CTNNB1 mutations, TERT polymorphism and CD8+ cell densities in resected hepatocellular carcinoma are associated with longer time to recurrence

Abstract

Background Hepatocellular carcinoma (HCC) is a fatal disease characterized by early genetic alterations in telomerase reverse transcriptase promoter (TERTp) and β-catenin (CTNNB1) genes and immune cell activation in the tumor microenvironment. As a novel approach, we wanted to assess patient survival influenced by combined presence of mutations and densities of CD8+ cytotoxic T cells. Methods Tissue samples were obtained from 67 HCC patients who had undergone resection. We analysed CD8+ T cells density, TERTp mutations, rs2853669 polymorphism, and CTNNB1 mutations. These variables were evaluated for time to recurrence (TTR) and disease free survival (DFS). Results TERTp mutations were found in 75.8% and CTNNB1 mutations in 35.6% of the patients. TERTp mutations were not associated with survival but polymorphism rs2853669 in TERTp was associated with improved TTR and DFS. CTNNB1 mutations were associated with improving TTR. High density of CD8+ T-lymphocytes in tumor center and invasive margin correlated with longer TTR and DFS. Combined genetic and immune factors further improved survival showing higher predictive values. E.g., combining CTNNB1 mutations and high density of CD8+ T-lymphocytes in tumor center yielded HRs of 0.12 (0.03–0.52), p = 0.005 for TTR and 0.25 (0.09–0.74), p = 0.01 for DFS. Conclusion The results outline a novel integrative approach for prognostication through combining independent predictive factors from genetic and immune cell profiles. However, larger studies are needed to explore multiple cell types in the tumor microenvironment.

Prognostic role and interaction of TERT promoter status, telomere length and MGMT promoter methylation in newly diagnosed IDH wild-type glioblastoma patients

“…The lack of association between the C variant and survival is unclear, but the heterogeneity of second-line therapies and re-surgery at relapse might likely have impacted on this correlation. Our association of the C variant of rs2853669 with a favorable patient outcome is in agreement with prognostic data from other cancer types 35 , 36 and likely depends on the destroying effect of the C allele on a pre-existing binding site for ETS transcription factors on TERT promoter, resulting in reduced TERT expression. 15 Nevertheless, even opposite results, with the C allele associated with a worse prognosis, have been reported.…”

Transcriptional data analysis reveals the association between infantile hemangiomas and venous malformations

“…In addition, CTNNB1 was also found to be closely related to a variety of tumor diseases such as liver cancer, gastrointestinal carcinoma and endometrial carcinoma (Ambrozkiewicz et al, 2022;Chao et al, 2022). Although few direct studies have shown the correlation between CTNNB1 and IH.…”

“…Recently, Duan X et al found that FOXC1A can regulate vascular integrity and brain vascular development through targeting CTNNB1 ( Duan et al, 2022 ). In addition, CTNNB1 was also found to be closely related to a variety of tumor diseases such as liver cancer, gastrointestinal carcinoma and endometrial carcinoma ( Ambrozkiewicz et al, 2022 ; Chao et al, 2022 ). Although few direct studies have shown the correlation between CTNNB1 and IH.…”

Circulating Tumor DNA Profiling in Liver Transplant for Hepatocellular Carcinoma, Cholangiocarcinoma, and Colorectal Liver Metastases: A Programmatic Proof of Concept

“…In addition to assessing for the presence of ctDNA, liquid biopsy can identify specific genes that predict patient outcomes based on cancer. For example, in HCC, CTNNB1 and TERT have been shown to be two of the most commonly mutated genes and were present frequently in our cohort [ 33 ]. The presence of these two mutations, along with a mutation in TP53 , in post-operative ctDNA has been associated with a decreased recurrence-free survival [ 30 ].…”