Tothill Laboratory: Rare Disease Oncogenomics (RADIO)

The Rare Disease Oncogenomics (RADIO) laboratory is dedicated to translational research of rare and less common cancers. Our research encompasses neuroendocrine tumours (NET), including tumours of sympathetic tissues (pheochromocytoma and parganglioma) and skin (Merkel cell carcinoma), as well as cancers of unknown primary (CUP). We use advanced molecular methods to survey the genomic landscape of cancer cells and their tumour “microenvironment” to better understand the underlying biology of these rare diseases, develop diagnostic and prognostic tests for the clinic, and to find new therapeutic targets for better and more precise cancer treatment.


A5 SDHB Genomics Study

Pheochromocytoma (from Greek, meaning dusky-coloured tumour) and paraganglioma (PPGL) are two related tumour types. They originate from the sympathetic and parasympathetic tissues found in the adrenal glands, near the spine or within other abdominal organs. PPGL is one of the most heritable neoplasms with approximately 30-40 per cent of patients carrying disease-causing mutations in one of more than 15 predisposing genes. Approximately 10-20 per cent of PPGL patients develop metastatic disease, where the cancer cells spread to other parts of the body. There are currently limited treatment options for metastatic PPGL. Furthermore, there are currently no recognised tests that can predict who may be at higher risk. Patients carrying mutations in the gene SDHB  (a gene change that is transmitted between generations)  are known to be more likely to develop metastases, although the exact reason why only some tumours become aggressive and metastasise is unknown. We are using genomics to understand the pathogenesis of metastatic PPGL in SDHB carriers, identify biomarkers of metastatic risk to inform optimal surveillance and find new therapeutic targets for patient treatment.

Key Sponsors
National Health and Medical Research Council (NHMRC)
Pheo-Para Alliance, USA
Paradifference, Sweden

Key Collaborations
Peter MacCallum Cancer Centre, Melbourne (Prof Rod Hicks)
Kolling Institute and Royal North Shore Hospital, Sydney (Prof Rory Clifton-Bligh, Prof Anthony Gill)
National Institute of Health, Bethesda, USA (Prof Karel Pacak)
American Australian Asian Adrenal Alliance (A5) (USA, Australia, New Zealand, Canada, Singapore)

Understanding the biology of Merkel cell carcinoma

Merkel cell carcinoma (MCC) is a highly aggressive and often fatal neuroendocrine skin cancer linked to viral infection and excessive sun exposure. We aim to better understand the biology of this disease in order to develop better treatments- especially viral-negative MCC, which is more common in Australia than in the US and Europe.  While immunotherapy has shown great promise in early clinical trials for the treatment of MCC, it is not effective in many patients. We want to understand why only some tumours respond to immunotherapy and whether this is linked to the genomics of the tumour or the immune response of the individual.

Key Collaborations
Peter MacCallum Cancer Centre, (Prof Rod Hicks, Dr Shahneen Sandhu, A/Prof Paul Neeson, Skin and Melanoma Unit)
University Hospital Essen/West German Cancer Centre/ German Cancer Consortium (DKTK) (Prof J├╝rgen Becker)
Melanoma Institute Australia, Sydney (Prof Richard Scolyer)
Royal North Shore Hospital, Sydney (Prof Anthony Gill)
Peter Doherty Institute (Prof Dale Godfrey)
ANZMTG (Australasian Merkel Interest Group, AMIGOs)(Sydney, Brisbane Adelaide, Melbourne)

Developing clinical genomic methods for cancer of unknown primary

Cancer of Unknown Primary (CUP) is a confirmed metastatic cancer for which standard diagnostic tools fail to identify a primary tumour tissue of origin (ToO). CUP has a notoriously poor prognosis with a mean survival of only 11 months from first diagnosis. CUP significantly challenges the current  model for patient care because identifying a ToO remains the universal starting point for cancer treatment. We are developing faster and more precise methods that can assist identifying the primary tumour in CUP and are engaged with a clinical study (Solving Unknown Primary CancER, SUPER) evaluating clinical genomics to identify ToO and the therapeutic vulnerabilities of CUP tumours.

Key Collaborations
Peter MacCallum Cancer Centre (Dr Linda Mileshkin, Prof David Bowtell, Dr Penny Schofield)
Australian SUPER study group (Victoria, NSW, NT, SA)

Key Sponsors
National Health and Medical Research Council (NHMRC)
Victorian Cancer Agency
Cancer Australia


See complete list of Richard Tothill’s publications.

  1. Dwight, T., Flynn, A., Amarasinghe, K., Benn, D.E. Lupat, R., Li, J.,…Tothill, R.W (2018). TERT Structural rearrangements in metastatic pheochromocytomas. Endocrine-Related Cancer. 25(1):1-9.
  2. Lefebure M*, Tothill RW*,…, Johnstone RW (2017). Genomic characterisation of Eµ-Myc mouse lymphomas identifies Bcor as a Myc co-operative tumour-suppressor gene. Nature Communications. Mar;8:14581 * contributed equally.

  3. Flynn,A, Dwight, T, Benn, D, Deb, S, Colebatch, AJ, Fox, S… Tothill, R.W (2017) Cousins not twins: intra and inter-tumoral heterogeneity in syndromic neuroendocrine tumours. Journal of Pathology. 242(3):273-283

  4. Flynn A, Dwight T, Harris J, Benn D, Zhou L, Hogg A, Catchpoole, D, … Tothill, RW (2016) Pheo-type: a diagnostic gene-expression assay for the classification of pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 101(3): 1034-43
  5. Moran S,…Tothill, R….et al. Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis. Lancet Oncol 17, 1386-1395 (2016).
  6. Wong SQ, Waldeck K, Vergara IA, Schroder J, Madore J, Wilmott JS, …Tothill, RW (2015). UV-Associated Mutations Underlie the Etiology of MCV-Negative Merkel Cell Carcinomas. Cancer Research 75(24):5228-34

  7. Flynn, A., Benn, D., Clifton-Bligh, R., Robinson, B., Trainer, A. H., James, P., … Tothill, R. W (2015). The genomic landscape of phaeochromocytoma. Journal of Pathology. 236(1): 78–89

  8. Tothill, RW, Shi, F, Paiman, L, Bedo, J, Kowalczyk, A, Mileshkin, L, et al (2015) Development and Validation of a Gene Expression Tumour Classifier for Cancer of Unknown Primary. Pathology 47(1): 7-12
  9. Tothill, R.W., Li, J., Mileshkin, L., Doig, K., Siganakis, T., Cowin, P., et al (2013) Massively-parallel sequencing assists the diagnosis and guided treatment of cancers of unknown primary. Journal of Pathology. 231(4): 413-23.

  10. Tothill R, Estall V, Rischin D. Merkel cell carcinoma: emerging biology, current approaches, and future directions. (2015) Am Soc Clin Oncol Educ Book; 35:e519–26.
  11. Meldrum, C., Doyle,M.A. and Tothill, R.W. (2011) Next-Generation Sequencing for Cancer Diagnostics: a Practical Perspective. Clinical Biochemist Reviews 32: 177-95