Developing clinical genomic methods for cancer of unknown primary

Project Details

Cancer of Unknown Primary (CUP) is a metastatic cancer where the primary tumour tissue of origin (ToO) remains unknown despite extensive diagnostic investigation. As ToO remains the universal starting point for cancer treatment, CUP significantly challenges the current paradigm for patient care. Survival outcome for patients with CUP is notoriously poor with a mean survival of only 11 months and it is the sixth most common cause of death in Australia. Better diagnostic methods and treatment options are therefore desperately needed in this patient group.

We are developing more precise methods that can assist identifying the primary tumour in CUP. Genomic technologies, including next-generation DNA and RNA sequencing, are being used to deeply profile individual patient samples in the clinical setting. The genomics data is being used to identify the primary tissue type by matching the molecular portrait of individual CUP tumours to hundreds of tumours of known origin.

Furthermore, detection of mutations in specific genes is being used to guide precision treatment using drugs designed to target mutated genes and their cellular pathways. Analysis of mutation burden, detection of oncogenic viruses as well as enumerating immune cells in CUP tumours can also provide evidence that immunotherapies may be effective in some patients.

Finally, we are establishing patient-derived organoids from CUP tumours as a way to rapidly grow cells in the lab. Our goal is to use these cells to determine drug response in the lab before treating individual patients in the clinic.

Underpinning our work on CUP is a national clinical study called SUPER (Solving Unknown Primary CancER). SUPER is designed to assess the value of new genomic methods for diagnosis and predicting treatment response in CUP as well develop optimal care pathways and understand the specific psychosocial needs of this patient group.


Dr Richard Tothill – Group Leader
Ms Atara Posner – PhD Student


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


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

Research Publications

  1. Moran S,…Tothill, R….et al. (2016) Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis. Lancet Oncol 17, 1386-1395
  2. 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
  3. Tothill, RW, 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.
  4. 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
  5. Tothill, RW, Kowalcyzk, A, Rischin, D, Boussioutas, A, Haviv, I,  van Laar, R, et al An expression-based site of origin diagnostic method designed for clinical application to cancer of unknown origin. Cancer Research. 2005. 65(10): 4031-40.

Research Group

Rare Disease Oncogenomics

Faculty Research Themes


School Research Themes

Cancer in Medicine

Key Contact

For further information about this research, please contact the research group leader.

Department / Centre

Clinical Pathology

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