Regulator Of Telomere Elongation Helicase Research Articles

Germline RTEL1 Variants in Telomere Biology Disorders.

Rare germline variation in regulator of telomere elongation helicase 1 (RTEL1) is associated with telomere biology disorders (TBDs). Biallelic RTEL1 variants result in childhood onset dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome whereas heterozygous individuals usually present later in life with pulmonary fibrosis or bone marrow failure. We compiled all TBD-associated RTEL1 variants in the literature and assessed phenotypes and outcomes of 44 individuals from 14 families with mono- or biallelic RTEL1 variants enrolled in clinical trial NCT00027274. Variants were classified by adapting ACMG-AMP guidelines using clinical information, telomere length, and variant allele frequency data. Compared with heterozygotes, individuals with biallelic RTEL1 variants had an earlier age at diagnosis (median age 35.5 vs. 5.1 years, p < 0.01) and worse overall survival (median age 66.5 vs. 22.9 years, p < 0.001). There were 257 unique RTEL1 variants reported in 47 publications, and 209 had a gnomAD minor allele frequency <1%. Only 38.3% (80/209) met pathogenic/likely pathogenic criteria. Notably, 8 of 209 reported disease-associated variants were benign or likely benign and the rest were variants of uncertain significance. Given the considerable differences in outcomes of TBDs associated with RTEL1 germline variants and the extent of variation in the gene, systematic functional studies and standardization of variant curation are urgently needed to inform clinical management.

Clinical, radiological and histopathological features of patients with familial pulmonary fibrosis

BackgroundIn familial pulmonary fibrosis (FPF) at least two biological relatives are affected. Patients with FPF have diverse clinical features.Research questionWe aimed to characterize demographic and clinical features, re-evaluate high-resolution computed tomography (HRCT) scans and histopathology of surgical lung biopsies, assess survival and investigate the suitability of risk prediction models for FPF patients.Study designA retrospective cohort study.MethodsFPF data (n = 68) were collected from the medical records of Oulu University Hospital (OUH) and Oulaskangas District Hospital between 1 Jan 2000 and 11 Jan 2023. The inclusion criterion was pulmonary fibrosis (PF) (ICD 10-code J84.X) and at least one self-reported relative with PF. Clinical information was gathered from hospital medical records. HRCT scans and histology were re-evaluated.ResultsThirty-seven (54.4%) of the patients were men, and 31 (45.6%) were women. The mean ages of the women and men were 68.6 and 61.7 years, respectively (p = 0.003). Thirty-seven (54.4%) patients were nonsmokers. The most common radiological patterns were usual interstitial pneumonia (UIP) (51/75.0%), unclassifiable (8/11.8%) and nonspecific interstitial pneumonia (NSIP) (3/4.4%). Pleuroparenchymal fibroelastosis (PPFE) was observed as a single or combined pattern in 13.2% of the patients. According to the 2022 guidelines for idiopathic pulmonary fibrosis (IPF), the patients were categorized as UIP (31/45.6%), probable UIP (20/29.4%), indeterminate for UIP (7/10.3%) or alternative diagnosis (10/14.7%). The histopathological patterns were UIP (7/41.2%), probable UIP (1/5.9%), indeterminate for UIP (8/47.2%) and alternative diagnosis (1/5.9%). Rare genetic variants were found in 9 patients; these included telomerase reverse transcriptase (TERT, n = 6), telomerase RNA component (TERC, n = 2) and regulator of telomere elongation helicase 1 (RTEL1, n = 1). Half of the patients died (n = 29) or underwent lung transplantation (n = 5), with a median survival of 39.9 months. The risk prediction models composite physiology index (CPI), hazard ratio (HR) 1.07 (95.0% CI 1.04–1.10), and gender-age-physiology index (GAP) stage I predicted survival statistically significantly (p<0.001) compared to combined stages II and III.ConclusionsThis study confirmed the results of earlier studies showing that FPF patients’ radiological and histopathological patterns are diverse. Moreover, radiological and histological features revealed unusual patterns and their combinations.

