Shirley Abitbol1, Rajae Dahmani1, Cédric Coulouarn2, Bruno Ragazzon3, Bernhard Mlecnik4, Nadia Senni1, Mathilde Savall1, Pascale Bossard1, Pierre Sohier5, Valerie Drouet1, Emilie Tournier3, Florent Dumont3, Romain Sanson5, Julien Calderaro6, Jessica Zucman-Rossi6, Mireille Vasseur-Cognet7, Pierre-Alexandre Just5, Benoît Terris5, Christine Perret8, Hélène Gilgenkrantz9. 1. INSERM, U1016, Institut Cochin, F-75014 Paris, France; CNRS, UMR8104, F-75014 Paris, France; Université Paris Descartes, F-75014 Paris, France; Equipe labellisée LNCC, France. 2. INSERM UMR 1241, INRA, Univ Rennes 1, Univ Bretagne Loire, Nutrition Metabolisms and Cancer (NuMeCan), F-35033 Rennes, France. 3. INSERM, U1016, Institut Cochin, F-75014 Paris, France; CNRS, UMR8104, F-75014 Paris, France; Université Paris Descartes, F-75014 Paris, France. 4. Inovarion, 75013 Paris, France. 5. INSERM, U1016, Institut Cochin, F-75014 Paris, France; CNRS, UMR8104, F-75014 Paris, France; Université Paris Descartes, F-75014 Paris, France; Equipe labellisée LNCC, France; APHP, Hôpitaux Universitaires Paris Centre, Hôpital Cochin, Pathology Department, 75014 Paris, France. 6. Inserm, UMR-1162, Functional Genomics of Solid Tumors, Université Paris Descartes, Université Paris Diderot, Université Paris 13, France. 7. UMR IRD 242, UPEC, CNRS 7618, UPMC 113, INRA 1392, Sorbonne Universités Paris and Institut d'Ecologie et des Sciences de l'Environnement de Paris, Bondy, France. 8. INSERM, U1016, Institut Cochin, F-75014 Paris, France; CNRS, UMR8104, F-75014 Paris, France; Université Paris Descartes, F-75014 Paris, France; Equipe labellisée LNCC, France. Electronic address: christine.perret@inserm.fr. 9. INSERM, U1016, Institut Cochin, F-75014 Paris, France; CNRS, UMR8104, F-75014 Paris, France; Université Paris Descartes, F-75014 Paris, France; Equipe labellisée LNCC, France; Centre de Recherche sur l'Inflammation-Inserm UMR 1149-Université Paris Diderot, Paris, France. Electronic address: helene.gilgenkrantz@inserm.fr.
Abstract
BACKGROUND & AIMS: The Wnt/β-catenin pathway is the most frequently deregulated pathway in hepatocellular carcinoma (HCC). Inactivating mutations of the gene encoding AXIN1, a known negative regulator of the Wnt/β-catenin signaling pathway, are observed in about 10% of HCCs. Whole-genome studies usually place HCC with AXIN1 mutations and CTNNB1 mutations in the group of tumors with Wnt/β-catenin activated program. However, it has been shown that HCCs with activating CTNNB1 mutations form a group of HCCs, with a different histology, prognosis and genomic signature to those with inactivating biallelic AXIN1 mutations. We aimed to elucidate the relationship between CTNNB1 mutations, AXIN1 mutations and the activation level of the Wnt/β-catenin program. METHODS: We evaluated two independent human HCC datasets for the expression of a 23-β-catenin target genes program. We modeled Axin1 loss of function tumorigenesis in two engineered mouse models and performed gene expression profiling. RESULTS: Based on gene expression, we defined three levels of β-catenin program activation: strong, weak or no activation. While more than 80% CTNNB1-mutated tumors were found in the strong or in the weak activation program, most of the AXIN1-mutated tumors (>70%) were found in the subgroup with no activation. We validated this result by demonstrating that mice with a hepatocyte specific AXIN1 deletion developed HCC in the absence of β-catenin induction. We defined a 329-gene signature common in human and mouse AXIN1 mutated HCC that is highly enriched in Notch and YAP oncogenic signatures. CONCLUSIONS: AXIN1-mutated HCCs occur independently of the Wnt/β-catenin pathway and involve Notch and YAP pathways. These pathways constitute potentially interesting targets for the treatment of HCC caused by AXIN1 mutations. LAY SUMMARY: Liver cancer has a poor prognosis. Defining the molecular pathways involved is important for developing new therapeutic approaches. The Wnt/β-catenin pathway is the most frequently deregulated pathway in hepatocellular carcinoma (HCC). Mutations of AXIN1, a member of this pathway, represent about 10% of HCC mutations. Using both human HCC collections and engineered mouse models of liver cancers with AXIN1 mutation or deletion, we defined a common signature of liver tumors mutated for AXIN1 and demonstrate that these tumors occur independently of the activation of the Wnt/β-catenin pathway.
