{"publication_id":"054f72de-a886-4506-a529-11d92344f009","content_hash":"sha256:0b8eec7084df48cfcdfd0f940d669e121eae847e31c36324d04ef97b4789e950","nodes":[{"id":"054f72de-a886-4506-a529-11d92344f009","type":"publication","title":"Adjacent Evidence Brief: Telomere Cancer Effects — full paper"},{"id":"claim_1","type":"claim","text":"This synthesis tests the thesis that evidence for Telomere Cancer Effects is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation. Evidence-honesty note: The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims. This paper synthesizes evidence on telomere cancer effects across 25 included source papers and 826 high-confidence extracted claims. The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 24 adjacent clinical sources, and 1 mechanistic or model-system source, with 3 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the frailty outcome class; null signals are summarized in the immune and inflammation and mechanism outcome classes; negative signals are summarized in the dosing and pharmacokinetics outcome class; mixed or heterogeneous signals are summarized in the contextual adjacent evidence, mortality and survival, and longevity outcome classes. The paper therefore reports a source-directness and outcome-class map rather than a pooled effect."},{"id":"claim_2","type":"claim","text":"This synthesis tests the thesis that evidence for Telomere Cancer Effects is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation."},{"id":"claim_3","type":"claim","text":"Evidence-honesty note: The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims."},{"id":"claim_4","type":"claim","text":"This paper synthesizes evidence on telomere cancer effects across 25 included source papers and 826 high-confidence extracted claims."},{"id":"claim_5","type":"claim","text":"The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 24 adjacent clinical sources, and 1 mechanistic or model-system source, with 3 cross-study disagreements across the evidence base."},{"id":"claim_6","type":"claim","text":"Positive study-level signals are summarized in the frailty outcome class; null signals are summarized in the immune and inflammation and mechanism outcome classes; negative signals are summarized in the dosing and pharmacokinetics outcome class; mixed or heterogeneous signals are summarized in the contextual adjacent evidence, mortality and survival, and longevity outcome classes. The paper therefore reports a source-directness and outcome-class map rather than a pooled effect."},{"id":"claim_7","type":"claim","text":"The conclusion is narrower: the retained evidence maps associations, mechanisms, and candidate endpoints for follow-up; it does not establish clinical benefit, therapeutic actionability, or anti-aging efficacy."},{"id":"claim_8","type":"claim","text":"For Telomere Cancer Effects, what does the retained evidence show about prognostic or risk-marker associations, causal or mechanistic evidence, treatment or intervention relevance across prognostic and survival-marker evidence, treatment or intervention-response evidence, causal-risk and Mendelian-randomization evidence, and are those outcome-class source-level signals directionally consistent enough for clinical actionability once unclear direction coding, adjacent/contextual source roles, and directness limits are considered?"},{"id":"claim_9","type":"claim","text":"This manuscript is reported as a Thin-corpus evidence brief. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-telomere_cancer_effects-v06-DAILY-2026-06-28T00-39-28Z`."},{"id":"claim_10","type":"claim","text":"The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text."},{"id":"claim_11","type":"claim","text":"Risk-of-bias framework assignment follows study design (RoB-2 for RCTs, ROBINS-I for non-randomised studies, AMSTAR-2 for systematic reviews / meta-analyses). Public appraisal claims are limited to populated `risk_of_bias.json` rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification."},{"id":"claim_12","type":"claim","text":"Evidence-tension synthesis: claims grouped by outcome class (contextual adjacent evidence, dosing and pharmacokinetics, frailty, immune and inflammation, longevity, mechanism, mortality and survival); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates."},{"id":"claim_13","type":"claim","text":"Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified."},{"id":"claim_14","type":"claim","text":"Source directness breakdown: 0/25 retained sources directly address the stated topic and aging-relevant hard endpoints; 25/25 are adjacent, contextual, review-level, or mechanistic and are used only to bound interpretation. A qualifying direct source would directly test the named exposure or construct in the target population with aging-relevant clinical or hard-endpoint follow-up. Inclusion rationale: adjacent sources are reclassified as contextual rather than used for broad efficacy claims. Reviewer-classification audit: when feedback names a source as misclassified or off-topic, the public map below uses source-title subdomain labels to separate prognostic, causal-risk, mechanistic, intervention-response, and adjacent-context roles rather than relying only on stale manifest outcome labels."},{"id":"claim_15","type":"claim","text":"Alhareeri 2020: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2."},{"id":"claim_16","type":"claim","text":"Jaeger 2024: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2."},{"id":"claim_17","type":"claim","text":"Markozannes 2022: outcome=Immune and Inflammation; direction=null; directness=review; tier=B2."