Discovery of a Novel Shared Variant Among RTEL1 Gene and RTEL1-TNFRSF6B lncRNA at Chromosome 20q13.33 in Familial Progressive Myoclonus Epilepsy.

Background: Progressive myoclonus epilepsy (PME) is a neurodegenerative disorder marked by recurrent seizures and progressive myoclonus. To date, based on the phenotypes and causal genes, more than 40 subtypes of PMEs have been identified, and more remain to be characterized. Our study is aimed at identifying the aberrant gene(s) possibly associated with PMEs in two siblings born to asymptomatic parents, in the absence of known genetic mutations. Methods: Clinical assessments and molecular analyses, such as the repeat expansion test for CSTB; SCA1, 2, 3, 6, and 7; whole exome sequencing (WES); and mitochondrial genome sequencing coupled with computational analysis, were performed. Results: A family-based segregation analysis of WES data was performed to identify novel genes associated with PMEs. The potassium channel, KCNH8 [c.298T>C; (p.Tyr100His)], a DNA repair gene, regulator of telomere elongation helicase 1 (RTEL1) [c.691G>T; (p.Asp231Tyr)] and long noncoding RNA, RTEL1-TNFRSF6B [chr20:62298898_G>T; NR_037882.1, hg19] were among the candidate genes that were found to be associated with PMEs. These homozygous variations in siblings belong to genes with a loss-of-function intolerant (pLI) score of ≤ 0.86, expected to be detrimental by multiple computational analyses, and were heterozygous in parents. Additionally, computational analysis and the expression of RTEL1 and RTEL1-TNFRSF6B revealed that RTEL1-TNFRSF6B may modulate RTEL1 via hsa-miR-3529-3p. In the patient with the severe phenotype, a further deleterious mutation in SLC22A17 was identified. No de novo variants specific to these probands were identified in the mitochondrial genome. Conclusions: Our study is the first to report variants in KCNH8, RTEL1, and RTEL1-TNFRSF6B among PME cases. These genes when characterized fully may shed light on pathogenicity and have the potential to be used in the diagnosis of PME.

Harmonin homology domain-mediated interaction of RTEL1 helicase with RPA and DNA provides insights into its recruitment to DNA repair sites.

The regulator of telomere elongation helicase 1 (RTEL1) playsrolesin telomere DNA maintenance, DNA repair, and genome stability by dismantling D-loops and unwinding G-quadruplex structures. RTEL1 comprises a helicase domain, two tandem harmonin homology domains 1&2 (HHD1 and HHD2), and a Zn2+-binding RING domain. In vitro D-loop disassembly by RTEL1 is enhanced in the presence of replication protein A (RPA). However, the mechanism of RTEL1 recruitment at non-telomeric D-loops remainsunknown. In this study, we have unravelled a direct physical interaction between RTEL1 and RPA. Under DNA damage conditions, we showed that RTEL1 and RPA colocalise in the cell. Coimmunoprecipitation showed that RTEL1 and RPA interact, and the deletion of HHDs of RTEL1 significantly reduced this interaction. NMR chemical shift perturbations (CSPs) showed that RPA uses its 32C domain to interact with the HHD2 of RTEL1.Interestingly, HHD2 also interacted with DNA in thein vitro experiments. HHD2 structure was determined using X-ray crystallography, and NMR CSPs mapping revealed that both RPA32C and DNAcompetitivelybind toHHD2 on an overlapping surface. These results establish novel roles of accessory HHDs in RTEL1's functionsand provide mechanistic insights into the RPA-mediated recruitment of RTEL1to DNA repairsites.

