Telomeres are repetitive DNA sequences at linear chromosome termini, protecting chromosomes against end-to-end fusion and damage, providing
chromosomal stability. Telomeres shorten with mitotic cellular division, but are maintained in cells with high proliferative capacity by
telomerase. Loss-of-function mutations in telomere-maintenance genes are genetic risk factors for
cirrhosis development in humans and murine models.
Telomerase deficiency provokes accelerated telomere shortening and dysfunction, facilitating
genomic instability and
oncogenesis. Here we examined whether
telomerase mutations and telomere shortening were associated with
hepatocellular carcinoma (HCC) secondary to
cirrhosis. Telomere length of peripheral blood leukocytes was measured by Southern blot and qPCR in 120 patients with HCC associated with
cirrhosis and 261 healthy subjects. HCC patients were screened for
telomerase gene variants (in TERT and
TERC) by Sanger sequencing. Age-adjusted telomere length was comparable between HCC patients and healthy subjects by both Southern blot and qPCR. Four non-synonymous TERT heterozygous variants were identified in four unrelated patients, resulting in a significantly higher mutation carrier frequency (3.3%) in patients as compared to controls (p = 0.02). Three of the four variants (T726M, A1062T, and V1090M) were previously observed in patients with other telomere diseases (severe
aplastic anemia,
acute myeloid leukemia, and
cirrhosis). A novel TERT variant, A243V, was identified in a 65-year-old male with advanced HCC and
cirrhosis secondary to
chronic hepatitis C virus (HCV) and alcohol ingestion, but direct assay measurements in vitro did not detect modulation of
telomerase enzymatic activity or processivity. In summary, constitutional variants resulting in
amino acid changes in the
telomerase reverse transcriptase were found in a small proportion of patients with
cirrhosis-associated HCC.