Telomerase gene mutations are associated with cirrhosis formation

Hartmann, Daniel; Srivastava, Ujala; Thaler, Michaela; Kleinhans, Karin N.; N’Kontchou, Gisèle; Scheffold, Annika; Bauer, Kerstin; Kratzer, Ramona F.; Kloos, Natalia; Katz, Sarah–Fee; Song, Zhangfa; Begus‐Nahrmann, Yvonne; Kleger, Alexander; Figura, Guido von; Strnad, Pavel; Lechel, André; Güneş, Çagatay; Potthoff, Andrej; Deterding, Katja; Wedemeyer, Heiner; Ju, Zhenyu; Song, Ge; Xu, Feng; Gillen, Sonja; Schrezenmeier, Hubert; Mertens, Thomas; Ziol, Marianne; Friess, Helmut; Jarek, Michael; Manns, Michael P.; Beaugrand, Michel; Rudolph, K. Lenhard

doi:10.1002/hep.24217

Cited by 145 publications

(107 citation statements)

References 43 publications

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“…The high rate of cytopenia after exposure to cytotoxic drugs in mutation carriers illustrates the abnormal repair capacities after external injury in these patients, and the phenotype heterogeneity according to age and environmental exposure. This is consistent with the fact that mutation carriers are more prone to develop liver cirrhosis associated to hepatitis C virus infection or alcohol exposure [24].…”

Section: Discussionsupporting

confidence: 86%

“…None of the treatment was associated with any objective pulmonary improvement assessed either by CT scan or an increase in VC or DLCO by 10% of the predicted value or greater. At the last visit before transplantation, VC and DLCO were 42% [75-22] and 22% [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] of predicted, respectively.…”

Section: Clinical Characteristics At the Diagnosis Of Pulmonary Fibrosismentioning

confidence: 99%

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Severe hematologic complications after lung transplantation in patients with telomerase complex mutations

Borie

Kannengiesser

Hirschi

et al. 2015

The Journal of Heart and Lung Transplantation

109

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Section: Discussionsupporting

confidence: 86%

Section: Clinical Characteristics At the Diagnosis Of Pulmonary Fibrosismentioning

confidence: 99%

Severe hematologic complications after lung transplantation in patients with telomerase complex mutations

Borie

Kannengiesser

Hirschi

et al. 2015

The Journal of Heart and Lung Transplantation

109

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“…Telomerase gene delivery inhibited experimental liver fibrosis in mice,36 and an increased incidence of germline telomerase mutations was detected in patients with cirrhosis compared to noncirrhosis controls, suggesting that telomere shortening can accelerate cirrhosis formation 37, 38. It was postulated that somatic TERT promoter mutations could counterbalance germline loss‐of‐function mutations in pulmonary fibrosis 39.…”

Section: Discussionmentioning

confidence: 99%

Telomerase reverse transcriptase mutations in plasma DNA in patients with hepatocellular carcinoma or cirrhosis: Prevalence and risk factors

Jiao

Watt

Stevenson

et al. 2018

Hepatology Communications

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Telomerase reverse transcriptase (TERT) mutation is the most frequent genetic alteration in hepatocellular carcinoma (HCC). Our aims were to investigate whether TERT mutations can be detected in circulating cell‐free DNA (cfDNA) of patients with HCC and/or cirrhosis and characterize clinical parameters associated with these mutations. We retrieved data on TERT C228T and C250T promoter mutations in 196 HCCs from The Cancer Genome Atlas. We measured these TERT mutations in plasma cfDNA in 218 patients with HCC and 81 patients with cirrhosis without imaging evidence of HCC. The prevalence of TERT mutations in The Cancer Genome Atlas HCC specimens was 44.4%. TERT mutations were detected with similar prevalence (47.7%) in plasma cfDNAs from 218 patients with HCC. TERT mutations, either within the HCC or in cfDNA, were associated with male sex, hepatitis C virus (HCV), alcoholic cirrhosis, family history of cancer, and poor prognosis. The high prevalence of TERT mutations in HCCs in male patients with cirrhosis caused by HCV and/or alcohol was confirmed in an independent set of HCCs (86.6%). Finally, TERT mutations were detected in cfDNA of 7 out of 81 (8.6%) patients with cirrhosis without imaging evidence of HCC, including 5 male patients with cirrhosis due to HCV and/or alcohol. Genes involved in xenobiotic and alcohol metabolism were enriched in HCCs with TERT mutations, and vitamin K2 was identified as an upstream regulator. Conclusion: TERT mutations are detectable in plasma cfDNA. Long‐term imaging surveillance of patients with cirrhosis with cfDNA TERT mutations without evidence of HCC is required to assess their potential as early biomarkers of HCC. (Hepatology Communications 2018;2:718‐731)

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“…In a series of 10 patients with liver cirrhosis and TERT or TERC mutations, all were considered to have cirrhosis secondary to hepatitis C, alcohol consumption, Wilson's disease, nonalcoholic steatohepatitis, or primary biliary cirrhosis [71,72]. Elevated liver enzyme levels or liver involvement was reported in 5-27% of patients with ILD and telomerase complex mutation [9,36].…”

Section: Extrapulmonary Manifestationsmentioning

confidence: 99%

“…The presence of a TERT or TERC mutation increases the risk of cirrhosis developing in cases of hepatitis C infection and probably with equivalent alcohol consumption [71,72]. Patients with the same mutation even in the same family may present normal or elevated liver enzyme levels with variable degrees of necrosis, inflammation, fibrosis and regeneration on liver histology [71].…”

Section: Extrapulmonary Manifestationsmentioning

confidence: 99%

Management of suspected monogenic lung fibrosis in a specialised centre

et al. 2017

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At least 10% of patients with interstitial lung disease present monogenic lung fibrosis suspected on familial aggregation of pulmonary fibrosis, specific syndromes or early age of diagnosis. Approximately 25% of families have an identified mutation in genes mostly involved in telomere homeostasis, and more rarely in surfactant homeostasis.Beyond pathophysiological knowledge, detection of these mutations has practical consequence for patients. For instance, mutations involved in telomere homeostasis are associated with haematological complications after lung transplantation and may require adapted immunosuppression. Moreover, relatives may benefit from a clinical and genetic evaluation that should be specifically managed.The field of genetics of pulmonary fibrosis has made great progress in the last 10 years, raising specific problems that should be addressed by a specialised team.

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Telomerase gene mutations are associated with cirrhosis formation

Cited by 145 publications

References 43 publications

Severe hematologic complications after lung transplantation in patients with telomerase complex mutations

Severe hematologic complications after lung transplantation in patients with telomerase complex mutations

Telomerase reverse transcriptase mutations in plasma DNA in patients with hepatocellular carcinoma or cirrhosis: Prevalence and risk factors

Management of suspected monogenic lung fibrosis in a specialised centre

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