Telomeric sequences, the structures comprised of hexanucleotide repeats and associated proteins, play a pivotal role in chromosome end protection and preservation of genomic stability. Herein we address telomere length (TL) dynamics in primary colorectal cancer (CRC) tumour tissues and corresponding liver metastases. TL was measured by multiplex monochrome real-time qPCR in paired samples of primary tumours and liver metastases along with non-cancerous reference tissues obtained from 51 patients diagnosed with metastatic CRC. Telomere shortening was observed in the majority of primary tumour tissues compared to non-cancerous mucosa (84.1%, p < 0.0001). Tumours located within the proximal colon had shorter TL than those in the rectum (p < 0.05). TL in liver metastases was not significantly different from that in primary tumours (p = 0.41). TL in metastatic tissue was shorter in the patients diagnosed with metachronous liver metastases than in those diagnosed with synchronous liver metastases (p = 0.03). The metastatic liver lesions size correlated with the TL in metastases (p < 0.05). Following the neoadjuvant treatment, the patients with rectal cancer had shortened telomeres in tumour tissue than prior to the therapy (p = 0.01). Patients with a TL ratio between tumour tissue and the adjacent non-cancerous mucosa of ≥ 0.387 were associated with increased overall survival (p = 0.01). This study provides insights into TL dynamics during progression of the disease. The results show TL differences in metastatic lesions and may help in clinical practice to predict the patient's prognosis.
BACKGROUND: Nibrin, as part of the NBN/MRE11/RAD50 complex, is mutated in Nijmegen breakage syndrome (NBS), which leads to impaired DNA damage response and lymphoid malignancy. RESULTS: Telomere length (TL) was markedly reduced in homozygous patients (and comparably so in all chromosomes) by ~40% (qPCR) and was slightly reduced in NBS heterozygotes older than 30 years (~25% in qPCR), in accordance with the respective cancer rates. Humanized cancer-free NBS mice had normal TL. Telomere elongation was inducible by telomerase and/or alternative telomere lengthening but was associated with abnormal expression of telomeric genes involved in aging and/or cell growth. Lymphoblastoid cells from NBS patients with long survival times (>12 years) displayed the shortest telomeres and low caspase 7 activity. CONCLUSIONS: NBS is a secondary telomeropathy. The two-edged sword of telomere attrition enhances the cancer-prone situation in NBS but can also lead to a relatively stable cellular phenotype in tumor survivors. Results suggest a modular model for progeroid syndromes with abnormal expression of telomeric genes as a molecular basis. METHODS: We studied TL and function in 38 homozygous individuals, 27 heterozygotes, one homozygous fetus, six NBS lymphoblastoid cell lines, and humanized NBS mice, all with the same founder NBN mutation: c.657_661del5.
- MeSH
- dítě MeSH
- heterozygot MeSH
- homeostáza telomer genetika MeSH
- homozygot MeSH
- jaderné proteiny genetika MeSH
- karyotypizace MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- modely nemocí na zvířatech MeSH
- myši transgenní MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- předškolní dítě MeSH
- progerie genetika patologie MeSH
- proteiny buněčného cyklu genetika MeSH
- syndrom Nijmegen breakage komplikace genetika patologie MeSH
- telomerasa metabolismus MeSH
- telomery patologie MeSH
- zvířata MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- myši MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Stárnutí je nesmírně komplexním dějem, který má mnoho projevů na úrovni molekulární, buněčné i celého organismu a týká se v určité podobě prakticky všech živých bytostí. Jde o proces charakterizovaný všeobecným progresivním zhoršováním fyziologických funkcí organismu vedoucím ke zvýšené náchylnosti k nemocem. Množství genů asociovaných s dlouhověkostí je určitým způsobem zapojeno do metabolismu. Sirtuiny a AMPK figurují v katabolických drahách, geny dráhy IIS a mTOR jsou zapojené do anabolismu. Intenzivně zkoumány jsou geny zapojené do oprav poškození DNA, geny regulující délku telomer, CETP, ACE, cytokiny IL-10 a IL-6, geny systému HLA, TP53, SOD3 a mnohé další. Látky jako rapamycin, inhibující dráhu mTOR, resveratrol a další aktivátory sirtuinů (SRT1720, SRT2104) a metformin aktivující AMPK mají schopnost u modelových organismů prodloužit život a zpomalit stárnutí. U člověka lze podobného účinku docílit i obyčejnou změnou životosprávy. Jde například o omezení příjmu energie, konzumaci košťálové zeleniny (obsahující flavonoidy a polyfenoly, jako je sulforafan a genistein) nebo o pravidelnou pohybovou aktivitu.
Aging is an extremely complex phenomenon that has many manifes-tations at the molecular, cellular, and whole-body levels, and in some form involves virtually all living beings. It is a process characterized by a general progressive deterioration of the physiological functions of the organism leading to increased susceptibility to diseases. This article summarizes the basic features and molecular hallmarks of aging and describes some of the genetic mechanisms of this phenomenon. It deals with the particular genes and molecular pathways involved in the regulation of aging as well as promising possibilities of interventions affecting this process
- MeSH
- lidé MeSH
- sirtuiny fyziologie genetika MeSH
- stárnutí buněk fyziologie genetika MeSH
- stárnutí * fyziologie genetika MeSH
- telomery patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Buněčná senescence je fyziologický stav obecně definovatelný jako stabilní zástava proliferace, tedy přerušení buněčného cyklu. Na rozdíl od buněk terminálně diferenciovaných, které taktéž nevykazují proliferační aktivitu, je zpravidla podmíněna nějakým typem stresu. Buňky s teoretickou schopností dělení (například progenitorové, kmenové či rakovinné) jsou drženy v senescentním stavu aktivitou specifických signálních drah. Množství senescentních buněk v průběhu ontogeneze organismu narůstá. Buněčná senescence tak nejen provází stárnutí, ale jak se ukazuje, významně tento proces ovlivňuje.
