Multi-omic analysis reveals new insights into rare adrenal cancers

The research was led by Associate Professor Richard Tothill of the Rare Disease Oncogenomics lab at the Collaborative Centre for Genomic Cancer Medicine, a joint venture of the University of Melbourne and Peter MacCallum Cancer Centre.

The international collaboration is the largest study of its kind on these adrenal cancers, combining genomics and multi-omic profiling to uncover features linked to metastatic disease progression and treatment response.

PC and PG are rare inherited disorders characterised by tumours affecting hormone-producing neuroendocrine cells throughout the body. While typically slow-growing, metastases develop in 10 to 20 per cent of patients, for which there are currently no reliable predictive biomarkers and no curative treatments available.

"These tumours can cause excessive hormone production leading to severe cardiovascular complications and even death if left untreated," said Associate Professor Tothill.

"Understanding what drives their metastatic behaviour is also critical for improving patient monitoring and care."

The study focused on hereditary SDHB-mutant PC and PG, which have a higher susceptibility for metastasis, yet not in all patients. By performing multi-omic analysis of 94 tumours from 79 patients using seven molecular profiling techniques, the researchers confirmed metastatic SDHB-mutant PCPG tumours are genomically distinct. They also showed the tumours could have different molecular profiles based on where they arose from in the body.

Dr Aidan Flynn, first author on the study and post-doctoral scientist in the Rare Disease Oncogenomics lab, said their analysis shed light on TERT and ATRX mutations as the most common metastasis-associated events, though these may not necessarily be predictive of early metastatic risk.

"While enriched in metastatic cases, the late timing of TERT/ATRX alterations may limit their utility as reliable predictive biomarkers in primary tumours," said Dr Flynn.

The researchers also uncovered evidence of potential treatment resistance, with some tumours acquiring mutations causing DNA repair deficiency resulting in hypermutation and a distinct mutation pattern.

Interestingly, the treatment-resistance mutation pattern was detected in cell-free DNA isolated from patient blood, again highlighting the potential of liquid biopsy in monitoring chemotherapy resistance. This aspect of the study was led by Dr Emma Boehm, PhD student in the Rare Disease Oncogenomics lab and endocrinologist at Peter Mac.

"We believe there may be potential for using liquid biopsies to detect these mutations via circulating tumour DNA, avoiding invasive tissue biopsies that can be an unsafe in PC and PG patients owing to sudden release of hormones from tumour cells." said Dr Boehm.

Through this multi-omic resource, the study has provided valuable new insights into the molecular landscapes and clinical behaviours of these aggressive cancers.

"While more research is still needed, our findings represent an important step towards improving metastatic risk prediction, biomarker development, and tailored therapeutic strategies for patients with inherited SDHB-mutant pheochromocytomas and paragangliomas," said Associate Professor Tothill.

Samples for the study were provided through a collaboration with the Peter MacCallum Cancer Centre’s Neuroendocrine Tumour Centre of Excellence—accredited to the European Neuroendocrine Tumor Society (ENETS)—led by Professor Michael Michael and Associate Professor Grace Kong. One of only two in the southern hemisphere, the specialised centre is accredited for its high standards in diagnosing and treating neuroendocrine tumours like PC and PG. They lead an extensive clinical and lab-based program which is guiding new therapies for this group of rare diseases.  Associate Professor Tothill’s Rare Disease Oncogenomics lab is a translational lab for the centre.

In addition to the Peter MacCallum Cancer Centre, the study received contributions from numerous national and international partners, including the Kolling Institute in Sydney, NIH (Bethesda, USA), and various centers within the A5 (American-Australian-Asian) Adrenal Alliance across Australia, USA, Canada, New Zealand, Singapore, and Sweden. Generous financial support was provided by the Pheo-Para Alliance (USA), SDHB Coalition (USA), Paradifference Foundation (Sweden), and the NHMRC.