GALNT14 Genetic Variants Harbor Differential Prognostic Values Linking to Distinct Macrophage Cell Types in Hepatocellular Carcinoma

Yu-De Chu,1,* Pei-Huan Ho,1,2,* Wei-Ting Chen,1,2,* Yu-Lin Shih,1 Ming-Wei Lai,2,3 Chao-Wei Hsu,1,2 Chau-Ting Yeh1,2,4 1Liver Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan; 2Department of Hepatology and Gastroenterology, Linkou Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan; 3Division of Pediatric Gastroenterology, Department of Pediatrics, Linkou Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan; 4Institute of Stem Cell and Translational Cancer Research, Linkou Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan*These authors contributed equally to this workCorrespondence: Chau-Ting Yeh, Liver Research Center, Linkou Chang Gung Memorial Hospital, No. 5, Fu-Shin Street, Guei-Shan District, Taoyuan, 333, Taiwan, Tel +886-3-3281200 ext.8102, Fax +886-3-3282824, Email [email protected] Chao-Wei Hsu, Liver Research Center, Linkou Chang Gung Memorial Hospital, No. 5, Fu-Shin Street, Guei-Shan District, Taoyuan, 333, Taiwan, Tel +886-3-3281200 ext.8102, Fax +886-3-3282824, Email [email protected]: Surgical resection is the primary curative treatment for hepatocellular carcinoma (HCC), while high recurrence rates can limit the prognosis, emphasizing the need for reliable biomarkers. GALNT14-rs9679162 is associated with postoperative prognosis and therapeutic responses. However, relying on one single nucleotide polymorphism (SNP) greatly limits its predictive power. This study aims to identify an SNP panel to improve prognosis prediction and explore its role in modulating tumor-infiltrating immune cells (TIICs).Patients and Methods: We included 345 HCC patients underwent surgical resection: 15 in the exploration cohort and 330 in the validation cohort. Genome-wide association study (GWAS) and PCR-based genotyping identified SNPs in linkage disequilibrium (LD) with rs9679162. The link between GALNT14 expression and TIICs was analyzed. Prognostic evaluation was performed using Kaplan-Meier survival analysis and Cox proportional hazards models, with statistical significance set at P < 0.05.Results: GWAS identified 39 SNP loci linked to rs9679162 and associated with postoperative prognosis. In the validation cohort, 10 SNPs were selected and categorized into four groups. Eight SNPs showed strong LD with rs9679162 and were significantly associated with recurrence-free survival and metastasis-free survival. The predictive performance of the combined SNP groups surpassed that of rs9679162 alone, with the most effective stratification achieved by combining groups-2+3. Additionally, GALNT14 expression, linked to the identified genotypes, correlated with M2-macrophage abundance within TIICs.Conclusion: An SNP panel in LD with rs9679162, particularly from group-2 (rs62140629, rs4952033, rs56284247) and group-3 (rs9679162, rs6752303), serves as a prognostic marker for HCC. GALNT14 expression was associated with M2-macrophages, suggesting an immune-regulatory mechanism.Keywords: hepatocellular carcinoma, genetic biomarker, SNP panel, personalized medicine, tumor-infiltrating macrophage