BACKGROUND & AIMS: The Wnt/β-catenin pathway is the most frequently deregulated pathway in hepatocellular carcinoma (HCC). Inactivating mutations of the gene encoding AXIN1, a known negative regulator of the Wnt/β-catenin signaling pathway, are observed in about 10% of HCCs. Whole-genome studies usually place HCC with AXIN1 mutations and CTNNB1 mutations in the group of tumors with Wnt/β-catenin activated program. However, it has been shown that HCCs with activating CTNNB1 mutations form a group of HCCs, with a different histology, prognosis and genomic signature to those with inactivating biallelic AXIN1 mutations. We aimed to elucidate the relationship between CTNNB1 mutations, AXIN1 mutations and the activation level of the Wnt/β-catenin program. METHODS: We evaluated two independent human HCC datasets for the expression of a 23-β-catenin target genes program. We modeled Axin1 loss of function tumorigenesis in two engineered mouse models and performed gene expression profiling. RESULTS: Based on gene expression, we defined three levels of β-catenin program activation: strong, weak or no activation. While more than 80% CTNNB1-mutated tumors were found in the strong or in the weak activation program, most of the AXIN1-mutated tumors (>70%) were found in the subgroup with no activation. We validated this result by demonstrating that mice with a hepatocyte specific AXIN1 deletion developed HCC in the absence of β-catenin induction. We defined a 329-gene signature common in human and mouseAXIN1 mutated HCC that is highly enriched in Notch and YAP oncogenic signatures. CONCLUSIONS:AXIN1-mutated HCCs occur independently of the Wnt/β-catenin pathway and involve Notch and YAP pathways. These pathways constitute potentially interesting targets for the treatment of HCC caused by AXIN1 mutations. LAY SUMMARY:Liver cancer has a poor prognosis. Defining the molecular pathways involved is important for developing new therapeutic approaches. The Wnt/β-catenin pathway is the most frequently deregulated pathway in hepatocellular carcinoma (HCC). Mutations of AXIN1, a member of this pathway, represent about 10% of HCC mutations. Using both human HCC collections and engineered mouse models of liver cancers with AXIN1 mutation or deletion, we defined a common signature of liver tumors mutated for AXIN1 and demonstrate that these tumors occur independently of the activation of the Wnt/β-catenin pathway.
Authors: Michael Torbenson; Chantal E McCabe; Daniel R O'Brien; Jun Yin; Tiffany Bainter; Nguyen H Tran; Saba Yasir; Zongming Eric Chen; Renu Dhanasekaran; Keun Soo Ahn; Lewis R Roberts; Chen Wang Journal: Hum Pathol Date: 2021-09-27 Impact factor: 3.526
Authors: Pedro Molina-Sánchez; Marina Ruiz de Galarreta; Melissa A Yao; Katherine E Lindblad; Erin Bresnahan; Elizabeth Bitterman; Tiphaine C Martin; Troy Rubenstein; Kai Nie; Jonathan Golas; Shambhunath Choudhary; Marina Bárcena-Varela; Abdulkadir Elmas; Veronica Miguela; Ying Ding; Zhengyan Kan; Lauren Tal Grinspan; Kuan-Lin Huang; Ramon E Parsons; David J Shields; Robert A Rollins; Amaia Lujambio Journal: Gastroenterology Date: 2020-08-16 Impact factor: 22.682