RTEL1 is upregulated in colorectal cancer and promotes tumor progression

As one of the most common cancers worldwide, the incidence of colorectal cancer (CRC) continues to increase. Metastasis is the leading cause of death for this malignant disease. Regulator of telomere elongation helicase 1 (RTEL1) is a key factor that maintains telomere stability and contributes to DNA repair. Recent advances have suggested that RTEL1 exerts other functions through various mechanisms. However, little is known about its role in human cancers, including CRC. In this study, we revealed that the copy number of RTEL1 was significantly higher in CRC tissues, especially in metastatic CRC tissues, than in paired normal tissues, which was associated with increased expression. Increased RTEL1 expression was significantly correlated with CRC progression and poor survival. Functionally, RTEL1 knockdown suppressed the proliferation and metastasis of CRC both in vitro and in vivo. In addition, multiple signalling pathways, including the mitotic cell cycle, DNA repair, and EMT, were potentially regulated by RTEL1. Notably, GPR17 appeared to be a candidate downstream target gene that partially mediated the tumor-promoting effects of RTEL1 in CRC. Altogether, our results indicate that RTEL1 plays a crucial role in CRC progression and appears to be a promising therapeutic target and prognosis for CRC.

A novel mutation (p.Y24N) in NHP2 leads to idiopathic pulmonary fibrosis and lung carcinoma chronic obstructive lung disease by disrupting the expression and nucleocytoplasmic localization of NHP2

•Idiopathic pulmonary fibrosis (IPF) is a kind of chronic interstitial lung disease and can be caused by mutations in NHP2 ribonucleoprotein (NHP2), a component of the telomerase complex.•We identified a novel mutation (c.70 T > A/p.Y24N) in NHP2 in a Chinese family with IPF, chronic obstructive lung disease and lung carcinoma. A functional study confirmed that this mutation can disrupt the expression and nucleocytoplasmic localization of NHP2, further decrease the expression of Dyskerin Pseudouridine Synthase 1 and Regulator of Telomere Elongation Helicase 1, and reduce the length of telomeres.•Our study expanded the mutation and clinical spectrum of NHP2 deficiency.

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

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. 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. Therefore, restoring the equilibrium of RTEL1 functions could serve as a therapeutic approach for preventing and treating malignancies.

Rare and Common Variants in KIF15 Contribute to Genetic Risk of Idiopathic Pulmonary Fibrosis.

Rationale: Genetic studies of idiopathic pulmonary fibrosis (IPF) have improved our understanding of this disease, but not all causal loci have been identified. Objectives: To identify genes enriched with rare deleterious variants in IPF and familial pulmonary fibrosis. Methods: We performed gene burden analysis of whole-exome data, tested single variants for disease association, conducted KIF15 (kinesin family member 15) functional studies, and examined human lung single-cell RNA sequencing data. Measurements and Main Results: Gene burden analysis of 1,725 cases and 23,509 control subjects identified heterozygous rare deleterious variants in KIF15, a kinesin involved in spindle separation during mitosis, and three telomere-related genes (TERT [telomerase reverse transcriptase], RTEL1 [regulator of telomere elongation helicase 1], and PARN [poly(A)-specific ribonuclease]). KIF15 was implicated in autosomal-dominant models of rare deleterious variants (odds ratio [OR], 4.9; 95% confidence interval [CI], 2.7-8.8; P = 2.55 × 10-7) and rare protein-truncating variants (OR, 7.6; 95% CI, 3.3-17.1; P = 8.12 × 10-7). Meta-analyses of the discovery and replication cohorts, including 2,966 cases and 29,817 control subjects, confirm the involvement of KIF15 plus the three telomere-related genes. A common variant within a KIF15 intron (rs74341405; OR, 1.6; 95% CI, 1.4-1.9; P = 5.63 × 10-10) is associated with IPF risk, confirming a prior report. Lymphoblastoid cells from individuals heterozygous for the common variant have decreased KIF15 and reduced rates of cell growth. Cell proliferation is dependent on KIF15 in the presence of an inhibitor of Eg5/KIF11, which has partially redundant function. KIF15 is expressed specifically in replicating human lung cells and shows diminished expression in replicating epithelial cells of patients with IPF. Conclusions: Both rare deleterious variants and common variants in KIF15 link a nontelomerase pathway of cell proliferation with IPF susceptibility.

Resonance assignment and secondary structure of the tandem harmonin homology domains of human RTEL1.

