Purpose: To explore the value of Tuberous sclerosis complex 2 (TSC2 ) mutations in evaluating the early recurrence of hepatocellular carcinoma (HCC) patients underwent hepatectomy.
Patients and Methods: A total of 183 HCC patients were enrolled. Next-generation sequencing was performed on tumor tissues to analyze genomic alterations, tumor mutational burden and variant allele fraction (VAF). The associations between TSC2  mutations and recurrence rate within 1 year, RFS and OS after hepatectomy were analyzed.
Results: Our results showed that TSC2  mutation frequency in HCC was 12.6%. Compared to patients without TSC2  mutation, the proportion of microvascular invasion (MVI) and Edmondson grade III–IV was significantly higher in patients with a TSC2  mutation (p< 0.05). The VAF of mutated TSC2  was higher in patients with maximum diameter of tumor > 5cm or MVI than that of other patients (p< 0.05). The frequency of TP53  mutation was significantly higher in patients with a TSC2  mutation than those without TSC2  mutation (p=0.003). Follow-up analysis showed that patients with a TSC2  mutation had significantly higher recurrence rate within 1 year (p =0.015) and poorer median recurrence-free survival (RFS) (p =0.010) than patients without TSC2  mutation. TSC2 mutations did not significantly affect overall survival of patients (p =0.480). The multivariate analysis results showed that the Barcelona Clinic Liver Cancer (BCLC) B-C stage, TSC2  mutations and preoperative serum alpha-fetoprotein level ≥ 400μg/L were independently associated with recurrence within 1 year after hepatectomy (HR=8.628, 95% CI: 3.836– 19.405, p =0.000; HR=3.885, 95% CI: 1.295– 11.653, p =0.015; HR=2.327, 95% CI: 1.018– 5.323, p =0.045; respectively), and poorer RFS after hepatectomy (HR=3.070, 95% CI: 1.971– 4.783, p =0.000; HR=1.861, 95% CI: 1.061– 3.267, p =0.030; HR=1.715, 95% CI: 1.093– 2.693, p =0.019; respectively).
Conclusion: TSC2  mutations were significantly associated with MVI in liver para-carcinoma tissue and Edmondson grade III–IV in patients with HCC and were independently associated with recurrence within 1 year and poorer RFS after hepatectomy. The TSC2 mutation may be a potential predictor for early recurrence in HCC patients underwent hepatectomy.
Keywords: hepatocellular carcinoma, tuberous sclerosis complex 2, next-generation sequencing, gene mutation, early recurrence