A GALNT14 Genotype Guided Therapeutic Strategy for Advanced Stage Hepatocellular Carcinoma

Abstract

BACKGROUND: Targeted agents are now the recommended first-line treatments for advanced hepatocellular carcinoma (aHCC) in western worlds. However, systemic chemotherapy or hepatic arterial infusion chemotherapy (HAIC) can achieve complete response in a substantial proportion of patients. We aimed to investigate whether a 3-single nucleotide polymorphism (SNP) signature (GALNT14-rs9679162-TT, WWOX-rs13338697-non-CT, and rs6025211-non-CT) could be used to guide our choice between chemotherapies and targeted agents. METHODS: The 3-SNP genotypes were determined and correlated with clinical outcomes in a cohort of 237 real-world aHCC patients with main portal vein thrombosis and/or distant metastasis (171 received systemic chemotherapy; 66 received HAIC). Cell-based experiments were performed to understand the mechanisms. FINDINGS: The 3-SNP signature alone or in combination with two clinical criteria (tumor diameter 10.5 months). Overexpression of GALNT14 in hepatoma cells reduced cellular FADD-like IL-1beta-converting enzyme-inhibitory protein (cFLIP) short form levels, resulting in increased drug sensitivity to cisplatin, mitoxantrone, doxorubicin, oxaliplatin and gemcitabine, but not 5-fluorouracil or sorafenib. INTERPRETATION: Pre-test for the 3-SNP signature in aHCC patients identified potential responders, who might benefit from systemic chemotherapy or HAIC. Systemic chemotherapy non-responders still benefited from subsequent sorafenib treatment. Accordingly, a therapeutic roadmap was proposed. Funding: This study was supported by a grant from Chang Gung Memorial Hospital, Linkou branch (CMRPG3F1602). Declaration of interests: All authors declare no conflicts of interest. Ethics Approval Statement: This study was conducted under approval of the Institutional Review Board, Chang Gung Memorial Hospital, Linkou, Taiwan.