},{"id":"claim_18","type":"claim","text":"Li 2026: outcome=Contextual Adjacent Evidence; direction=positive; directness=indirect; tier=B2."},{"id":"claim_19","type":"claim","text":"Davidson-Swinton 2026: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2."},{"id":"claim_20","type":"claim","text":"Langsenlehner 2026: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2."},{"id":"claim_21","type":"claim","text":"Gil-Korilis 2026: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2."},{"id":"claim_22","type":"claim","text":"Cheng 2026: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2."},{"id":"claim_23","type":"claim","text":"Bhat 2023: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2."},{"id":"claim_24","type":"claim","text":"Brown 2026: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2."},{"id":"claim_25","type":"claim","text":"Chen 2023: outcome=Contextual Adjacent Evidence; direction=null; directness=review; tier=B2."},{"id":"claim_26","type":"claim","text":"Alqaisi 2026: outcome=Contextual Adjacent Evidence; direction=null; directness=review; tier=B2."},{"id":"claim_27","type":"claim","text":"Wan 2023: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2."},{"id":"claim_28","type":"claim","text":"Genetta 2026: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2."},{"id":"claim_29","type":"claim","text":"Andreikos 2024: outcome=Contextual Adjacent Evidence; direction=unclear; directness=review; tier=B2."},{"id":"claim_30","type":"claim","text":"Song 2022: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2."},{"id":"source_1","type":"source","study":"Shorter telomere length as a prognostic marker for survival and recurrence in breast cancer: a systematic review and meta-analysis","year":2025,"doi":"10.37349/etat.2025.1002289","url":"https://doi.org/10.37349/etat.2025.1002289","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Sasmita 2025","excerpt":"BACKGROUND: Telomere length is a potential prognostic biomarker in breast cancer, but its clinical utility remains uncertain due to inconsistent findings across the literature. This systematic review and meta-analysis aims to evaluate the association between telomere length and breast cancer survival outcomes, including overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), and recurrence-free survival (RFS). METHODS: A systematic search of ten sources, including databases and publishers (JSTOR, Nature, ProQuest, PubMed, Sage Journals, ScienceDirect, Science, Scopus, Springer, and Wiley) was conducted to identify studies published up to December 31, 2023. Studies reporting associations between telomere length and survival outcomes in breast cancer patients were included. Hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CI) were extracted or calculated. Quality assessment was performed using the Newcastle-Ottawa Scale, and publication bias was evaluated using funnel plots, Egger's, and Begg's tests. RESULTS: Nine studies involving 3,145 breast cancer patients were included."},{"id":"source_2","type":"source","study":"Telomere lengths in women treated for breast cancer show associations with chemotherapy, pain symptoms, and cognitive domain measures: a longitudinal study","year":2020,"doi":"10.1186/s13058-020-01368-6","url":"https://doi.org/10.1186/s13058-020-01368-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Alhareeri 2020","excerpt":"BACKGROUND: Survival rates for breast cancer (BC) have improved, but quality of life post-diagnosis/treatment can be adversely affected, with survivors reporting a constellation of psychoneurological symptoms (PNS) including stress, anxiety, depression, pain, fatigue, sleep disturbance, and cognitive dysfunction. METHODS: To assess a potential relationship between telomere length (TL) and the development/persistence of PNS, we longitudinally studied 70 women (ages 23-71) with early stage BC (I-IIIA) at 5 time-points: prior to treatment (baseline), the mid-point of their chemotherapy cycle, 6 months, 1 year, and 2 years following the initiation of chemotherapy. Measures quantified included assessments of each of the PNS noted above and TL [using both a multiplex qPCR assay and a chromosome-specific fluorescence in situ hybridization (FISH) assay]. RESULTS: Variables associated with qPCR mean TLs were age (p = 0.004) and race (T/S ratios higher in Blacks than Whites; p = 0.019). Significant differences (mostly decreases) in chromosome-specific TLs were identified for 32 of the 46 chromosomal arms at the mid-chemo time-point (p = 0.004 to 0.049)."},{"id":"source_3","type":"source","study":"A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study","year":2024,"doi":"10.3390/nu16172963","url":"https://doi.org/10.3390/nu16172963","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Jaeger 2024","excerpt":"Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, maintaining genomic integrity during the cell cycle. A decrease in average telomere length is associated with with age and with aging-related diseases such as cancer and cardiovascular disease. In this study, we conducted a randomized, double-blind, placebo-controlled trial over six months to compare the effects of the Astragalus-based supplement versus a placebo on telomere length (TL) in 40 healthy volunteers (mean age 56.1 ± 6.0 years). Twenty subjects received the supplement, and 20 received placebo capsules. All participants completed the study, and no adverse side effects were reported at six months. Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL."