CTNNB1 Alternation Is a Potential Biomarker for Immunotherapy Prognosis in Patients With Hepatocellular Carcinoma

Abstract

BackgroundThe emergence of immune checkpoint inhibitors (ICIs) marks the beginning of a new era of immunotherapy for hepatocellular carcinoma (HCC), however, not all patients respond successfully to this treatment. A major challenge for HCC immunotherapy is the development of ways to screen for those patients that would benefit from this type of treatment and determine the optimal treatment plan for individual patients. Therefore, it is important to find a biomarker which allows for the stratification of HCC patients, which distinguishes responders from non-responders, thereby further improving the clinical benefits for those undergoing immunotherapy.MethodsWe used univariate and multivariate Cox risk proportional regression models to evaluate the relationship between non-synonymous mutations with a mutation frequency greater than 10%. We made a prognosis of an immunotherapy HCC cohort using mutation and prognosis data. An additional three HCC queues from the cbioportal webtool were used for further verification. The CIBERSORT, IPS, quanTIseq, and MCPcounter algorithms were used to evaluate the immune cells. PCA and z-score algorithm were used to calculate immune-related signature with published gene sets. Gene set enrichment analysis (GSEA) was used to compare the differences in the pathway-based enrichment scores of candidate genes between mutant and wild types.ResultsUnivariate and multivariate Cox results showed that only CTNNB1-Mutant(CTNNB1-MUT) was associated with progression-free survival (PFS) of HCC patients in the immunotherapy cohort. After excluding the potential bias introduced by other clinical features, it was found that CTNNB1-MUT served as an independent predictor of the prognosis of HCC patients after immunotherapy (P < 0.05; HR > 1). The results of the tumor immune microenvironment (TIME) analysis showed that patients with CTNNB1-MUT had significantly reduced activated immune cells [such as T cells, B cells, M1-type macrophages, and dendritic cells (DCs)], significantly increased M2-type macrophages, a significantly decreased expression of immunostimulating molecules, low activity of the immune activation pathways (cytokine pathway, immune cell activation and recruitment) and highly active immune depletion pathways (fatty acid metabolism, cholesterol metabolism, and Wnt pathway).ConclusionsIn this study, we found CTNNB1-MUT to be a potential biomarker for HCC immunotherapy patients, because it identified those patients are less likely to benefit from ICIs.

Integrative molecular profiling identifies two molecularly and clinically distinct subtypes of blastic plasmacytoid dendritic cell neoplasm

“…First, we observed a significant enrichment of mutations affecting ARID1A, ATRX , and CTNNB1 in MSI high cases, which is in keeping with previous reports in colorectal, gastric and endometroid cancer and others 46-48 . ARID1A poses a prominent interaction partner of mismatch repair (MMR) protein MSH2, while ATRX mutations were previously found to be a sex-biased predictor of MSI-status across a variety of solid tumors and CTNNB1 was recurrently implicated in the pathogenesis of an especially unfavorable subset of endometroid tumors and in immune checkpoint inhibitor resistance 47,49,50 ( Figure 2A ).…”

Therapeutic efficacy of atezolizumab plus bevacizumab for hepatocellular carcinoma with WNT/β‑catenin signal activation

“…Approximately 40% of HCC cases were reported to show constitutive activation of WNT/β-catenin signaling induced by relevant gene mutations ( 8 , 9 ). Constitutive WNT/β-catenin activation had negative effects on the DCR and PFS of patients receiving anti-programmed cell death 1 antibody therapy ( 10 – 12 ). Briefly, these studies indicated that WNT/β-catenin may be a biomarker for the response of patients with HCC to ICIs.…”

“…Approximately 40% of HCC cases harbor mutations of WNT/β-catenin that result in the immune microenvironment lacking immune cell filtration, so-called ‘immune exclusion’ or ‘non-inflamed cold’ in HCC ( 8 , 9 ). Furthermore, HCC with immune exclusion associated with WNT/β-catenin signal activation is resistant to ICIs ( 10 – 12 ). Therefore, it is important to identify the subclass of immune condition in HCC induced by WNT/β-catenin signal activation prior to chemotherapy.…”

A Risk Model Based on Sorafenib-Response Target Genes Predicts the Prognosis of Patients with HCC

“…The MCPcounter and CIBERSORT algorithms were separately applied to TCGA gene-expression data obtained from patients with HCC in order to calculate immune cell levels [ 20 ]. The TCGA HCC risk-model score was merged with patient immune cell data.…”