Massih Ningarhari1, Stefano Caruso1, Théo Z Hirsch1, Quentin Bayard1, Andrea Franconi1, Anne-Laure Védie1, Bénédicte Noblet1, Jean-Frédéric Blanc2, Giuliana Amaddeo3, Nathalie Ganne4, Marianne Ziol5, Valérie Paradis6, Catherine Guettier7, Julien Calderaro8, Guillaume Morcrette9, Youngsoo Kim10, A Robert MacLeod10, Jean-Charles Nault11, Sandra Rebouissou12, Jessica Zucman-Rossi13. 1. Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006, Paris, France; Functional Genomics of Solid Tumors laboratory, Équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France. 2. Service Hépato-Gastroentérologie et Oncologie Digestive, Hôpital Haut-Lévêque, CHU de Bordeaux, F-33000, Bordeaux, France; Service de Pathologie, Hôpital Pellegrin, CHU de Bordeaux, F-33076, Bordeaux, France; Université Bordeaux, Inserm, Research in Translational Oncology, BaRITOn, F-33076, Bordeaux, France. 3. Service d'Hépato-Gastro-Entérologie, Hôpital Henri Mondor, APHP, Université Paris Est Créteil, Inserm U955, Institut Mondor de Recherche Biomédicale, F-94010, Créteil, France. 4. Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006, Paris, France; Functional Genomics of Solid Tumors laboratory, Équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France; Service d'Hépatologie, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, APHP, F-93140, Bondy, France. 5. Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006, Paris, France; Functional Genomics of Solid Tumors laboratory, Équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France; Service d'Anatomo-Pathologie, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, APHP, F-93140, Bondy, France. 6. Service de Pathologie, Hôpital Beaujon, APHP, F-92110, Clichy, France; Université Paris Diderot, CNRS, Centre de Recherche sur l'Inflammation (CRI), Paris, F-75890, France. 7. Service d'Anatomie Pathologique, CHU Bicêtre, APHP, F-94270, Le Kremlin-Bicêtre, France. 8. Service d'Anatomopathologie, Hôpital Henri Mondor, APHP, Institut Mondor de Recherche Biomédicale, F-94010, Créteil, France. 9. Service de Pathologie Pédiatrique, Assistance Publique Hôpitaux de Paris, Hôpital Robert Debré, F-75019, Paris, France. 10. Ionis Pharmaceuticals, Carlsbad, CA, 92010, USA. 11. Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006, Paris, France; Functional Genomics of Solid Tumors laboratory, Équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France; Service d'Hépatologie, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, APHP, F-93140, Bondy, France. Electronic address: naultjc@gmail.com. 12. Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006, Paris, France; Functional Genomics of Solid Tumors laboratory, Équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France. Electronic address: sandra.rebouissou@inserm.fr. 13. Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006, Paris, France; Functional Genomics of Solid Tumors laboratory, Équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France; Hôpital Européen Georges Pompidou, APHP, F-75015, Paris, France. Electronic address: jessica.zucman-rossi@inserm.fr.
Abstract
BACKGROUND & AIMS: Telomerase activation is the earliest event in hepatocellular carcinoma (HCC) development. Thus, we aimed to elucidate the role of telomere length maintenance during liver carcinogenesis. METHODS: Telomere length was measured in the tumor and non-tumor liver tissues of 1,502 patients (978 with HCC) and integrated with TERT alterations and expression, as well as clinical and molecular (analyzed by genome, exome, targeted and/or RNA-sequencing) features of HCC. The preclinical efficacy of anti-TERT antisense oligonucleotides (ASO) was assessed in vitro in 26 cell lines and in vivo in a xenograft mouse model. RESULTS: Aging, liver fibrosis, male sex and excessive alcohol consumption were independent determinants of liver telomere attrition. HCC that developed in livers with long telomeres frequently had wild-type TERT with progenitor features and BAP1 mutations. In contrast, HCC that developed on livers with short telomeres were enriched in the non-proliferative HCC class and frequently had somatic TERT promoter mutations. In HCCs, telomere length is stabilized in a narrow biological range around 5.7 kb, similar to non-tumor livers, by various mechanisms that activate TERT expression. Long telomeres are characteristic of very aggressive HCCs, associated with the G3 transcriptomic subclass, TP53 alterations and poor prognosis. In HCC cell lines, TERT silencing with ASO was efficient in highly proliferative and poorly differentiated cells. Treatment for 3 to 16 weeks induced cell proliferation arrest in 12 cell lines through telomere shortening, DNA damage and activation of apoptosis. The therapeutic effect was also obtained in a xenograft mouse model. CONCLUSIONS: Telomere maintenance in HCC carcinogenesis is diverse, and is associated with tumor progression and aggressiveness. The efficacy of anti-TERT ASO treatment in cell lines revealed the oncogenic addiction to TERT in HCC, providing a preclinical rationale for anti-TERT ASO treatment in HCC clinical trials. LAY SUMMARY: Telomeres are repeated DNA sequences that protect chromosomes and naturally shorten in most adult cells because of the inactivation of the TERT gene, coding for the telomerase enzyme. Here we show that telomere attrition in the liver, modulated by aging, sex, fibrosis and alcohol, associates with specific clinical and molecular features of hepatocellular carcinoma, the most frequent primary liver cancer. We also show that liver cancer is dependent on TERT reactivation and telomere maintenance, which could be targeted through a novel therapeutic approach called antisense oligonucleotides.