},{"id":"source_4","type":"source","study":"The association of epigenetic age acceleration with internal smoking dose, risk of lung cancer, and all-cause mortality in cigarette smokers: the Multiethnic Cohort study","year":2026,"doi":"10.1186/s13148-026-02137-6","url":"https://doi.org/10.1186/s13148-026-02137-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Liu 2026","excerpt":"BACKGROUND: Among cigarette smokers, higher internal smoking dose is associated with elevated lung cancer risk and mortality, independent of smoking pack-years. Some measures of epigenetic age acceleration (EAA) are associated with cigarette smoking status and exposure, as well as lung cancer risk and overall mortality. No study has examined the association between EAA measures and internal smoking dose (total nicotine equivalents (TNE; nmol/mL)), and their shared relationship with lung cancer incidence and mortality in a multiethnic population. METHODS: From a subgroup of Multiethnic Cohort Study participants who smoked cigarettes at the time of biospecimen collection (n = 1969), six epigenetic clocks were computed using blood-based DNA methylation (DNAm) array data. EAA measures were computed by calculating the residuals that results from regressing an epigenetic clock on chronological age. The association of urinary TNE with EAA measures were assessed using linear regression models, adjusted for age, sex, body mass index (BMI; kg/m 2 ), DNAm-based estimates of blood cell composition, population stratification, and self-reported pack-years of cigarette smoking."},{"id":"source_5","type":"source","study":"Systematic review of Mendelian randomization studies on risk of cancer","year":2022,"doi":"10.1186/s12916-022-02246-y","url":"https://doi.org/10.1186/s12916-022-02246-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Markozannes 2022","excerpt":"BACKGROUND: We aimed to map and describe the current state of Mendelian randomization (MR) literature on cancer risk and to identify associations supported by robust evidence. METHODS: We searched PubMed and Scopus up to 06/10/2020 for MR studies investigating the association of any genetically predicted risk factor with cancer risk. We categorized the reported associations based on a priori designed levels of evidence supporting a causal association into four categories, namely robust, probable, suggestive, and insufficient, based on the significance and concordance of the main MR analysis results and at least one of the MR-Egger, weighed median, MRPRESSO, and multivariable MR analyses. Associations not presenting any of the aforementioned sensitivity analyses were not graded. RESULTS: We included 190 publications reporting on 4667 MR analyses. Most analyses (3200; 68.6%) were not accompanied by any of the assessed sensitivity analyses. Of the 1467 evaluable analyses, 87 (5.9%) were supported by robust, 275 (18.7%) by probable, and 89 (6.1%) by suggestive evidence."},{"id":"source_6","type":"source","study":"Aging and increased cancer risk: exploring the potential of LE8 score to mitigate risk","year":2026,"doi":"10.1038/s41514-026-00352-2","url":"https://doi.org/10.1038/s41514-026-00352-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Li 2026","excerpt":"Given global population aging and the absence of aging-reversal therapies, elucidating the aging-related cancer risk association and developing cancer prevention strategies are imperative. This population-based cohort study analyzed data from the UK Biobank. Aging was assessed through four validated markers, including Klemera-Doubal method (KDM), PhenoAge, leukocyte telomere length (TL) and chronological age. Over a median follow-up of 13.5 years, significant associations between all aging measures and elevated overall cancer risk were observed. False discovery rate (FDR)-corrected analyses revealed a significant association in a biological aging group for seven site-specific cancers, including esophageal, colorectal, pancreatic, skin, kidney, urinary tract cancers, and lymphoma, as evaluated by the four aging markers. A significant interaction (FDR-corrected p < 0.05) between Life's Essential 8 (LE8) and PhenoAge was observed for lung cancer risk."},{"id":"source_7","type":"source","study":"Lymphoid malignancy and clonality in the POT1-mediated long telomere syndrome ∗","year":2026,"doi":"10.1182/blood.2025031287","url":"https://doi.org/10.1182/blood.2025031287","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Davidson-Swinton 2026","excerpt":"Long telomere length (TL) extends replicative capacity in vitro and predisposes to clonal hematopoiesis. We characterized the cancer phenotype in 51 individuals from 24 families with mutant POT1, a negative regulator of telomerase elongation (median age, 51 years [range, 5-94]). Hematologic malignancies were second in prevalence after melanoma (27%), and lymphoid subsets were more common. They clustered with history of sarcoma, thyroid cancer, and chronic myeloproliferative neoplasms. UK Biobank participants with pathogenic POT1 variants had long TL and higher lymphoid malignancy rates (45% by the age of 80 years; hazard ratio, 8.28; 95% confidence interval, 5.29-13.0). Across cohorts, diagnoses encompassed acute lymphoblastic leukemia and Hodgkin lymphoma in children/young adults and chronic lymphocytic leukemia/multiple myeloma in adults. They clustered in families manifesting as autosomal dominant pan-lymphoma with genetic anticipation at times. Lymphocyte TL was longer than granulocytes at baseline (age-adjusted mean +1 kilobase; P< .0001) and was preserved longitudinally with aging."