Chemical Biopsy for GNMT as Noninvasive and Tumorigenesis-Relevant Diagnosis of Liver Cancer

Early diagnosis of hepatocellular carcinoma (HCC) is difficult; the lack of convenient biomarker-based diagnostic modalities renders high-risk HCC patients burdened by life-long periodical examinations. Here, a new chemical biopsy approach was developed for noninvasive diagnosis of HCC using urine samples. Bioinformatic screening for tumor suppressors yielded glycine N-methyltransferase (GNMT) as a biomarker with clinical relevance to HCC tumorigenesis. A liquid chromatography–mass spectrometry (LC-MS)-based chemical biopsy detecting nonradioactive 13C-sarcosine from 13C-glycine was designed to noninvasively assess liver GNMT activity extrahepatically. 13C-Sarcosine showed a strong correlation with GNMT in normal and cancerous liver cells. In an autochthonous animal model developing visible cancer nodules at 17 weeks, the urinary 13C-sarcosine chemical biopsy exhibited notable changes as early as 8 weeks, showing significant correlations with liver GNMT and molecular pathological changes. Our chemical biopsy approach should facilitate early and noninvasive diagnosis of HCC, with direct relevance to tumorigenesis, which can be straightforwardly applied to other diseases.