BACKGROUND & AIMS: Telomerase activation is the earliest event in hepatocellular carcinoma (HCC) development. Thus, we aimed to elucidate the role of telomere length maintenance during liver carcinogenesis. METHODS: Telomere length was measured in the tumor and non-tumor liver tissues of 1,502 patients (978 with HCC) and integrated with TERT alterations and expression, as well as clinical and molecular (analyzed by genome, exome, targeted and/or RNA-sequencing) features of HCC. The preclinical efficacy of anti-TERT antisense oligonucleotides (ASO) was assessed in vitro in 26 cell lines and in vivo in a xenograft mouse model. RESULTS: Aging, liver fibrosis, male sex and excessive alcohol consumption were independent determinants of liver telomere attrition. HCC that developed in livers with long telomeres frequently had wild-type TERT with progenitor features and BAP1 mutations. In contrast, HCC that developed on livers with short telomeres were enriched in the non-proliferative HCC class and frequently had somatic TERT promoter mutations. In HCCs, telomere length is stabilized in a narrow biological range around 5.7 kb, similar to non-tumor livers, by various mechanisms that activate TERT expression. Long telomeres are characteristic of very aggressive HCCs, associated with the G3 transcriptomic subclass, TP53 alterations and poor prognosis. In HCC cell lines, TERT silencing with ASO was efficient in highly proliferative and poorly differentiated cells. Treatment for 3 to 16 weeks induced cell proliferation arrest in 12 cell lines through telomere shortening, DNA damage and activation of apoptosis. The therapeutic effect was also obtained in a xenograft mouse model. CONCLUSIONS: Telomere maintenance in HCC carcinogenesis is diverse, and is associated with tumor progression and aggressiveness. The efficacy of anti-TERT ASO treatment in cell lines revealed the oncogenic addiction to TERT in HCC, providing a preclinical rationale for anti-TERT ASO treatment in HCC clinical trials. LAY SUMMARY: Telomeres are repeated DNA sequences that protect chromosomes and naturally shorten in most adult cells because of the inactivation of the TERT gene, coding for the telomerase enzyme. Here we show that telomere attrition in the liver, modulated by aging, sex, fibrosis and alcohol, associates with specific clinical and molecular features of hepatocellular carcinoma, the most frequent primary liver cancer. We also show that liver cancer is dependent on TERT reactivation and telomere maintenance, which could be targeted through a novel therapeutic approach called antisense oligonucleotides.
Authors: Gabriella Assante; Sriram Chandrasekaran; Stanley Ng; Aikaterini Tourna; Carolina H Chung; Kowsar A Isse; Jasmine L Banks; Ugo Soffientini; Celine Filippi; Anil Dhawan; Mo Liu; Steven G Rozen; Matthew Hoare; Peter Campbell; J William O Ballard; Nigel Turner; Margaret J Morris; Shilpa Chokshi; Neil A Youngson Journal: Genome Med Date: 2022-06-23 Impact factor: 15.266
Authors: Josep M Llovet; Roser Pinyol; Robin K Kelley; Anthony El-Khoueiry; Helen L Reeves; Xin Wei Wang; Gregory J Gores; Augusto Villanueva Journal: Nat Cancer Date: 2022-04-28
Authors: Rocio I R Macias; Maria J Monte; Maria A Serrano; Jesús M González-Santiago; Isabel Martín-Arribas; André L Simão; Rui E Castro; Javier González-Gallego; José L Mauriz; Jose J G Marin Journal: Aging (Albany NY) Date: 2021-10-11 Impact factor: 5.682