Genetic variation across and within individuals

Nature Reviews Genetics, Journal Year: 2024, Volume and Issue: 25(8), P. 548 - 562

Published: March 28, 2024

Language: Английский

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T cell immune deficiency rather than chromosome instability predisposes patients with short telomere syndromes to squamous cancers

Cancer Cell, Journal Year: 2023, Volume and Issue: 41(4), P. 807 - 817.e6

Published: April 1, 2023

Patients with short telomere syndromes (STS) are predisposed to developing cancer, believed stem from chromosome instability in neoplastic cells. We tested this hypothesis a large cohort assembled over the last 20 years. found that only solid cancers which patients STS squamous cell carcinomas of head and neck, anus, or skin, spectrum reminiscent seen immunodeficiency. Whole-genome sequencing showed no increase instability, such as translocations chromothripsis. Moreover, STS-associated acquired maintenance mechanisms, including telomerase reverse transcriptase (TERT) promoter mutations. A detailed study immune status revealed striking T immunodeficiency at time cancer diagnosis. similar impaired tumor surveillance was documented mice telomeres. conclude patients' predisposition is due exhaustion rather than autonomous defects cells themselves.

Language: Английский

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Genetic architecture of telomere length in 462,666 UK Biobank whole-genome sequences

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(9), P. 1832 - 1840

Published: Aug. 27, 2024

Telomeres protect chromosome ends from damage and their length is linked with human disease aging. We developed a joint telomere metric, combining quantitative PCR whole-genome sequencing measurements 462,666 UK Biobank participants. This metric increased SNP heritability, suggesting that it better captures genetic regulation of length. Exome-wide rare-variant gene-level collapsing association studies identified 64 variants 30 genes significantly associated length, including allelic series in ACD RTEL1. Notably, 16% these are known drivers clonal hematopoiesis-an age-related somatic mosaicism myeloid cancers several nonmalignant diseases. Somatic variant analyses revealed gene-specific associations lengthened telomeres individuals large SRSF2-mutant clones, compared shortened expansions driven by other genes. Collectively, our findings demonstrate the impact rare on larger effects observed among also hematopoiesis.

Language: Английский

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Immunosenescence promotes cancer development: from mechanisms to treatment strategies

Cell Communication and Signaling, Journal Year: 2025, Volume and Issue: 23(1)

Published: March 10, 2025

The body's innate immune system plays a pivotal role in identifying and eliminating cancer cells. However, as the ages, its functionality can deteriorate, becoming dysfunctional, inefficient, or even inactive—a condition referred to immunosenescence. This decline significantly increases risk of malignancies. While pro-cancer effects T-cell aging have been widely explored, there remains notable gap literature regarding impact on cells, such macrophages neutrophils. review seeks address this gap, with emphasis these cell types. Furthermore, although certain immunotherapies, including checkpoint inhibitors (ICIs), demonstrated efficacy across broad spectrum cancers, elderly patients are less likely derive clinical benefit from treatments. In some cases, they may experience immune-related adverse events (irAEs). senolytic strategies shown promise exerting anti-cancer effects, their reactions potential off-target present significant challenges. aims elucidate immunosenescence, implications for safety ICIs, anti-aging treatment strategies. addition, optimizing therapies minimize enhance therapeutic outcomes critical focus future research endeavors. Senescence is an inevitable phenomenon human body, scientists explored specific mechanisms by which immunosenescence advances development cancer. summarizes characteristics be used level surveillance cancers due "Targeting immunosenescence" new idea strategy therapy.

Language: Английский

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The many faces of the helicase RTEL1 at telomeres and beyond

Trends in Cell Biology, Journal Year: 2023, Volume and Issue: 34(2), P. 109 - 121

Published: July 31, 2023

Language: Английский

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Telomere Checkpoint in Development and Aging

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(21), P. 15979 - 15979

Published: Nov. 5, 2023

The maintenance of genome integrity through generations is largely determined by the stability telomeres. Increasing evidence suggests that telomere dysfunction may trigger changes in cell fate, independently length. Telomeric multiple tandem repeats are potentially highly recombinogenic. Heterochromatin formation, transcriptional repression, suppression homologous recombination and chromosome end protection all required for stability. Genetic epigenetic defects affecting homeostasis cause length-independent internal telomeric DNA damage. Growing evidence, including based on Drosophila research, points to a checkpoint mechanism coordinates fate with state. According this scenario, telomeres, irrespective their length, serve as primary sensor instability capable triggering death or developmental arrest. factors released from shortened dysfunctional telomeres thought mediate these processes. Here, we discuss novel signaling role RNAs early development. Telomere ensures multicellular organisms but aggravates aging process, promoting accumulation damaged senescent cells.

Language: Английский

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Telomeres and aging: on and off the planet!

