Oncogenomics Laboratory within Department of Clinical Pathology and the Centre for Cancer Research at the University of Melbourne. He received his PhD in 2005 at the University of Melbourne and Peter Mac. Preceding this time he was a research scientist working on genomic technology development at Glaxo-Welcome (UK). Since 2001 he has established a career in the field of cancer genomics researching several solid cancer types. His work has been highly translational with a heavy focus on development and adoption of breakthrough genomic technologies for discovery and clinical applications. His lab’s research is focused on rare diseases including Merkel cell carcinoma, phaeochromocytoma/paraganglioma and other neuroendocrine malignancies. He is also the principal investigator for an MRFF funded national genomics study called SUPER-NEXT employing clinical whole-genome sequencing and liquid biopsies for cancers of unknown primary.