Constitutional telomerase mutations are genetic risk factors for cirrhosis

Calado, Rodrigo T.; Brudno, Jennifer N.; Mehta, Paulomi; Kovacs, Joseph; Wu, Colin O.; Zago, Marco Antônio; Chanock, Stephen J.; Boyer, Thomas D.; Young, Neal S.

doi:10.1002/hep.24173

Cited by 155 publications

(144 citation statements)

References 49 publications

(78 reference statements)

Supporting

Mentioning

127

Contrasting

Unclassified

Order By: Relevance

“…Somewhat surprisingly, we have identified 5 variants which we believe are likely to be bystanders ( Figure 1; Table 1; families 11 and [19][20][21][22]. We consider a heterozygous variant to be a bystander if it has been reported on the ExAC database.…”

Section: Variants That Are Bystandersmentioning

confidence: 87%

“…Alongside the typical mucocutaneous and BMF features of DC, 12 patients have also been observed presenting with AA, myelodysplasia (MDS), 13 pulmonary fibrosis, 14 and/or liver disease. 15 Similarly, dominantly inherited variants in TERT have been identified in DC patients 16,17 as well as in patients with idiopathic or familial AA, 18 pulmonary fibrosis, 14,19 liver disease, 20 and familial MDS/acute myeloid leukemia (AML). 15,21 Although TERC and TERT variants are associated with a number of disease phenotypes, the investigation of telomerase variants is further complicated by variable penetrance within families, late onset of disease, subclinical features, and disease anticipation due to progressive telomere shortening through successive generations.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Triallelic and epigenetic-like inheritance in human disorders of telomerase

Collopy

Walne

Cardoso

et al. 2015

Blood

View full text Add to dashboard Cite

Key Points• Telomerase variants in patients with bone marrow failure syndromes are difficult to categorize as diseasecausing or otherwise.• DC can derive from triallelic mutations in 2 telomerase genes and epigenetic-like inheritance of short telomeres.Dyskeratosis congenita (DC) and related diseases are a heterogeneous group of disorders characterized by impaired telomere maintenance, known collectively as the telomeropathies. Disease-causing variants have been identified in 10 telomere-related genes including the reverse transcriptase (TERT) and the RNA component (TERC) of the telomerase complex. Variants in TERC and TERT can impede telomere elongation causing stem cells to enter premature replicative senescence and/or apoptosis as telomeres become critically short. This explains the major impact of the disease on highly proliferative tissues such as the bone marrow and skin. However, telomerase variants are not always fully penetrant and in some families disease-causing variants are seen in asymptomatic family members. As a result, determining the pathogenic status of newly identified variants in TERC or TERT can be quite challenging. Over a 3-year period, we have identified 26 telomerase variants (16 of which are novel) in 23 families. Additional investigations (including family segregation and functional studies) enabled these to be categorized into 3 groups: (1) disease-causing (n 5 15), (2) uncertain status (n 5 6), and (3) bystanders (n 5 5). Remarkably, this process has also enabled us to identify families with novel mechanisms of inheriting human telomeropathies. These include triallelic mutations, involving 2 different telomerase genes, and an epigenetic-like inheritance of short telomeres in the absence of a telomerase mutation. This study therefore highlights that telomerase variants have highly variable functional and clinical manifestations and require thorough investigation to assess their pathogenic contribution. (Blood. 2015;126(2):176-184)

show abstract

Section: Variants That Are Bystandersmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Triallelic and epigenetic-like inheritance in human disorders of telomerase

Collopy

Walne

Cardoso

et al. 2015

Blood

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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)

show abstract

“…Telomerase mutations are genetic risk factors for apparently acquired aplastic anemia (6), idiopathic pulmonary fibrosis (7,8), liver disorders (9)(10)(11), and acute myeloid leukemia (12,13). The clinical phenotype of individuals within families harboring a given mutation is variable, extending from asymptomatic carriers through mild laboratory findings to severe aplastic anemia (clinically indistinguishable from acquired aplastic anemia and without the accompanying physical examination features of dyskeratosis congenita).…”

Section: Introductionmentioning

confidence: 99%

Defective telomere elongation and hematopoiesis from telomerase-mutant aplastic anemia iPSCs

Winkler

Hong²,

Decker³

et al. 2013

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

Critically short telomeres activate p53-mediated apoptosis, resulting in organ failure and leading to malignant transformation. Mutations in genes responsible for telomere maintenance are linked to a number of human diseases. We derived induced pluripotent stem cells (iPSCs) from 4 patients with aplastic anemia or hypocellular bone marrow carrying heterozygous mutations in the telomerase reverse transcriptase (TERT) or the telomerase RNA component (TERC) telomerase genes. Both mutant and control iPSCs upregulated TERT and TERC expression compared with parental fibroblasts, but mutant iPSCs elongated telomeres at a lower rate compared with healthy iPSCs, and the deficit correlated with the mutations' impact on telomerase activity. There was no evidence for alternative lengthening of telomere (ALT) pathway activation. Elongation varied among iPSC clones derived from the same patient and among clones from siblings harboring identical mutations. Clonal heterogeneity was linked to genetic and environmental factors, but was not influenced by residual expression of reprogramming transgenes. Hypoxia increased telomere extension in both mutant and normal iPSCs. Additionally, telomerase-mutant iPSCs showed defective hematopoietic differentiation in vitro, mirroring the clinical phenotype observed in patients and demonstrating that human telomere diseases can be modeled utilizing iPSCs. Our data support the necessity of studying multiple clones when using iPSCs to model disease.

show abstract

Constitutional telomerase mutations are genetic risk factors for cirrhosis

Cited by 155 publications

References 49 publications

Triallelic and epigenetic-like inheritance in human disorders of telomerase

Triallelic and epigenetic-like inheritance in human disorders of telomerase

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

Defective telomere elongation and hematopoiesis from telomerase-mutant aplastic anemia iPSCs

Contact Info

Product

Resources

About