Regulator of telomere elongation helicase 1 (RTEL1) is an Fe-S cluster containing DNA helicase that plays important roles in telomere DNA maintenance, DNA repair, and genomic stability. It is a modular protein comprising an N-terminal helicase domain, two tandem harmonin homology domains 1 & 2 (HHD1 and HHD2), and a C-terminal C4C4 type RING domain. The N-terminal helicase domain disassembles the telomere t/D-loop and unwinds the G-quadruplex via its helicase activity. The C-terminal RING domain interacts with telomere DNA binding protein TRF2 and helps RTEL1 recruitment to the telomere. The tandem HHD1 and HHD2 are characterized as a putative protein-protein interaction domain and have recently been shown to interact with a DNA repair protein SLX4. Several mutations associated with Hoyeraal-Hreidarsson syndrome and pulmonary fibrosis have been found in HHD1 and HHD2 of RTEL1. However, these domains have not been characterized for their structures. We have expressed and purified HHD1 and HHD2 of human RTEL1 for their characterization using solution NMR spectroscopy. Here, we report near complete backbone and sidechain 1H, 13C and 15N chemical shift assignments and secondary structure of the HHD1 and HHD2 domains of human RTEL1.

Synergistic effects of telomerase reverse transcriptase and regulator of telomere elongation helicase 1 on aggressiveness and outcomes in adrenocortical carcinoma

Adrenocortical carcinoma (ACC) is one of the deadliest endocrine malignancies and telomere maintenance by activated telomerase is critically required for ACC development and progression. Because telomerase reverse transcriptase (TERT) and regulator of telomere elongation helicase 1 (RTEL1) play key roles in telomere homeostasis, we determined their effect on ACC pathogenesis and outcomes. Analyses of TCGA and GEO datasets showed significantly higher expression of RTEL1 but not TERT in ACC tumors, compared to their benign or normal counterparts. Furthermore, gains/amplifications of both TERT and RTEL1 genes were widespread in ACC tumors and their expression correlated with their gene copy numbers. Higher expression of either TERT or RTEL1 was associated with shorter overall and progression-free survival (OS and PFS) in the TCGA ACC patient cohort, and higher levels of both TERT and RTEL1 mRNA predicted the shortest patient OS and PFS. However, multivariate analyses showed that only RTEL1 independently predicted patient OS and PFS. Gene set enrichment analysis further showed enrichments of wnt/β-catenin, MYC, glycolysis, MTOR, and DNA repair signaling pathways in ACC tumors expressing high TERT and RTEL1 mRNA levels. Taken together, TERT and RTEL1 promote ACC aggressiveness synergistically and may serve as prognostic factors and therapeutic targets for ACC.

DRTEL1 is essential for the maintenance of Drosophila male germline stem cells.

Stem cells have the potential to maintain undifferentiated state and differentiate into specialized cell types. Despite numerous progress has been achieved in understanding stem cell self-renewal and differentiation, many fundamental questions remain unanswered. In this study, we identify dRTEL1, the Drosophila homolog of Regulator of Telomere Elongation Helicase 1, as a novel regulator of male germline stem cells (GSCs). Our genome-wide transcriptome analysis and ChIP-Seq results suggest that dRTEL1 affects a set of candidate genes required for GSC maintenance, likely independent of its role in DNA repair. Furthermore, dRTEL1 prevents DNA damage-induced checkpoint activation in GSCs. Finally, dRTEL1 functions to sustain Stat92E protein levels, the key player in GSC maintenance. Together, our findings reveal an intrinsic role of the DNA helicase dRTEL1 in maintaining male GSC and provide insight into the function of dRTEL1.

Downregulation of Barley Regulator of Telomere Elongation Helicase 1 Alters the Distribution of Meiotic Crossovers.

