The Value Of TSC2 Mutations In Predicting The Early Recurrence Of Hepatocellular Carcinoma Patients Underwent Hepatectomy

Purpose:Hepatocellular carcinoma(HCC)is one of the most common cancers,and its incidence is increasing year by year.The main surgical treatments for HCC patients include liver resection,liver transplantation and ablation.However,the risk of recurrence after surgical treatment is high.Therefore,it is of great significance to explore biomarkers that can predict postoperative recurrence,which will help us identify the population at high risk of postoperative recurrence,timely monitor changes in the disease and conduct early intervention.With the development of next-generation gene sequencing(NGS)technology,the detection of cancer-related gene mutations has gradually become popular.This study used next-generation sequencing to detect cancer-related gene mutations in tumor tissues of 183 patients with HCC who underwent hepatectomy,and explored 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 who were treated by hepatectomy at the Affiliated Hospital of Qingdao University from March 2017 to February 2020 were enrolled in this study and corresponding formalin-fixed tissues were collected from patients for next generation sequencing(NGS).Next generation sequencing was performed on tumor tissues to analyze genomic alterations,tumor mutational burden(TMB)and variant allele fraction(VAF).The information of enrolled patients were collected,including serological and pathological rusults and follow-up results.The correlation between TSC2 mutation and clinicopathological characteristics and rate of recurrence within 1 year after hepatectomy of patients were analyzed by X~2 test or Fisher’s exact test,and variables with p<0.05 were further analyzed by logistic regression model.We also explored the relationship of clinicopathological characteristics and VAF of TSC2 mutation.In survival analysis,Kaplan-Meier curves were performed to discuss the correlation between TSC2 mutations and RFS and OS.We analyzed the relationship between gene mutations,clinicopathological characteristics and RFS and OS by univarate Cox regression model,and variables with p<0.05 were subjected to the multivariate Cox regression analysis.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 gradeⅢ-Ⅳwas significantly higher in patients with a TSC2mutation(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).In patients with a TSC2 mutation,the frequency of TP53 mutation was higher than patients without TSC2mutation(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 didn’t significantly affect overall survival of patients(p=0.480).The multivariate analysis results showed that the Barcelona Clinic Liver Cancer(BCLC)B-C stage,TSC2mutations 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 gradeⅢ-Ⅳin 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.