Development of mutated β-catenin gene signature to identify CTNNB1 mutations from whole and spatial transcriptomic data in patients with HCC

作者：Brandon M. Lehrich, Junyan Tao, Silvia Liu, Théo Z. Hirsch, Tyler M. Yasaka, Catherine Cao, Evan R. Delgado, Xiangnan Guan, Shan Lu, Long Pan, Y. Liu, Sucha Singh, Minakshi Poddar, Aaron Bell, Aatur D. Singhi, Jessica Zucman‐Rossi, Yulei Wang, Satdarshan P. Monga · 发表于：JHEP Reports · 年份：2024 · DOI：10.1016/j.jhepr.2024.101186 · 被引用次数：20 · 研究领域：Hepatocellular Carcinoma Treatment and Prognosis、Ferroptosis and cancer prognosis、Single-cell and spatial transcriptomics

Background & Aims Patients with β-catenin (encoded by CTNNB1)-mutated hepatocellular carcinoma (HCC) demonstrate heterogenous responses to first-line immune checkpoint inhibitors (ICIs). Precision-medicine based treatments for this subclass are currently in clinical development. Here, we report derivation of Mutated β-catenin Gene Signature (MBGS) to predict CTNNB1-mutational status in patients for future personalized medicine. Methods Co-expression of mutant-Nrf2 and hMet ± mutant-β-catenin in murine livers in mice led to HCC development. Using bulk RNA-seq and intersectional transcriptomic analysis of various β-catenin-mutated and non-mutated HCC models, MBGS was derived. Integrated RNA/whole-exome-sequencing and spatial transcriptomic data from multiple HCC patient cohorts was assessed to address ability of MBGS to detect CTNNB1 mutation, tumor immune microenvironment and/or predict therapeutic responses. Results Bulk RNA-seq comparing HCCs in mutant β-catenin-Nrf2, β-catenin-Met and β-catenin-Nrf2-Met to Nrf2-Met HCC model yielded 95 common upregulated genes. In TCGA-LIHC, differential gene expression analysis with FDR=0.05 and log2FC>1.5 on the 95 common genes comparing CTNNB1-mutated vs wild-type patients narrowed the gene panel to 13-genes MBGS. MBGS predicted CTNNB1-mutations in TCGA (n=374) and French (n=398) patient cohorts with ROC AUC of 0.90 and 0.94, respectively. Additionally, increased MBGS expression score was associated with lack of significant overall survi...