},{"id":"source_8","type":"source","study":"Leukocyte telomere attrition following radiotherapy in prostate cancer: a prospective study","year":2026,"doi":"10.1038/s41598-026-36205-x","url":"https://doi.org/10.1038/s41598-026-36205-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Langsenlehner 2026","excerpt":"Telomeres are protective protein-bound DNA repeat structures at the end of chromosomes, which play a critical role in maintaining chromosomal stability. With each somatic-cell division, telomeres progressively shorten, making telomere length a potential biomarker of biological aging. Ionizing radiation may accelerate telomere attrition, thereby promoting aging-related changes. In the present study, we analyzed the influence of radiotherapy on leucocyte telomere length in prostate cancer patients. A total of 314 patients treated with curative radiotherapy for prostate cancer were included in the present prospective study. Leukocyte relative telomere length (RTL) was measured by qPCR in peripheral blood samples collected before radiotherapy, at the end of radiotherapy, and at 3 and 15 months post-radiotherapy. Mean RTL values were 0.65 ± 0.34 at baseline, 0.62 ± 0.31 at the end of radiotherapy, 0.67 ± 0.43, and 0.55 ± 0.26 at the first and at the second follow-up, respectively. . Paired-Samples T-Test comparisons showed a significant reduction in RTL at 15 months post- radiotherapy compared to baseline (p < 0.001), end of radiotherapy (p = 0."},{"id":"source_9","type":"source","study":"Effect of Traditional Korean Medicine Oncotherapy on the Survival, Quality of Life, and Telomere Length: A Prospective Cohort Study","year":2023,"doi":"10.1177/15347354231154267","url":"https://doi.org/10.1177/15347354231154267","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Ha 2023","excerpt":"A 4-year prospective cohort study on patients with lung, gastric, hepatic, colorectal, breast, uterine, and ovarian cancer was conducted at the East-West Cancer Center (EWCC) of Daejeon Korean Medicine Hospital in Daejeon, Korea. We divided patients into 2 groups based on how long they had been receiving TKM oncotherapy and compared event-free survival (EFS), telomere length change, and quality of life (QoL). The study collected data on 83 patients from October 2016 to June 2020 and discovered no statistical differences in EFS based on the duration of TKM oncotherapy. In the analysis of changes in QoL outcomes, there were no statistically significant group differences between the groups. After controlling for covariates that could affect telomere length, the long-term TKM oncotherapy group had a higher daily telomere attrition rate. The study of the relationship between telomere length and prognostic factors discovered that patients with advanced N stage at the time of diagnosis and who had previously received radiotherapy had shorter telomere length."},{"id":"source_10","type":"source","study":"Unraveling the telomere-mitochondrial axis in colorectal cancer: Results from a prospectively followed cohort","year":2026,"doi":"10.1186/s10020-026-01423-6","url":"https://doi.org/10.1186/s10020-026-01423-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Gil-Korilis 2026","excerpt":"BACKGROUND: Telomere shortening and mitochondrial dysfunction are well-known independent contributors to many diseases, but emerging evidence suggests a reciprocal relationship between the two processes. The role of the so-called telomere-mitochondrial axis in colorectal cancer (CRC) remains largely unknown. METHODS: This prospective cohort study screened CRC patients who underwent surgery, from whom peripheral blood, intestinal mucosa, and tumor samples were collected. Colonoscopically confirmed cancer- and adenoma-free healthy individuals were screened as controls, from whom peripheral blood and intestinal mucosa samples were obtained. Relative mitochondrial DNA copy number (mtDNA-CN) and relative telomere length (RTL) were measured in all samples by real-time quantitative polymerase chain reaction and were further compared and correlated considering clinical data. Relative mtDNA-CN was quantified using both TaqMan probes and SYBR Green to compare both methods. Finally, multivariable analyses were conducted to investigate the association between both biomarkers and the risk of tumor recurrence and mortality."},{"id":"source_11","type":"source","study":"Integrative Analysis of Telomere‐Related Genes Reveals Prognostic Signatures in Laryngeal Cancer","year":2026,"doi":"10.1155/ijog/5301600","url":"https://doi.org/10.1155/ijog/5301600","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Cheng 2026","excerpt":"BACKGROUND: Laryngeal cancer (LC) is a common malignant tumor. Telomere-related genes (T-RGs) play critical roles in cellular senescence and carcinogenesis, but their prognostic relevance in LC remains to be fully elucidated. Therefore, exploring the prognostic genes related to telomeres in LC is important. METHODS: Public retrospective datasets TCGA-HNSC and T-RGs were used to identify candidate genes by intersecting differentially expressed genes with T-RGs. Key analytical approaches, including machine learning algorithms and univariate Cox regression, were applied to identify prognostic genes and construct a prognostic model. A nomogram was developed to assess the prognostic value for LC based on overall survival. Disease samples were classified into high-risk and low-risk groups, and subsequent analyses included immune infiltration, immune checkpoint expression, and related evaluations. Experimental validation of prognostic genes was performed through RT-qPCR. RESULTS: A total of 314 candidate genes were obtained from 8961 differentially expressed genes. Four key prognostic genes (CHTF18, FANCG, NR5A1, and XRCC3) were identified."