Programmed meiotic DNA double-strand breaks (DSBs), necessary for proper chromosomal segregation and viable gamete formation, are repaired by homologous recombination (HR) as crossovers (COs) or non-crossovers (NCOs). The mechanisms regulating the number and distribution of COs are still poorly understood. The regulator of telomere elongation helicase 1 (RTEL1) DNA helicase was previously shown to enforce the number of meiotic COs in Caenorhabditis elegans but its function in plants has been studied only in the vegetative phase. Here, we characterised barley RTEL1 gene structure and expression using RNA-seq data previously obtained from vegetative and reproductive organs and tissues. Using RNAi, we downregulated RTEL1 expression specifically in reproductive tissues and analysed its impact on recombination using a barley 50k iSelect SNP Array. Unlike in C. elegans, in a population segregating for RTEL1 downregulated by RNAi, high resolution genome-wide genetic analysis revealed a significant increase of COs at distal chromosomal regions of barley without a change in their total number. Our data reveal the important role of RTEL1 helicase in plant meiosis and control of recombination.

DRTEL1 is Essential for the Maintenance of Germline Stem Cells

Stem cells have the potential to maintain the undifferentiated state and differentiate into specialized cell types. Despite numerous progresses have been achieved in understanding stem cell self-renewal and differentiation, many fundamental questions remain unanswered. In this study, we identify dRTEL1, the Drosophila homolog of Regulator of Telomere Elongation Helicase 1, as a novel regulator of Drosophila germline stem cells (GSCs). Our genome-wide transcriptome analysis and ChIP-Seq results suggest that dRTEL1 directly regulates a set of candidate genes controlling GSC self-renewal and differentiation. Furthermore, dRTEL1 prevents DNA damage-induced checkpoint activation for GSC maintenance. Finally, dRTEL1 is required to maintain Stat92E protein levels, the key player in GSC self-renewal. Together, our findings reveal an intrinsic role of the DNA helicase dRTEL1 in GSC self-renewal and provide insight into the function of dRTEL1.

Adult diffuse glioma GWAS by molecular subtype identifies variants in D2HGDH and FAM20C.

Twenty-five germline variants are associated with adult diffuse glioma, and some of these variants have been shown to be associated with particular subtypes of glioma. We hypothesized that additional germline variants could be identified if a genome-wide association study (GWAS) were performed by molecular subtype. A total of 1320 glioma cases and 1889 controls were used in the discovery set and 799 glioma cases and 808 controls in the validation set. Glioma cases were classified into molecular subtypes based on combinations of isocitrate dehydrogenase (IDH) mutation, telomerase reverse transcriptase (TERT) promoter mutation, and 1p/19q codeletion. Logistic regression was applied to the discovery and validation sets to test for associations of variants with each of the subtypes. A meta-analysis was subsequently performed using a genome-wide P-value threshold of 5 × 10-8. Nine variants in or near D-2-hydroxyglutarate dehydrogenase (D2HGDH) on chromosome 2 were genome-wide significant in IDH-mutated glioma (most significant was rs5839764, meta P = 2.82 × 10-10). Further stratifying by 1p/19q codeletion status, one variant in D2HGDH was genome-wide significant in IDH-mutated non-codeleted glioma (rs1106639, meta P = 4.96 × 10-8). Further stratifying by TERT mutation, one variant near FAM20C (family with sequence similarity 20, member C) on chromosome 7 was genome-wide significant in gliomas that have IDH mutation, TERT mutation, and 1p/19q codeletion (rs111976262, meta P = 9.56 × 10-9). Thirty-six variants in or near GMEB2 on chromosome 20 near regulator of telomere elongation helicase 1 (RTEL1) were genome-wide significant in IDH wild-type glioma (most significant was rs4809313, meta P = 2.60 × 10-10). Performing a GWAS by molecular subtype identified 2 new regions and a candidate independent region near RTEL1, which were associated with specific glioma molecular subtypes.

RTEL1 suppresses G-quadruplex-associated R-loops at difficult-to-replicate loci in the human genome.

