Identification of CHI3L1 and MASP2 as a biomarker pair for liver cancer through integrative secretome and transcriptome analysis

Hepatocellular carcinoma (HCC) is the fifth most frequent neoplasm with more than 500000 new cases diagnosed yearly. Novel liver cancer biomarkers are needed. By tandem mass spectrometry we analyzed the secretomes of 12 individual paired samples of liver cancer and adjacent normal tissues and identified 1528 proteins with >2 unique peptide hits. The false discovery rate was 3.4%. Using spectral counting, we found 87 proteins in the HCC group and 86 proteins in the normal group that showed fivefold overexpression. These proteins provided a rich source of biomarker candidates. We presented a novel paradigm in combining biomarkers that include an up-regulated cancer biomarker and a down-regulated organ-enriched marker, and identified chitinase-3-like protein 1(CHI3L1) and mannan-binding lectin serine peptidase 2 (MASP2) as the top biomarker pair for HCC diagnosis using integrative transcriptomics and proteomics analysis. Using ELISA assays, we further evaluated this biomarker pair in a separate cohort of 25 serum samples of liver cancer patients and 15 age-matched normal controls. The combined marker pair (YKL40/MASP2 ratio) performed better than either marker alone with an AUC of 0.97 for liver cancer diagnosis. Further validation of the biomarker pair in HCC patients versus disease controls and independent cohorts is warranted.