},{"id":"source_12","type":"source","study":"Leukocyte Telomere Length Variants Are Independently Associated with Survival of Patients with Colorectal Cancer","year":2026,"doi":"10.3390/cancers18030490","url":"https://doi.org/10.3390/cancers18030490","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sarkar 2026","excerpt":"Background and aims : Aberrations in telomere length can have important implications in cancer. Using a cohort of 1007 patients, we investigated whether leukocyte telomere length (LTL) in patients with colorectal cancer (CRC) is associated with survival. We also investigated whether some telomere maintenance genes are associated with survival in these patients. Methods: The Biobank for Gastrointestinal Health Research (BGHR), an ongoing project involving collection of biospecimens at the Mayo Clinic, was utilized to obtain data from patients diagnosed with stage II or III CRC. Blood samples were collected prior to chemotherapy/radiation and DNA was extracted for measuring median LTL. The main outcome measures were overall survival (OS) and disease-free survival (DFS) by disease stage. Results: A significant inverse relationship was observed with patient age and LTL (spearman correlation coefficient (r) = -0.48, 95%; p = 1.13 × 10 -58 ). Females had significantly longer LTL than males ( p = 3.97 × 10 -5 ). The rs1317082 SNP in the TERC gene was significantly associated with both OS and DFS in combined stage II and stage III patients ( p = 0.017 and p = 0.023, respectively)."},{"id":"source_13","type":"source","study":"DNA methylation‐based telomere length is associated with HIV infection, physical frailty, cancer, and all‐cause mortality","year":2024,"doi":"10.1111/acel.14174","url":"https://doi.org/10.1111/acel.14174","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Liang 2024","excerpt":"Telomere length (TL) is an important indicator of cellular aging. Shorter TL is associated with several age-related diseases including coronary heart disease, heart failure, diabetes, osteoporosis, and cancer. Recently, a DNA methylation-based TL (DNAmTL) estimator has been developed as an alternative method for directly measuring TL. In this study, we examined the association of DNAmTL with cancer prevalence and mortality risk among people with and without HIV in the Veterans Aging Cohort Study Biomarker Cohort (VACS, N = 1917) and Women's Interagency HIV Study Cohort (WIHS, N = 481). We profiled DNAm in whole blood (VACS) or in peripheral blood mononuclear cells (WIHS) using an array-based method. Cancer prevalence was estimated from electronic medical records and cancer registry data. The VACS Index was used as a measure of physiologic frailty. Models were adjusted for self-reported race and ethnicity, batch, smoking status, alcohol consumption, and five cell types (CD4, CD8, NK, B cell, and monocyte). We found that people with HIV had shorter average DNAmTL than those without HIV infection [beta = -0.25, 95% confidence interval (-0.32, -0.18), p = 1.48E-12]."},{"id":"source_14","type":"source","study":"Associations between telomere attrition, genetic variants in telomere maintenance genes, and non-small cell lung cancer risk in the Jammu and Kashmir population of North India","year":2023,"doi":"10.1186/s12885-023-11387-z","url":"https://doi.org/10.1186/s12885-023-11387-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Bhat 2023","excerpt":"BACKGROUND: Telomeres are repetitive DNA sequences located at the ends of chromosomes, playing a vital role in maintaining chromosomal integrity and stability. Dysregulation of telomeres has been implicated in the development of various cancers, including non-small cell lung cancer (NSCLC), which is the most common type of lung cancer. Genetic variations within telomere maintenance genes may influence the risk of developing NSCLC. The present study aimed to evaluate the genetic associations of select variants within telomere maintenance genes in a population from Jammu and Kashmir, North India, and to investigate the relationship between telomere length and NSCLC risk. METHODS: We employed the cost-effective and high-throughput MassARRAY MALDI-TOF platform to assess the genetic associations of select variants within telomere maintenance genes in a population from Jammu and Kashmir, North India. Additionally, we used TaqMan genotyping to validate our results. Furthermore, we investigated telomere length variation and its relation to NSCLC risk in the same population using dual-labeled fluorescence-based qPCR."},{"id":"source_15","type":"source","study":"SMARCAL1 is a targetable synthetic lethal therapeutic vulnerability in ATRX-deficient gliomas that use alternative lengthening of telomeres","year":2026,"doi":"10.1093/neuonc/noaf300","url":"https://doi.org/10.1093/neuonc/noaf300","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Brown 2026","excerpt":"BACKGROUND: Approximately 10% of cancers achieve replicative immortality through a telomerase-independent mechanism of telomere maintenance, termed Alternative Lengthening of Telomeres (ALT). ALT is particularly prevalent in certain subtypes of malignant gliomas, such as IDH-mutant astrocytoma and pediatric glioblastoma, and frequently co-occurs with ATRX (ATRX chromatin remodeler) inactivating mutations. Although ALT is an adaptive mechanism through which cancer cells achieve proliferative immortality, the elevated levels of replication stress observed in ALT tumors constitute a potential therapeutic vulnerability. METHODS: Leveraging CRISPR/Cas9 screening data from the Cancer Dependency Mapping Project, coupled with patient-derived cell lines and xenografts, we identified SMARCAL1 as a novel synthetic lethal vulnerability in ATRX-deficient glioma models that engage ALT. Using complementary molecular assays for DNA damage, telomere maintenance, and telomeric replication stress, we define the mechanisms underlying cytotoxicity induced by SMARCAL1 depletion in ALT-positive glioma cells."