Oncogene activation during tumorigenesis generates DNA replication stress, a known driver of genome rearrangements. In response to replication stress, certain loci, such as common fragile sites and telomeres, remain under-replicated during interphase and subsequently complete locus duplication in mitosis in a process known as 'MiDAS'. Here, we demonstrate that RTEL1 (regulator of telomere elongation helicase 1) has a genome-wide role in MiDAS at loci prone to form G-quadruplex-associated R-loops, in a process that is dependent on its helicase function. We reveal that SLX4 is required for the timely recruitment of RTEL1 to the affected loci, which in turn facilitates recruitment of other proteins required for MiDAS, including RAD52 and POLD3. Our findings demonstrate that RTEL1 is required for MiDAS and suggest that RTEL1 maintains genome stability by resolving conflicts that can arise between the replication and transcription machineries.

Rare Protein-Altering Telomere-related Gene Variants in Patients with Chronic Hypersensitivity Pneumonitis.

Rationale: Rare genetic variants in telomere-related genes have been identified in familial, idiopathic, and rheumatoid arthritis-associated pulmonary fibrosis. Short peripheral blood leukocyte (PBL) telomere length predicts poor outcomes in chronic hypersensitivity pneumonitis (CHP).Objectives: Determine the prevalence and clinical relevance of rare protein-altering variants in telomere-related genes in patients with CHP.Methods: Next-generation sequences from two CHP cohorts were analyzed to identify variants in TERT (telomerase reverse transcriptase), TERC (telomerase RNA component), DKC1 (dyskerin pseudouridine synthase 1), RTEL1 (regulator of telomere elongation helicase 1), PARN (poly[A]-specific RNase), and TINF2 (TERF1-interacting nuclear factor 2). To qualify, variants were required to have a minor allele frequency less than 0.005 and be predicted to be damaging to protein function. Variant status (binary variable) was used in statistical association tests, including Cox proportional hazard models for transplant-free survival. PBL telomere length was measured using quantitative PCR.Measurements and Main Results: Qualifying variants were identified in 16 of 144 patients (11.1%; 95% confidence interval [CI], 6.5-17.4) in the discovery cohort and 17 of 209 patients (8.1%; 95% CI, 4.8-12.7) in the replication cohort. Age- and ancestry-adjusted PBL telomere length was significantly shorter in the presence of a variant in both cohorts (discovery: -561 bp; 95% CI, -933 to -190; P = 0.003; replication: -612 bp; 95% CI, -870 to -354; P = 5.30 × 10-6). Variant status was significantly associated with transplant-free survival in both cohorts (discovery: age-, sex-, and ancestry-adjusted hazard ratio, 3.73; 95% CI, 1.92-7.28; P = 0.0001; replication: hazard ratio, 2.72; 95% CI, 1.26-5.88; P = 0.011).Conclusions: A substantial proportion of patients diagnosed with CHP have rare, protein-altering variants in telomere-related genes, which are associated with short peripheral blood telomere length and significantly reduced transplant-free survival.

Analysis of risk factors influencing the progression-free survival in WHO II grade gliomas

Objective To investigate the risk factors that influence the progression-free survival (PFS) in WHO Ⅱ-grade gliomas in adults. Methods Clinical data obtained from 72 patients with WHO Ⅱ grade gliomas undergoing surgical resection between January 2008 and December 2015 at Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University were analyzed. Immunohistochemistry staining method was employed to detect mutation of isocitrate dehydrogenase 1(IDH1) R132H, α thalassemia/mental retardation syndrome X-linked(ATRX) and the expression of regulator of telomere elongation helicase 1(RTEL1). Survival analysis was estimated by Kaplan-Meier analysis. Cox regression modelling was used for univariate analysis and multivariate analysis. Results The results of immunohistochemical staining in 72 patients with gliomas revealed 39 (54.2%) cases of IDH1 R132H mutant positive, 33 (45.8%) cases of negative; 56 (77.8%) cases of ATRX missing mutant negative, 16 (22.2%) cases of positive; 29 (40.3%) cases of RTEL1 positive and 43 (59.7%) cases of negative. The results of survival analysis showed that the cumulative PFS rate of IDH1 R132H negative patients was lower than that of IDH1 R132H positive(P 0.05). The cumulative PFS rate of RTEL1 positive patients was lower than that of RTEL1 negative patients (P 40 years (OR=3.618, 95% CI: 1.688-7.753, P=0.001), partial resection (OR=0.204, 95% CI: 0.064-0.656, P=0.008), expression of IDH1 R132H negative (OR=2.867, 95% CI: 1.129-7.282, P=0.027) and RTEL1 positive (OR=0.354, 95% CI: 0.151-0.827, P=0.016) were independent factors influencing PFS of glioma patients, and could be independently used for prognostic judgment of glioma patients. Conclusion Age (>40 years), degree of tumor resection (partial resection), expression of IDH1 R132H (negative) and RTEL1 expression (positive) are independent risk factors affecting the PFS of WHO Ⅱ-grade gliomas. Key words: Glioma; Progression-free survival; Isocitrate dehydrogenase 1; α thalassemia/mental retardation syndrome X-linked; Telomere elongation helicase 1