Biogerontology, Journal Year: 2024, Volume and Issue: 25(2), P. 313 - 327

Published: April 1, 2024

Abstract Improving human healthspan in our rapidly aging population has never been more imperative. Telomeres, protective “caps” at the ends of linear chromosomes, are essential for maintaining genome stability eukaryotic genomes. Due to their physical location and “end-replication problem” first envisioned by Dr. Alexey Olovnikov, telomeres shorten with cell division, implications which remarkably profound. Telomeres hallmarks molecular drivers aging, as well fundamental integrating components cumulative effects genetic, lifestyle, environmental factors that erode telomere length over time. Ongoing attrition resulting limit replicative potential imposed cellular senescence serves a powerful tumor suppressor function, also underlies spectrum age-related degenerative pathologies, including reduced fertility, dementias, cardiovascular disease cancer. However, very little data exists regarding extraordinary stressors exposures associated long-duration space exploration eventual habitation other planets, nor how such missions will influence telomeres, reproduction, health, risk, aging. Here, we briefly review current understanding, advanced significantly recent years result NASA Twins Study, most comprehensive evaluation health spaceflight ever conducted. Thus, Study is forefront personalized medicine approaches astronauts sets stage subsequent missions. We extrapolate from understanding future missions, highlighting biological biochemical strategies may enable survival, consider prospect longevity extreme environment space.

Language: Английский

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Breaking down causes, consequences, and mediating effects of telomere length variation on human health

Genome biology, Journal Year: 2024, Volume and Issue: 25(1)

Published: May 17, 2024

Abstract Background Telomeres form repeated DNA sequences at the ends of chromosomes, which shorten with each cell division. Yet, factors modulating telomere attrition and health consequences thereof are not fully understood. To address this, we leveraged data from 326,363 unrelated UK Biobank participants European ancestry. Results Using linear regression bidirectional univariable multivariable Mendelian randomization (MR), elucidate relationships between leukocyte length (LTL) 142 complex traits, including diseases, biomarkers, lifestyle factors. We confirm that telomeres age show a stronger decline in males than females, these contributing to majority 5.4% LTL variance explained by phenome. MR reveals 23 traits LTL. Smoking cessation high educational attainment associate longer LTL, while weekly alcohol intake, body mass index, urate levels, female reproductive events, such as childbirth, shorter also identify 24 affected risk for cardiovascular, pulmonary, some autoimmune diseases being increased short other conditions cancers. Through MR, may partially mediate impact attainment, childbirth on proxied lifespan. Conclusions Our study sheds light modulators, consequences, mediatory role telomeres, portraying an intricate relationship lifestyle, socio-economic

Language: Английский

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Assessing the contribution of rare protein-coding germline variants to prostate cancer risk and severity in 37,184 cases

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 19, 2025

Abstract To assess the contribution of rare coding germline genetic variants to prostate cancer risk and severity, we perform here a meta-analysis 37,184 cases 331,329 male controls from five cohorts with whole exome or genome sequencing data, one cohort imputed array data. At gene level, our case-control collapsing analysis confirms associations between damaging in four genes increased risk: SAMHD1 , BRCA2 ATM at study-wide significance level ( P < 1×10 −8 ), CHEK2 suggestive threshold 2.6×10 −6 ). Our case-only analysis, reveals that AOX1 are associated more aggressive disease (OR = 2.60 [1.75–3.83], 1.35×10 as well confirming role determining severity. single-variant study missense variant TERT is substantially reduced 0.13 [0.07–0.25], 4.67×10 −10 non-synonymous further three ANO7 SPDL1 AR ) HOXB13 BIK Altogether, this work provides deeper insights into architecture biological basis potential implications for clinical prediction therapeutic strategies.

Language: Английский

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Clinical Use of ZSCAN4 for Telomere Elongation in Hematopoietic Stem Cells

NEJM Evidence, Journal Year: 2025, Volume and Issue: 4(3)

Published: Feb. 25, 2025

Extremely short telomeres in patients with dyskeratosis congenita and related telomere biology disorders (TBDs) lead to premature cellular senescence bone marrow failure. Zinc finger SCAN domain-containing 4 (ZSCAN4) elongates by recombination. We report a clinical study which EXG34217, the term given for autologous CD34+ hematopoietic stem cells from TBD exposed temperature-sensitive Sendai virus vector encoding human ZSCAN4 at 33°C 24 hours, was infused into without preconditioning. Four were enrolled; two experienced successful mobilization during second attempt underwent apheresis EXG34217 infusion, follow-up of 5 months (both ongoing). observed elongation (1.06- 1.34-fold) ex vivo. In one patient, treatment associated change mean absolute neutrophil count (ANC) 1.78×103 3.18×103 cells/μl; lymphocyte subpopulation length changed 3.6 6.7 kb (50th percentile age). other lowest ANC 0.6×103/μl 1.2×103/μl; this has occurred patient receiving prior intermittent low-dose granulocyte-colony-stimulating factor injections. During mobilization, all mild moderate pain or after line replacement, had blood infection fever hypoxemia. After no acute safety issues noted; long-term cardiac pulmonary adverse events these similar symptoms patient's underlying conditions. Although definitive conclusions cannot be drawn EXG34217-treated patients, results warrant further investigation treating TBDs. (Funded Elixirgen Therapeutics; ClinicalTrials.gov number, NCT04211714.).

Language: Английский

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