Affiliations: [a] Liver Research Unit, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan | [b] Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan | [c] College of Medicine, Chang Gung University, Taoyuan, Taiwan | [d] Community Medicine Research Center, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
Correspondence:
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Corresponding authors: Yu-De Chu and Chau-Ting Yeh, Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan. Tel.: +886 3 3281200 ext 7773; E-mail: [email protected]@cgmh.org.tw.
Abstract: BACKGROUND: Sorafenib and lenvatinib are tyrosine kinase inhibitors widely used in the targeted therapy to treat advanced hepatocellular carcinoma (aHCC). The GALNT14-rs9679162 genotype is a predictor of therapeutic outcome in multiple gastrointestinal cancers. OBJECTIVE: To investigate the predictive role of the GALNT14-rs9679162 genotype in aHCC treated with sorafenib or lenvatinib. METHODS: Totally 350 real-world patients with aHCC received sorafenib or lenvatinib were enrolled for GALNT14-rs9679162 genotyping and outcome analysis. Kaplan-Meier and Cox regression analysis were conducted to evaluate therapeutic outcomes. Cell-based assays were performed to determine the underlying mechanism. RESULTS: Kaplan-Meier and Cox regression analysis showed that the “GG” genotype was not associated with overall survival (OS) when all patients were included. However, it was associated with shorter OS in specific clinical subgroups, including anti-hepatitis C virus antibody-positive (n= 108; P= 0.005) and hepatitis B surface antigen-negative (n= 117; P= 0.002) patients. Intriguingly, hepatitis B virus X protein trans-suppressed the GALNT14 promoter, thereby reducing the elevated expression of GALNT14 in hepatoma cells, which partially contributed to the inability of the GALNT14-rs9679162 genotypes to predict the outcome of hepatitis B-related HCC. Finally, by analyzing the outcomes of 52 patients with aHCC treated with lenvatinib, patients with the “GG” genotype were associated with a favorable/shorter time-to-response (P= 0.013). CONCLUSIONS: The GALNT14-rs9679162 “GG” genotype predicted shorter OS in patients with HBsAg-negative aHCC treated with sorafenib, but predicted a favorable response in all patients with aHCC treated with lenvatinib.
Keywords: Single nucleotide polymorphism, Rs9679162 genotype, advanced hepatocellular carcinoma (HCC), genetic biomarker and overall survival
