Telomere biology and telomerase mutations in cirrhotic patients with hepatocellular carcinoma

Flávia S. Donaires, Natália F. Scatena, Raquel M. Alves-Paiva, Joshua D. Podlevsky, Dhenugen Logeswaran, Barbara A. Santana, Andreza C. Teixeira, Julian Chen, Rodrigo T. Calado, Ana L.C. Martinelli

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere0183287
JournalPLoS One
Volume12
Issue number8
DOIs
StatePublished - Aug 1 2017

Fingerprint

telomerase
Telomerase
telomeres
Telomere
hepatoma
Hepatocellular Carcinoma
Fibrosis
mutation
Biological Sciences
Mutation
Telomere Shortening
Chromosomes
Southern Blotting
Genes
shortenings
Healthy Volunteers
Southern blotting
DNA sequences
Chromosomal Instability
chronic hepatitis C

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Donaires, F. S., Scatena, N. F., Alves-Paiva, R. M., Podlevsky, J. D., Logeswaran, D., Santana, B. A., ... Martinelli, A. L. C. (2017). Telomere biology and telomerase mutations in cirrhotic patients with hepatocellular carcinoma. PLoS One, 12(8), [e0183287]. https://doi.org/10.1371/journal.pone.0183287

Telomere biology and telomerase mutations in cirrhotic patients with hepatocellular carcinoma. / Donaires, Flávia S.; Scatena, Natália F.; Alves-Paiva, Raquel M.; Podlevsky, Joshua D.; Logeswaran, Dhenugen; Santana, Barbara A.; Teixeira, Andreza C.; Chen, Julian; Calado, Rodrigo T.; Martinelli, Ana L.C.

In: PLoS One, Vol. 12, No. 8, e0183287, 01.08.2017.

Research output: Contribution to journalArticle

Donaires, FS, Scatena, NF, Alves-Paiva, RM, Podlevsky, JD, Logeswaran, D, Santana, BA, Teixeira, AC, Chen, J, Calado, RT & Martinelli, ALC 2017, 'Telomere biology and telomerase mutations in cirrhotic patients with hepatocellular carcinoma', PLoS One, vol. 12, no. 8, e0183287. https://doi.org/10.1371/journal.pone.0183287
Donaires FS, Scatena NF, Alves-Paiva RM, Podlevsky JD, Logeswaran D, Santana BA et al. Telomere biology and telomerase mutations in cirrhotic patients with hepatocellular carcinoma. PLoS One. 2017 Aug 1;12(8). e0183287. https://doi.org/10.1371/journal.pone.0183287
Donaires, Flávia S. ; Scatena, Natália F. ; Alves-Paiva, Raquel M. ; Podlevsky, Joshua D. ; Logeswaran, Dhenugen ; Santana, Barbara A. ; Teixeira, Andreza C. ; Chen, Julian ; Calado, Rodrigo T. ; Martinelli, Ana L.C. / Telomere biology and telomerase mutations in cirrhotic patients with hepatocellular carcinoma. In: PLoS One. 2017 ; Vol. 12, No. 8.
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abstract = "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.",
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AU - Logeswaran, Dhenugen

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