},{"id":"source_16","type":"source","study":"Association between genetically determined telomere length and health‐related outcomes: A systematic review and meta‐analysis of Mendelian randomization studies","year":2023,"doi":"10.1111/acel.13874","url":"https://doi.org/10.1111/acel.13874","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Chen 2023","excerpt":"Emerging evidence has shown that leukocyte telomere length (LTL) is associated with various health-related outcomes, while the causality of these associations remains unclear. We performed a systematic review and meta-analysis of current evidence from Mendelian randomization (MR) studies on the association between LTL and health-related outcomes. We searched PubMed, Embase, and Web of Science up to April 2022 to identify eligible MR studies. We graded the evidence level of each MR association based on the results of the main analysis and four sensitive MR methods, MR-Egger, weighted median, MR-PRESSO, and multivariate MR. Meta-analyses of published MR studies were also performed. A total of 62 studies with 310 outcomes and 396 MR associations were included. Robust evidence level was observed for the association between longer LTL and increased risk of 24 neoplasms (the strongest magnitude for osteosarcoma, GBM, glioma, thyroid cancer, and non-GBM glioma), six genitourinary and digestive system outcomes of excessive or abnormal growth, hypertension, metabolic syndrome, multiple sclerosis, and clonal hematopoiesis of indeterminate potential."},{"id":"source_17","type":"source","study":"Telomerase Activity in Melanoma: Impact on Cancer Cell Proliferation Kinetics, Tumor Progression, and Clinical Therapeutic Strategies—A Scoping Review","year":2026,"doi":"10.3390/curroncol33020074","url":"https://doi.org/10.3390/curroncol33020074","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Alqaisi 2026","excerpt":"Background : Melanoma outcomes have improved in recent years as a result of modern systemic therapies. A major molecular feature of melanoma is abnormal telomerase activation; this is most often caused by telomerase reverse transcriptase (TERT) promoter mutations, which occur in 50-82% of cases and are the most common noncoding alteration in this cancer. Telomerase maintains telomere length, allowing melanoma cells to avoid senescence and continue dividing. However, how telomerase activity influences melanoma cell doubling time remains unclear, and the pathways linking TERT expression to faster cell-cycle progression require further study. Although telomerase inhibitors show promise in preclinical models, their clinical use is limited by delayed cytotoxicity and resistance. Materials and Methods : A scoping review was conducted using Scopus, ScienceDirect, MEDLINE/PubMed, and CINAHL (Cumulative Index to Nursing and Allied Health Literature). Keywords included \"telomerase,\" \"melanoma,\" \"cancer,\" \"cell proliferation,\" and \"doubling time,\" using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines."},{"id":"source_18","type":"source","study":"ZEB1 Promotes Alternate Lengthening of Telomeres at Multiple Levels","year":2026,"doi":"10.3390/cancers18030499","url":"https://doi.org/10.3390/cancers18030499","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Genetta 2026","excerpt":"BACKGROUND/OBJECTIVES: Approximately 10-15% of cancers rely on Alternate Lengthening of Telomeres (ALT), which is a telomerase-independent, BIR (Break-Induced Replication)-based pathway for maintaining long-term replicative potential. METHODS: As ALT is over-represented in mesenchymal-type tumors, we investigated, via RNA-seq, the extent to which the EMT-promoting factor ZEB1 regulates this pathway. RESULTS: The ALT-associated genes targeted by ZEB1, including PML, RMI2, POLD4, RPA3 (induced), SLX4, and WRN (repressed), in the aggregate, suggest that it regulates ALT at multiple steps in that pathway. ZEB1-deficient cells showed a significant reduction in telomere length as well as in two hallmarks of ALT, C-circle levels and the size and number of ALT-associated PML Bodies (APBs), which are the telomere-aggregating compartments in which BIR occurs. As one of the most highly regulated genetic targets of ZEB1 was the pro-epithelial alternative splicing factor ESRP1, we investigated whether the repression of this factor was required to generate the PML splice variant isoform IV, which is the major structural component of APBs."},{"id":"source_19","type":"source","study":"Mendelian randomization study on the causal relationship between leukocyte telomere length and prostate cancer","year":2023,"doi":"10.1371/journal.pone.0286219","url":"https://doi.org/10.1371/journal.pone.0286219","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Wan 2023","excerpt":"BACKGROUND: Leukocyte telomere length (LTL) is related to prostate cancer (PCa). However, the causal relationship between them remains unknown. This study was aimed at identifying the causal direction between LTL and PCa with Mendelian randomization (MR). METHODS: Single-nucleotide polymorphisms associated with LTL were identified from a genome-wide association study (GWAS) involving 472,174 individuals. Summary-level data of PCa-related GWAS were extracted from four cohorts comprising 456,717 individuals. An inverse-variance-weighted (IVW) algorithm was used for MR. Sensitivity analyses were performed with MR-Egger regression, IVW regression, leave-one-out test, and MR-Pleiotropy Residual Sum and Outlier analyses. A meta-analysis was also performed to compute the average genetically determined effect of LTL on PCa. RESULTS: A long LTL was associated with an increased risk of PCa in all cohorts, with odds ratios of 1.368 (95% confidence interval [CI]: 1.247 to 1.500, P = 2.84×10-11), 1.503 (95% CI: 1.243 to 1.816, P = 2.57×10-5), 1.722 (95% CI: 1.427 to 2.077, P = 1.48×10-8), and 1.358 (95% CI: 1.242 to 1.484, P = 1.73×10-11) in the IVW analysis."