Diagnostic and prognostic potential of tissue phospholipidomics in hepatocellular carcinoma: A prospective cohort study

Abstract Background: Previous studies have indicated that hepatocellular carcinoma (HCC) is linked to abnormal phospholipid (PL) metabolism. However, whether alterations of phospholipids in hepatic tissues contribute to the diagnosis and prognosis of HCC remains unclear. Methods: A quantitative and comprehensive phospholipidomic analysis was conducted using hydrophilic liquid chromatography-electrospray ionization-triquadrupole-mass spectrometry (HILIC-ESI-MS/MS). This analysis facilitated the comparison of 214 distinct PLs between paired samples from HCC tissues and tumor-adjacent normal hepatic tissues (NATs) in a prospective cohort (n=87). Differential metabolites were identified through paired t tests and orthogonal partial least-squares discriminant analysis (OPLS-DA). The survival analysis of phospholipids for HCC was assessed using univariate and multivariable Cox regression models. Results: Significant differences were found between HCC and NAT for phospholipid profile, and 85 phospholipids demonstrated a high accuracy in discerning two types of tissue. The increased HCC/ NAT ratio of lysophosphatidylglycerol (LPG) class was associated with greater HCC specific mortality (Hazard ratio (HR) = 6.50, 95% confidence interval (CI): 1.88-22.51,P = 0.002), and the association was still significant (HR = 4.82, 95% CI: 1.34-17.29, P = 0.017) even after adjustment covariances. LPG (18:1) and LPG (18:2) differentiated HCC from NAT with great capacities (the area under the curve (AUC)>0.75) and had prognostic significance for HCC specific mortality before (HR = 5.17 and 5.51, respectively, both ofP < 0.01) and after adjustment (HR = 4.14 and 4.15, respectively, both of P < 0.05). Conclusions: Phospholipids could serve as potential biomarkers with significant diagnostic and prognostic implications. A more profound understanding of cancer-associated phospholipid metabolism could pave the way for innovative therapeutic strategies.