Development of mutated β-catenin gene signature to identify CTNNB1 mutations from whole and spatial transcriptomic data in patients with HCC
Brandon M. Lehrich,
Junyan Tao,
Silvia Liu,
Theo Z. Hirsch,
Tyler M. Yasaka,
Catherine Cao,
Evan R. Delgado,
Xiangnan Guan,
Shan Lu,
Long Pan,
Yuqing Liu,
Sucha Singh,
Minakshi Poddar,
Aaron Bell,
Aatur D. Singhi,
Jessica Zucman-Rossi,
Yulei Wang,
Satdarshan P. Monga
Affiliations
Brandon M. Lehrich
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Medical Scientist Training Program, University of Pittsburgh, Pittsburgh, PA, USA
Junyan Tao
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
Silvia Liu
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
Theo Z. Hirsch
Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, Paris, France; Institut du Cancer Paris CARPEM, AP-HP, Department of Oncology, Hopital Européen Georges Pompidou, Paris, France
Tyler M. Yasaka
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Medical Scientist Training Program, University of Pittsburgh, Pittsburgh, PA, USA
Catherine Cao
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Evan R. Delgado
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
Xiangnan Guan
Translational Medicine, Genentech Inc., San Francisco, CA, USA
Shan Lu
Translational Medicine, Genentech Inc., San Francisco, CA, USA
Long Pan
Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, Paris, France; Institut du Cancer Paris CARPEM, AP-HP, Department of Oncology, Hopital Européen Georges Pompidou, Paris, France
Yuqing Liu
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Sucha Singh
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Minakshi Poddar
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Aaron Bell
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
Aatur D. Singhi
Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
Jessica Zucman-Rossi
Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, Paris, France; Institut du Cancer Paris CARPEM, AP-HP, Department of Oncology, Hopital Européen Georges Pompidou, Paris, France
Yulei Wang
Translational Medicine, Genentech Inc., San Francisco, CA, USA
Satdarshan P. Monga
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Corresponding author. Address: Pittsburgh Liver Research Center, University of Pittsburgh, School of Medicine and UPMC, 200 Lothrop Street S-409 BST, Pittsburgh, PA 15213, USA. Tel.: +1 412 648-9966; Fax.: +1 412 648-1916.
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 the Mutated β-catenin Gene Signature (MBGS) to predict CTNNB1-mutational status in patients with HCC for future application in personalized medicine treatment regimens. Methods: Co-expression of mutant-Nrf2 and hMet ± mutant-β-catenin in murine livers in mice led to HCC development. The MBGS was derived using bulk RNA-seq and intersectional transcriptomic analysis of β-catenin-mutated and non-mutated HCC models. Integrated RNA/whole-exome-sequencing and spatial transcriptomic data from multiple cohorts of patients with HCC was assessed to address the ability of MBGS to detect CTNNB1 mutation, the tumor immune microenvironment, and/or predict therapeutic responses. Results: Bulk RNA-seq comparing HCC specimens in mutant β-catenin-Nrf2, β-catenin-Met and β-catenin-Nrf2-Met to Nrf2-Met HCC model yielded 95 common upregulated genes. In The Cancer Genome Atlas (TCGA)-LIHC dataset, differential gene expression analysis with false discovery rate (FDR) = 0.05 and log2(fold change) >1.5 on the 95 common genes comparing CTNNB1-mutated vs. wild-type patients narrowed the gene panel to a 13-gene MBGS. MBGS predicted CTNNB1-mutations in TCGA (n = 374) and French (n = 398) patient cohorts with AUCs of 0.90 and 0.94, respectively. Additionally, a higher MBGS expression score was associated with lack of significant improvement in overall survival or progression-free survival in the atezolizumab-bevacizumab arm vs. the sorafenib arm in the IMbrave150 cohort. MBGS performed comparable or superior to other CTNNB1-mutant classifiers. MBGS overlapped with Hoshida S3, Boyault G5/G6, and Chiang CTNNB1 subclass tumors in TCGA and in HCC spatial transcriptomic datasets visually depicting these tumors to be situated in an immune excluded tumor microenvironment. Conclusions: MBGS will aid in patient stratification to guide precision medicine therapeutics for CTNNB1-mutated HCC subclass as a companion diagnostic, as anti-β-catenin therapies become available. Impact and implications:: As precision medicine for liver cancer treatment becomes a reality, diagnostic tools are needed to help classify patients into groups for the best treatment choices. We have developed a molecular signature that could serve as a companion diagnostic and uses bulk or spatial transcriptomic data to identify a unique subclass of liver tumors. This subgroup of liver cancer patients derive limited benefit from the current standard of care and are expected to benefit from specialized directed therapies that are on the horizon.
