Myelodysplasia and liver disease extend the spectrum of RTEL1 related telomeropathies

Cardoso, Shirleny; Ellison, Alicia; Walne, Amanda J.; Cassiman, David; Raghavan, Manoj; Kishore, Bhuvan; Ancliff, Philip; Rodríguez‐Vigil, Carmen; Dobbels, Bieke; Río-Machín, Ana; Seraihi, Ahad Al; Pontikos, Nikolas; Tummala, Hemanth; Vulliamy, Tom; Dokal, Inderjeet

doi:10.3324/haematol.2017.167056

Cited by 16 publications

(24 citation statements)

References 15 publications

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“…RTEL1 encodes the regulator of telomere elongation helicase 1, which is essential for telomere maintenance and regulation of homologous recombination. Germline biallelic RTEL1 variants are responsible for dyskeratosis congenita and its severe variant Hoyeraal‐Hreidarsson syndrome, while heterozygous carriers with pulmonary fibrosis, myelodysplasia and liver disease have been described . Thus, our findings on FANCI , MAST1 , POLH and RTEL1 would warrant further investigation in other large‐scale studies on familial BC and the setup of functional studies to assess the impact of the variants.…”

Section: Discussioncontrasting

confidence: 99%

“…Germline biallelic RTEL1 variants are responsible for dyskeratosis congenita and its severe variant Hoyeraal-Hreidarsson syndrome, 39 while heterozygous carriers with pulmonary fibrosis, [40][41][42] myelodysplasia and liver disease have been described. 43 Thus, our findings on FANCI, MAST1, POLH and RTEL1 would warrant further investigation in other large-scale studies on familial BC and the setup of functional studies to assess the impact of the variants. There was some discrepancy between our findings on ATM in GENESIS and previous findings from a pooled analysis of seven case-control studies that included the Breast Cancer Family Registry (BCFR) study 9 in terms of risk estimates.…”

Section: Discussionmentioning

confidence: 83%

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Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing

Girard

Eon-Marchais

Olaso

et al. 2018

Intl Journal of Cancer

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Pathogenic variants in BRCA1 and BRCA2 only explain the underlying genetic cause of about 10% of hereditary breast and ovarian cancer families. Because of cost‐effectiveness, multigene panel testing is often performed even if the clinical utility of testing most of the genes remains questionable. The purpose of our study was to assess the contribution of rare, deleterious‐predicted variants in DNA repair genes in familial breast cancer (BC) in a well‐characterized and homogeneous population. We analyzed 113 DNA repair genes selected from either an exome sequencing or a candidate gene approach in the GENESIS study, which includes familial BC cases with no BRCA1 or BRCA2 mutation and having a sister with BC ( N = 1,207), and general population controls ( N = 1,199). Sequencing data were filtered for rare loss‐of‐function variants (LoF) and likely deleterious missense variants (MV). We confirmed associations between LoF and MV in PALB2 , ATM and CHEK2 and BC occurrence. We also identified for the first time associations between FANCI , MAST1 , POLH and RTEL1 and BC susceptibility. Unlike other associated genes, carriers of an ATM LoF had a significantly higher risk of developing BC than carriers of an ATM MV (OR LoF = 17.4 vs. OR MV = 1.6; p Het = 0.002). Hence, our approach allowed us to specify BC relative risks associated with deleterious‐predicted variants in PALB2 , ATM and CHEK2 and to add MAST1 , POLH , RTEL1 and FANCI to the list of DNA repair genes possibly involved in BC susceptibility. We also highlight that different types of variants within the same gene can lead to different risk estimates.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 83%

Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing

Girard

Eon-Marchais

Olaso

et al. 2018

Intl Journal of Cancer

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“…(22,27,28) Recent studies describe pathogenic heterozygous RTEL1 variants in a cohort of patients with aplastic anemia at the National Institutes of Health regardless of telomere length, suggesting that variants in RTEL1 may result in disease due to defects in DNA repair and genome stability rather than telomere length maintenance. (25,28) Nonetheless, we identified 122 gene variants of unknown clinical significance in this cohort, and the corresponding telomere lengths may have provided some insight as to their potential pathogenicity.…”

Section: Discussionmentioning

confidence: 96%

“…(19)(20)(21)(22)(23)(24) Notably, among 35 patients with RTEL1 variants in one series from an international bone marrow failure registry, 4 patients had cirrhosis. (25) In another series of 27 patients with telomere lengths below the first percentile, 9 had cirrhosis and 1 had an RTEL1 variant. (26) One limitation of our study is that we did not have sufficient blood samples to measure telomere length in all patients in this series.…”