Cellular senescence is a physiological state generally defined as a stable arrest of proliferation by preventing the cells from cycling. Unlike terminally differentiated cells, that also do not show proliferative activity, cellular senescence is stress induced and blocks the proliferation of cells with theoretical ability to divide (such as progenitor, stem or cancer cells) due to the activity of specific signaling pathways. The number of senescent cells increases during the ontogenesis of an organism. Senescent cells are not only associated with aging, but also significantly influence this process - a fact that is becoming increasingly well documented.
- MeSH
- lidé MeSH
- progerie etiologie genetika patologie MeSH
- stárnutí buněk * fyziologie MeSH
- stárnutí * fyziologie patologie MeSH
- telomery patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Disruption of genomic integrity due to deficient DNA repair capacity and telomere shortening constitute hallmarks of malignant diseases. Incomplete or deficient repair of DNA double-strand breaks (DSB) is manifested by chromosomal aberrations and their frequency reflects inter-individual differences of response to exposure to mutagenic compounds. In this study, we investigated chromosomal integrity in peripheral blood lymphocytes (PBL) from newly diagnosed cancer patients, including 47 breast (BC) and 44 colorectal cancer (CRC) patients and 90 matched healthy controls. Mutagen sensitivity was evaluated by measuring chromatid breaks (CTAs) induced by bleomycin and supplemented by the chemiluminescent measurement of γ-H2AX phosphorylation in 19 cancer patients (11 BC, 8 CRC). Relative telomere length (RTL) was determined in 22 BC, 32 CRC, and 64 controls. We observed statistically significant increased level of CTAs (P = .03) and increased percentage of aberrant cells (ACs) with CTAs (P = .05) in CRC patients compared with controls after bleomycin treatment. No differences were observed between BC cases and corresponding controls. CRC and BC patients with shorter RTL (below median) exhibited significantly higher amount of ACs (P = .02), CTAs (P = .02), and cells with high frequency of CTAs (≥12 CTAs/PBL; P = .03) after bleomycin treatment. No such associations were observed in healthy controls. γ-H2AX phosphorylation after bleomycin treatment in PBL did not differ between CRC and BC patients. Our results suggest that altered DSB repair measured by sensitivity towards mutagen in PBL occurs particularly in CRC carcinogenesis. Irrespective of cancer type, telomere shortening may be associated with a decreased capacity to repair DSB.
- MeSH
- bleomycin škodlivé účinky farmakologie MeSH
- chromozomální aberace účinky léků MeSH
- chromozomální poruchy patologie MeSH
- chromozomy účinky léků MeSH
- dospělí MeSH
- dvouřetězcové zlomy DNA účinky léků MeSH
- kolorektální nádory genetika metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfocyty MeSH
- nádory prsu genetika metabolismus MeSH
- oprava DNA účinky léků MeSH
- pilotní projekty MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- telomery účinky léků patologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
BACKGROUND: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings. OBJECTIVE: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. DESIGN, SETTING, AND PARTICIPANTS: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis. RESULTS AND LIMITATIONS: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13). CONCLUSIONS: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk. PATIENT SUMMARY: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.
- MeSH
- celogenomová asociační studie MeSH
- fenotyp MeSH
- genetická predispozice k nemoci MeSH
- hodnocení rizik MeSH
- homeostáza telomer * MeSH
- jednonukleotidový polymorfismus * MeSH
- karcinom z renálních buněk krev genetika patologie MeSH
- leukocyty chemie MeSH
- lidé MeSH
- mendelovská randomizace MeSH
- nádory ledvin krev genetika patologie MeSH
- odds ratio MeSH
- rizikové faktory MeSH
- studie případů a kontrol MeSH
- telomery genetika patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, N.I.H., Intramural MeSH
- MeSH
- diagnostické techniky neurologické MeSH
- holocaust * psychologie MeSH
- klinická studie jako téma MeSH
- lidé MeSH
- neurodegenerativní nemoci MeSH
- neurozobrazování metody MeSH
- posttraumatická stresová porucha MeSH
- psychický stres * MeSH
- telomery patologie MeSH
- výzkum MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- novinové články MeSH
Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82,P-value = 8.5 × 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51,P-value = 4.0 × 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk.
- MeSH
- B-buněčný lymfom genetika patologie MeSH
- dospělí MeSH
- genetická predispozice k nemoci * MeSH
- genetické asociační studie metody MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- prospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- telomery patologie MeSH
- věkové faktory MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, N.I.H., Intramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
- Research Support, U.S. Gov't, P.H.S. MeSH
OBJECTIVES: Telomeres are repetitive non-coding DNA sequences on the ends of eukaryotic chromosomes. Relative leukocyte telomere length (LrTL) is considered to reflect biological ageing and fitness. Therefore, we examined whether LrTL would reflect rTL in aortic tissue (ArTL) and whether it could be used as a marker of biological heart age. DESIGN: We analysed telomere length in aortic and leukocyte samples from 73 heart recipients (63 males, 10 females; age 52.2±11.7 years). Relative telomere length was measured using a quantitative PCR-based method. RESULTS: Neither LrTL nor ArTL correlated significantly with the age of heart recipients. Mean ArTL was slightly shorter than LrTL (p=0.06) and there was a slight but significant inverse correlation between LrTL and ArTL (p=0.019). CONCLUSIONS: The age of patients with end stage heart failure was not associated with leukocyte or aortic telomere length. An inverse correlation between LrTL and ArTL suggests that LrTL is unlikely to be an important predictor of biological ageing in these patients.
