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A feasibility study by Professor James McCullagh shows promise for biomarker discovery using a combination of circulating tumour DNA sequencing and metabolomic analysis.

In this paper published in the journal Cancers, Professor James McCullagh (Department of Chemistry) and colleagues investigate combining genetic and metabolic analysis to identify novel markers in blood plasma in the context of intrahepatic cholangiocarcinoma (ICC; bile duct cancer).

ICC is a rare but deadly cancer and most patients are diagnosed when the disease is at a late-stage, when the median survival is less than a year. Previous analysis has identified several DNA mutations, rearrangements and copy number variations in ICC. Of particular interest is a mutation of the enzyme isocitrate dehydrogenase (IDH) in 5-25% ICC cases, which leads to the production of the metabolite 2-hydroxyglutarate (2-HG). This increase in 2-HG affects a number of cellular processes involved in cancer initiation, which has led to 2-HG being labelled as an ‘oncometabolite’. Since IDH is a potential target for treatment in ICC and a number of other cancers, identification of IDH mutations and 2-HG can not only help to detect the presence of cancer but may also be able to direct treatment selection.

This proof-of-principle study used genomic and untargeted metabolomic analysis of plasma samples from ICC and healthy patients. ICC patients had altered metabolic profiles and the researchers were able to detect an IDH mutation in one of the four patients with ICC, in accordance with the known mutation incidence rate. Importantly, this patient also had a corresponding increase in 2-HG. These promising observations now need to be validated using a larger cohort study.