Section: Discussionmentioning

confidence: 98%

“…Variants in RTEL1 have been associated with a spectrum of disease, including pulmonary fibrosis, lung cancer, glioma, and bone marrow failure syndromes such as dyskeratosis congenita and its more severe form, Hoyeraal‐Hreidarsson syndrome . Notably, among 35 patients with RTEL1 variants in one series from an international bone marrow failure registry, 4 patients had cirrhosis . In another series of 27 patients with telomere lengths below the first percentile, 9 had cirrhosis and 1 had an RTEL1 variant …”

Section: Discussionmentioning

confidence: 99%

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Telomerase Variants in Patients with Cirrhosis Awaiting Liver Transplantation

et al. 2019

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Telomeres are repetitive DNA sequences that protect the ends of linear chromosomes, and they are maintained by a ribonucleoprotein complex called telomerase. Variants in genes encoding for telomerase components have been associated with a spectrum of disease in the lung, skin, bone marrow, and liver. Mutations in the telomerase reverse transcriptase and telomerase RNA component genes have been observed at a higher prevalence in patients with liver disease compared with the general population; however, the presence of variants in other components of the telomerase complex and their impact on clinical outcomes has not been explored. We evaluated 86 patients with end‐stage liver disease for variants in an expanded panel of eight genes, and found that 17 patients (20%) had likely deleterious variants by in silico analysis. Seven unique likely deleterious variants were identified in the regulator of telomere elongation helicase 1 ( RTEL1 ) gene that encodes for a DNA helicase important in telomere maintenance and genomic stability. In gene burden association analysis of their clinical data, the presence of any RTEL1 variant was associated with a 29% lower baseline white blood cell count (95% confidence interval [CI], ‐7% to ‐46%; P Value = 0.01) compared with patients without RTEL1 variants, and the presence of any exonic missense RTEL1 variant was associated with a 42% lower baseline platelet count (95% CI, ‐5% to ‐65%: P Value = 0.03). The presence of any telomerase variant was associated with an increased number of readmissions within 1 year after transplantation demonstrated by an incident rate ratio (IRR) of 3.15 (95% CI, 1.22 to 8.57). No association with survival was observed. Conclusion : Among patients who underwent liver transplantation, the presence of any exonic missense variant was associated with a longer postoperative length of stay with an IRR of 2.16 (95% CI, 1.31 to 3.68).

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Regulator of telomere elongation helicase 1 gene and its association with malignancy

2022

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Background With the progression of next‐generation sequencing technologies, researchers have identified numerous variants of the regulator of telomere elongation helicase 1 ( RTEL1 ) gene that are associated with a broad spectrum of phenotypic manifestations, including malignancies. At the molecular level, RTEL1 is involved in the regulation of the repair, replication, and transcription of deoxyribonucleic acid (DNA) and the maintenance of telomere length. RTEL1 can act both as a promotor and inhibitor of tumorigenesis. Here, we review the potential mechanisms implicated in the malignant transformation of tissues under conditions of RTEL1 deficiency or its aberrant overexpression. Recent findings A major hemostatic challenge during RTEL1 dysfunction could arise from its unbalanced activity for unwinding guanine‐rich quadruplex DNA (G4‐DNA) structures. In contrast, RTEL1 deficiency leads to alterations in telomeric and genome‐wide DNA maintenance mechanisms, ribonucleoprotein metabolism, and the creation of an inflammatory and immune‐deficient microenvironment, all promoting malignancy. Additionally, we hypothesize that functionally similar molecules could act to compensate for the deteriorated functions of RTEL1 , thereby facilitating the survival of malignant cells. On the contrary, RTEL1 over‐expression was directed toward G4‐unwinding, by promoting replication fork progression and maintaining intact telomeres, may facilitate malignant transformation and proliferation of various pre‐malignant cellular compartments. Conclusions Therefore, restoring the equilibrium of RTEL1 functions could serve as a therapeutic approach for preventing and treating malignancies.

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Myelodysplasia and liver disease extend the spectrum of RTEL1 related telomeropathies

Cited by 16 publications

References 15 publications

Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing

Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing

Telomerase Variants in Patients with Cirrhosis Awaiting Liver Transplantation

Regulator of telomere elongation helicase 1 gene and its association with malignancy

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