A novel panel based on Immune infiltration and tumor mutational burden for prognostic prediction in hepatocellular carcinoma

Abstract

Background : Tumor mutation burden (TMB) was associated with prognosis in various malignancies, but it remains to be elucidated in hepatocellular carcinoma (HCC). We aimed to investigate the prognostic effects of TMB and its relationship with immune infiltration so as to establish a panel model capable of predicting prognosis. Methods : TMB was calculated in all 374 HCC patients from the Cancer Genome Atlas, and high TMB and low TMB groups were determined based on propensity score matching and X-tile analysis. WCGNA was utilized to screen out genes related to immune cells and TMB, followed by multivariate analysis to generated the final TMB-Infiltration (TMB-IF) panel. 453 HCC patients from ICGC-LIRI-JP, GSE76427 and GSE20017 verified the robustness and extensibility of TMB-IF. Additionally, whole-exome sequencing (WES) was performed in 8 follow-up patients to investigate the relationship between HCC recurrence and TMB. Results : Patients in high TMB group had worse prognosis than those in low TMB group, with a cutoff TMB value of 4.9. Enrichment analysis demonstrated that differentially expressed genes were mainly related to T cell activation, cell membrane localization and matrix composition. Tumor immune infiltration analysis revealed the infiltrations of Th2, Th17, and Tgd were up-regulated in high TMB group, while those of Tr1, MAIT, and DC were up-regulated in low TMB group. And TMB-IF fit well with the actual survival observation, with a C-index 0.785 (0.700-0.870), which verified in ICGC-LIRI-JP was 0.670 (0.573-0.767), and 0.774 (0.670-0.877) in GSE76427. In addition, TMB-IF showed a good performance in predicting tumor vascular invasion with a C-index of 0.847 (0.778-0.916). Conclusions : Higher TMB means worse prognosis in HCC patients. Patients with higher frequency of immune-related gene mutations and TMB are prone to relapse after radical treatment.