Discovery of Biomarkers for Tasmanian Devil Cancer (DFTD) by Metabolic Profiling of Serum

Abstract

Devil facial tumor disease (DFTD) is a transmissible cancer threatening Tasmanian devils (Sarcophilus harrisii) with extinction. There is no preclinical test available for DFTD, and thus our aim was to find biomarkers for DFTD by metabolic fingerprinting. Seventy serum samples from wild Tasmanian devils (35 controls, 35 with tumors) were analyzed by liquid chromatography-high-resolution mass spectrometry. Features were selected by multivariate models (PLS/DA, random forests) comparing age-matched training set (n = 20 × 2) and further complying with fold-change threshold (≥1.4) and Mann-Whitney U-tests with correction for multiple hypotheses (false discovery rate (FDR) q < 0.05). An array of overlapping peptide segments of the N-terminal end of fibrinogen were the strongest positive DFTD markers. These peptides recorded fold-change up to 90, FDR-corrected p value below 0.01, and area under ROC curve of at least 0.80 and also correlated with tumor size (Spearman R > 0.45, p < 0.01). Additional potential markers included amino acid and lipid metabolites, while cortisol and urea were the most significant health predictors (AUC ≥ 0.90). PLS/DA resulted in AUC = 0.997 for the training set and overall sensitivity of 91% and specificity of 97%. A support vector machine model utilizing only the major peptide marker and seven other metabolites led to overall 94% sensitivity and specificity. The novel findings in this first DFTD metabolomics study shed light on metabolic changes in Tasmanian devils affected by DFTD and provide a valuable step toward the development of prognostic biomarkers.

MHC diversity and female age underpin reproductive success in an Australian icon; the Tasmanian Devil

“…This devastating disease is spread among devils via biting during social interactions 35 . The devil’s immune system is unable to mount an effective immune response to the tumour as DFTD cells are able to avoid immune recognition by down-regulating MHC expression 36 , 37 . Metabolic failure, tumour related cachexia and metastases result in devil death within 6 to 9 months of the emergence of the first lesions 38 .…”

Cathelicidin-3 Associated With Serum Extracellular Vesicles Enables Early Diagnosis of a Transmissible Cancer

“…In an effort to identify DFTD serum biomarkers that could potentially serve to predict preclinical stages, Karu et al. ( 24 ) demonstrated that a panel of fibrinogen peptides and seven metabolites could differentiate devils with overt DFTD from healthy controls with high sensitivity and specificity. Another study found elevated levels of the receptor tyrosine-protein kinase ERBB3 in the serum of devils infected with DFTD compared to healthy controls ( 25 ).…”

Cathelicidin-3 associated with serum extracellular vesicles enables early diagnosis of a transmissible cancer

“…McCallum et al (McCallum et al, 2009) suggested that the disease is unlikely to spread between individuals prior to the development of clinical signs, however this assumption has not been validated due to the lack of a preclinical test. In an effort to identify DFTD serum biomarkers that could potentially serve to predict preclinical stages, Kau et al (Karu et al, 2016) demonstrated that a panel of fibrinogen peptides and seven metabolites could differentiate devils with overt DFTD from healthy controls with high sensitivity and specificity. Another study found elevated levels of the receptor tyrosine-protein kinase ERBB3 in the serum of devils infected with DFTD compared to healthy controls (Hayes et al, 2017).…”