Telomere length is key to hepatocellular carcinoma diversity and telomerase addiction is an actionable therapeutic target.

Telomerase activation is the earliest event in hepatocellular carcinoma (HCC) development. We aimed to elucidate telomere length (TL) control during liver carcinogenesis.TL was measured in the tumor and non-tumor liver tissues of 1,502 patients (978 with HCC) and integrated with TERT alterations and expression, clinical and molecular features of HCC analyzed by genome, exome, targeted or RNA sequencing. 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 gender and excessive alcohol consumption were independent determinants of liver telomere attrition. HCC developed in liver with long telomeres were frequently TERT wildtype with progenitor features and BAP1 mutation. In contrast, HCC developed on liver with short TL were enriched in non-proliferative HCC class and somatic TERT promoter mutations. In HCCs, TL is stabilized around 5.7 Kb by various mechanism activating TERT expression, in a narrow biological range similar to non-tumor livers. Long telomeres in tumors are features of very aggressive HCCs, associated with the G3 transcriptomic subclass, TP53 alterations and poor prognosis. In HCC cell lines, TERT silencing with antisense oligonucleotide was efficient in highly proliferative and poorly differentiated cells. Treatment during 3 to 16 weeks induced cell proliferation arrest in 12 cell lines through telomere shortening, DNA damage and apoptosis activation. Therapeutic effect was also obtained in a xenograft mouse model.Telomere maintenance in HCC carcinogenesis is diverse, associated with tumor progression and aggressiveness. Anti-TERT ASO efficacy in HCC cell lines revealed TERT oncogenic addiction and a preclinical rationale for TERT ASO in HCC clinical trial.

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