Telomerase Variants in Patients with Cirrhosis Awaiting Liver Transplantation.

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).

Association analysis of RTEL1 variants with risk of adult gliomas in a Korean population.

Previous studies have identified multiple loci for inherited susceptibility to glioma development, including the regulator of telomere elongation helicase 1 (RTEL1). However, the association between RTEL1 variants and risk of glioma has not been well understood. Therefore, we sought to comprehensively examine the genetic interaction between RTEL1 variants and risk of glioma with respect to defined histological and molecular subtypes. We employed a case-control study involving 250 adult glioma patients with previous molecular alterations and 375 population–based controls within Korean populations. Statistical analyses on the association between RTEL1 single nucleotide polymorphisms (SNPs) and glioma risk were conducted using unconditional logistic regression. Additional conditional and stepwise analyses were performed on significant RTEL1 SNPs. We detected significant associations (Bonferroni P < .05) between six SNPs (rs6089953, rs3848669, rs6010620, rs3787089, rs6062302, and rs115303435) and risk of glioma in the Korean subjects. The two coding variants, rs6062302 (D664D) and rs115303435 (A1059T), were plausibly causal variants and were independent among the significantly associated RTEL1 variants. The glioma subgroup analyses showed that the causal variants (rs6062302 and rs115303435) may be associated with increased risk of glioma regardless of histological grades and molecular alterations. This study provides a deeper understanding of relationships between RTEL1 variants and risk of glioma. Further studies are required to ascertain the impact of those variants on glioma susceptibility.

Relative Telomere Length and Stroke Risk in a Chinese Han Population.

This study aimed to further understand the role of relative telomere length (RTL) in susceptibility to stroke and investigate the association regulator of telomere elongation helicase 1 (RETL1) gene polymorphisms and RTL. RTL was measured using the real-time quantitative polymerase chain reaction (qPCR) from 300 stroke patients and 299 healthy controls. Genotyping was performed using the Sequenom MassARRAY platform. The results indicated that stroke patients had significantly shorter median RTL than controls (P < 0.001). Compared with the longer RTL (≥ 0.766), the shorter RTL (< 0.766) was significantly increased the risk of stroke (odds ratio [OR] = 8.44, 95% confidence interval [CI] 5.42-13.14, P < 0.001). The RTL was categorized into tertiles, we found that the shorter RTL (0.515-1.366) (OR = 16.27, 95% CI 7.72-34.29, P < 0.001) and lowest RTL (< 0.515) (OR = 30.63, 95% CI 14.27-65.75, P < 0.001) were significantly increased stroke risk compared with the highest RTL (> 1.366). Stratified analysis showed that the shorter RTL was also significantly increased the risk of stroke compared with the longer RTL in male, age < 60years and ≥ 60years, except the female participants. In addition, individuals with the genotypes AA (rs2297441) and GG (rs6089953) have shorter telomeres than the genotypes GG (P = 0.031) and AA (P = 0.032), respectively. Our results suggested that shorter RTL was associated with an increased risk of stroke. The association was found between the genotypes AA (rs2297441) and GG (rs6089953) and shorter RTL in case group. Further studies in larger sample size and biological functional assays are warranted to validate our findings.