Patatin‐Like Phospholipase Domain Containing 3 I 148 M Variant Affects Hepatocellular Carcinoma Recurrence After Liver Resection

BACKGROUND: Patatin-like phospholipase domain 3 (PNPLA3) I148M (rs738409 C>G) variant has been reported as a risk factor for metabolic dysfunction-associated steatotic liver disease/steatohepatitis and contributes to hepatic fibrosis and hepatocellular carcinoma (HCC); however, its role in recurrence after liver resection remains unclear. This study aimed to evaluate the effect of PNPLA3 variants on HCC recurrence after liver resection. METHODS: One hundred sixteen patients with non-viral HCC who underwent curative liver resection were retrospectively analysed. PNPLA3 rs738409 genotype was identified using blood-derived genomic DNA. Recurrence-free survival (RFS) was compared across genotypes, and multivariate analysis was performed to identify the independent risk factors for recurrence. Postoperative changes in fibrosis indexes over 2 years were also evaluated according to genotype. RESULTS: The number of patients in each PNPLA3 genotype group was as follows: CC (n = 20), CG (n = 55) and GG (n = 41). The CG/GG group showed significantly poorer RFS than the CC group, and multivariate analysis identified the PNPLA3 CG/GG genotype as an independent risk factor, especially for late recurrence. To better evaluate the effect on the remnant liver, patients with early recurrence were excluded from the study. In the CG/GG group, the fibrosis indices worsened over the 2 years following surgery, whereas they remained stable in the CC group. Among the patients with CG/GG, those with worsening fibrosis had a significantly higher rate of late recurrence. CONCLUSIONS: Patients with the PNPLA3 CG/GG genotype, especially those with progressive fibrosis, have a high risk of recurrence after liver resection. PNPLA3 genotyping may help identify patients at high risk of late recurrence who require careful long-term surveillance.