Telomere biology and telomerase mutations in cirrhotic patients with hepatocellular carcinoma.
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-fun...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5558955?pdf=render |
| _version_ | 1811233184207077376 |
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| author | Flávia S Donaires Natália F Scatena Raquel M Alves-Paiva Joshua D Podlevsky Dhenugen Logeswaran Barbara A Santana Andreza C Teixeira Julian J-L Chen Rodrigo T Calado Ana L C Martinelli |
| author_facet | Flávia S Donaires Natália F Scatena Raquel M Alves-Paiva Joshua D Podlevsky Dhenugen Logeswaran Barbara A Santana Andreza C Teixeira Julian J-L Chen Rodrigo T Calado Ana L C Martinelli |
| author_sort | Flávia S Donaires |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T11:17:21Z |
| format | Article |
| id | doaj.art-eff92107e14f4c0bad8391e108f36032 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T11:17:21Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-eff92107e14f4c0bad8391e108f360322022-12-22T03:35:28ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01128e018328710.1371/journal.pone.0183287Telomere biology and telomerase mutations in cirrhotic patients with hepatocellular carcinoma.Flávia S DonairesNatália F ScatenaRaquel M Alves-PaivaJoshua D PodlevskyDhenugen LogeswaranBarbara A SantanaAndreza C TeixeiraJulian J-L ChenRodrigo T CaladoAna L C MartinelliTelomeres 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.http://europepmc.org/articles/PMC5558955?pdf=render |
| spellingShingle | Flávia S Donaires Natália F Scatena Raquel M Alves-Paiva Joshua D Podlevsky Dhenugen Logeswaran Barbara A Santana Andreza C Teixeira Julian J-L Chen Rodrigo T Calado Ana L C Martinelli Telomere biology and telomerase mutations in cirrhotic patients with hepatocellular carcinoma. PLoS ONE |
| title | Telomere biology and telomerase mutations in cirrhotic patients with hepatocellular carcinoma. |
| title_full | Telomere biology and telomerase mutations in cirrhotic patients with hepatocellular carcinoma. |
| title_fullStr | Telomere biology and telomerase mutations in cirrhotic patients with hepatocellular carcinoma. |
| title_full_unstemmed | Telomere biology and telomerase mutations in cirrhotic patients with hepatocellular carcinoma. |
| title_short | Telomere biology and telomerase mutations in cirrhotic patients with hepatocellular carcinoma. |
| title_sort | telomere biology and telomerase mutations in cirrhotic patients with hepatocellular carcinoma |
| url | http://europepmc.org/articles/PMC5558955?pdf=render |
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