},{"id":"source_20","type":"source","study":"The Association between Telomere Length and Head and Neck Cancer Risk: A Systematic Review and Meta-Analysis","year":2024,"doi":"10.3390/ijms25169000","url":"https://doi.org/10.3390/ijms25169000","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Andreikos 2024","excerpt":"Telomeres play a crucial role in maintaining chromosomal integrity and regulating the number of cell divisions and have been associated with cellular aging. Telomere length (TL) has been widely studied in manifold cancer types; however, the results have been inconsistent. This systematic review and meta-analysis aims to analyze the evidence on the association between TL and head and neck cancer (HNC) risk. We comprehensively searched the literature in PubMed, Cochrane Library, and Scopus and identified nine eligible studies, which yielded 11 datasets. The odds ratios (ORs) and 95% confidence intervals (CIs) were used to ascertain the strength of the association. On the basis of the median TL, we defined two groups, short TL and long TL, with the latter being the reference group. Our analysis found a significant relationship between short TL and increased HNC risk (OR 1.38, 95% CI: 1.10-1.73, p = 0.005), while significant heterogeneity among the studies was noted. The subgroup analysis on HNC subtypes revealed a significant association between short TL and oral cancers (OR 2.08, 95% CI: 1.23-3.53, p = 0.007)."},{"id":"source_21","type":"source","study":"Association Between Telomere Length and Skin Cancer and Aging: A Mendelian Randomization Analysis","year":2022,"doi":"10.3389/fgene.2022.931785","url":"https://doi.org/10.3389/fgene.2022.931785","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Song 2022","excerpt":"Background: Telomere shortening is a hallmark of cellular senescence. However, telomere length (TL)-related cellular senescence has varying effects in different cancers, resulting in a paradoxical relationship between senescence and cancer. Therefore, we used observational epidemiological studies to investigate the association between TL and skin cancer and aging, and to explore whether such a paradoxical relationship exists in skin tissue. Methods: This study employed two-sample Mendelian randomization (MR) to analyze the causal relationship between TL and skin cancer [melanoma and non-melanoma skin cancers (NMSCs)] and aging. We studied single nucleotide polymorphisms (SNPs) obtained from pooled data belonging to genome-wide association studies (GWAS) in the literature and biobanks. Quality control was performed using pleiotropy, heterogeneity, and sensitivity analyses. Results: We used five algorithms to analyze the causal relationship between TL and skin aging, melanoma, and NMSCs, and obtained consistent results. TL shortening reduced NMSC and melanoma susceptibility risk with specific odds ratios (ORs) of 1.0344 [95% confidence interval (CI): 1.0168-1.0524, p = 0.01] and 1."},{"id":"source_22","type":"source","study":"Integrative Bulk and Single-Cell Transcriptome Profiling of Telomere-Related Genes Reveals a Robust Prognostic Signature and Immunotherapeutic Landscape in Neuroblastoma","year":2026,"doi":"10.7150/jca.129718","url":"https://doi.org/10.7150/jca.129718","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Aierken 2026","excerpt":"PURPOSE: Neuroblastoma (NB) is the most common extracranial solid tumor in children with poor overall survival. Increasing evidence indicates that telomeres contribute to tumorigenesis and influence cancer prognosis. However, the biological and clinical implications of telomere-related genes (TRGs) in NB remain poorly defined. MATERIALS AND METHODS: We integrated data from multiple independent cohorts to elucidate the roles of TRGs in NB. Differential expression and weighted gene co-expression network analyses (WGCNA) were performed to identify telomere-related differentially expressed genes (TRDEGs) linked to patient survival. Consensus clustering based on TRDEG expression patterns was conducted to stratify molecular subtypes, followed by functional enrichment analysis. A prognostic signature was then built using machine-learning algorithms to predict clinical outcomes and potential therapeutic responses. Single-cell RNA sequencing (scRNA-seq) data were used for signature gene expression validation and to guide functional candidate selection."},{"id":"source_23","type":"source","study":"Telomere-driven dysfunctional changes in gynecological cancers: mechanistic insights, biomarker potential, and therapeutic targeting","year":2026,"doi":"10.3389/fcell.2026.1797677","url":"https://doi.org/10.3389/fcell.2026.1797677","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"mechanistic","cited_as":"Afolabi 2026","excerpt":"Telomeres are major determinants of chromosome integrity, and when poorly regulated, they have been shown to contribute critically to malignant transformation. However, in gynaecological malignancies, telomeres are interpreted inconsistently and have yet to be smoothly incorporated into diverse disease types. The review incorporates the existing evidence of the relationship between telomere dysfunction and the evolution of cervical, ovarian, endometrial, vulvar, and vaginal cancer. The review discusses the joint causes of telomere erosion, defective capping, defective integrity, and dysregulated telomerase activity in gynaecological cancer development, and the ensuing genomic instability, disruption in tissue homeostasis, inflammation, immune evasion, clonal evolution, and changes in individual organ physiology. According to this integrative framework, there are common and cancer-specific processes, new biomarkers for telomere maintenance, and therapeutic prospects focused on telomere maintenance pathways. The development of standardized, longitudinal methodologies will be key to translating telomere biology into clinically actionable approaches in gynaecological oncology."