Ningarhari Massih, Caruso Stefano, Hirsch Théo Z, Bayard Quentin, Franconi Andrea, Védie Anne-Laure, Noblet Bénédicte, Blanc Jean-Frédéric, Amaddeo Giuliana, Ganne Nathalie, Ziol Marianne, Paradis Valérie, Guettier Catherine, Calderaro Julien, Morcrette Guillaume, Kim Youngsoo, MacLeod A Robert, Nault Jean-Charles, Rebouissou Sandra, Zucman-Rossi Jessica
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 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.
J Hepatol. 2021 May;74(5):1155-1166. doi: 10.1016/j.jhep.2020.11.052. Epub 2020 Dec 15.
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.
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.
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.
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.
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.
端粒酶激活是肝细胞癌（HCC）发生发展过程中最早出现的事件。因此，我们旨在阐明端粒长度维持在肝癌发生过程中的作用。
对1502例患者（978例HCC患者）的肿瘤及非肿瘤肝组织进行端粒长度测量，并将其与TERT改变、表达以及HCC的临床和分子特征（通过基因组、外显子组、靶向和/或RNA测序分析）进行整合。在26种细胞系中体外评估抗TERT反义寡核苷酸（ASO）的临床前疗效，并在异种移植小鼠模型中进行体内评估。
衰老、肝纤维化、男性性别和过量饮酒是肝脏端粒损耗的独立决定因素。在端粒较长的肝脏中发生的HCC通常具有野生型TERT，具有祖细胞特征和BAP1突变。相比之下，在端粒较短的肝脏上发生的HCC在非增殖性HCC类别中更为富集，并且经常发生体细胞TERT启动子突变。在HCC中，通过激活TERT表达的各种机制，端粒长度在约5.7 kb的狭窄生物学范围内稳定，类似于非肿瘤肝脏。长端粒是极具侵袭性的HCC的特征，与G3转录组亚类、TP53改变和不良预后相关。在HCC细胞系中，用ASO沉默TERT在高增殖和低分化细胞中有效。治疗3至16周通过端粒缩短、DNA损伤和凋亡激活诱导12种细胞系中的细胞增殖停滞。在异种移植小鼠模型中也获得了治疗效果。
HCC发生过程中端粒维持具有多样性，并且与肿瘤进展和侵袭性相关。抗TERT ASO治疗在细胞系中的疗效揭示了HCC对TERT的致癌依赖性，为HCC临床试验中的抗TERT ASO治疗提供了临床前理论依据。
端粒是重复的DNA序列，可保护染色体，并且在大多数成年细胞中由于编码端粒酶的TERT基因失活而自然缩短。在这里，我们表明肝脏中的端粒损耗受衰老、性别、纤维化和酒精的调节，与最常见的原发性肝癌——肝细胞癌的特定临床和分子特征相关。我们还表明，肝癌依赖于TERT重新激活和端粒维持，这可以通过一种称为反义寡核苷酸的新型治疗方法来靶向。