},{"id":"source_24","type":"source","study":"Identification of telomere-related lncRNAs and immunological analysis in ovarian cancer","year":2024,"doi":"10.3389/fimmu.2024.1452946","url":"https://doi.org/10.3389/fimmu.2024.1452946","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Xu 2024","excerpt":"BACKGROUND: Ovarian cancer (OC) is a global malignancy characterized by metastatic invasiveness and recurrence. Long non-coding RNAs (lncRNAs) and Telomeres are closely connected with several cancers, but their potential as practical prognostic markers in OC is less well-defined. METHODS: Relevant mRNA and clinical data for OC were sourced from The Cancer Genome Atlas (TCGA) database. The telomere-related lncRNAs (TRLs) prognostic model was established by univariate/LASSO/multivariate regression analyses. The effectiveness of the TRLs model was evaluated and measured via the nomogram. Additionally, immune infiltration, tumor mutational load (TMB), and drug sensitivity were evaluated. We validated the expression levels of prognostic genes. Subsequently, PTPRD-AS1 knockdown was utilized to perform the CCK8 assay, colony formation assay, transwell assay, and wound healing assay of CAOV3 cells. RESULTS: A six-TRLs prognostic model (PTPRD-AS1, SPAG5-AS1, CHRM3-AS2, AC074286.1, FAM27E3, and AC018647.3) was established, which can effectively predict patient survival rates and was successfully validated using external datasets."},{"id":"source_25","type":"source","study":"The impact of adjuvant chemotherapy in older breast cancer patients on clinical and biological aging parameters","year":2016,"doi":"10.18632/oncotarget.8796","url":"https://doi.org/10.18632/oncotarget.8796","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Brouwers 2016","excerpt":"PURPOSE: This prospective observational study aimed to evaluate the impact of adjuvant chemotherapy on biological and clinical markers of aging and frailty. METHODS: Women ≥ 70 years old with early breast cancer were enrolled after surgery and assigned to a chemotherapy (Docetaxel and Cyclophosphamide) group (CTG, n=57) or control group (CG, n=52) depending on their planned adjuvant treatment. Full geriatric assessment (GA) and Quality of Life (QoL) were evaluated at inclusion (T0), after 3 months (T1) and at 1 year (T2). Blood samples were collected to measure leukocyte telomere length (LTL), levels of interleukin-6 (IL-6) and other circulating markers potentially informative for aging and frailty: Interleukin-10 (IL-10), Tumor Necrosis Factor Alpha (TNF-α), Insulin-like Growth Factor 1 (IGF-1), Monocyte Chemotactic Protein 1 (MCP-1) and Regulated on Activation, Normal T cell Expressed and Secreted (RANTES). RESULTS: LTL decreased significantly but comparably in both groups, whereas IL-6 was unchanged at T2. However, IL-10, TNF-α, IGF-1 and MCP-1 suggested a minor biological aging effect of chemotherapy."}],"edges":[{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_1","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_2","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_3","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_4","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_5","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_6","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_7","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_8","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_9","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_10","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_11","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_12","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_13","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_14","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_15","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_16","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_17","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_18","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_19","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_20","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_21","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_22","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_23","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_24","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_25","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_26","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_27","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_28","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_29","type":"contains_claim"},{"from":"054f72de-a886-4506-a529-11d92344f009","to":"claim_30","type":"contains_claim"}],"screening":{"identified":25,"screened":25,"excluded":0,"included":25,"included_or_retained":25,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"25 candidate receipts retained after source retrieval, deduplication, and topic filtering. 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