Dynamics of telomere erosion and its association with genome instability in myelodysplastic syndromes (MDS) and acute myelogenous leukemia arising from MDS: a marker of disease prognosis?

Telomere length was evaluated by terminal repeat fragment method (TRF) in 50 patients with myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML) arising from MDS and in 21 patients with untreated primary AML to ascertain, whether telomere erosion was associated with progression of MDS towards overt leukemia. Heterogeneity of TRF among MDS FAB subgroups (P=0.004) originated from its shortening in increased number of patients during progression of the disease. Chromosomal aberrations were present in 32% MDS patients with more eroded telomeres (P=0.022), nevertheless a difference between mean TRF in the subgroups with normal and abnormal karyotype diminished during progression of MDS. A negative correlation between individual TRF and IPSS value (P=0.039) showed that telomere dynamics might serve as a useful prognostic factor for assessment of an individual MDS patient's risk and for decision of an optimal treatment strategy.     

Short telomeres: a novel potential predictor of relapse in Ewing sarcoma.

PURPOSE: Despite advances in therapy, >50% of patients with Ewing sarcoma will relapse. The current prognostic factors are not optimal for risk prediction. Studies have shown that telomere length could predict outcome in different malignancies. Our aim was to evaluate whether telomere length could be a better prognostic factor in Ewing sarcoma and correlate the results with clinical variables, outcome, and chromosomal instability. EXPERIMENTAL DESIGN: Telomere length was determined in the primary tumor and peripheral blood of 32 patients with Ewing sarcoma. Chromosomal instability was evaluated by combining classical cytogenetics, comparative genomic hybridization and random aneuploidy. Telomere length was correlated to clinical variables, chromosomal instability, and outcome. RESULTS: In 75% of the tumors, changes in telomere length, when compared with the corresponding peripheral blood lymphocytes, were noted. The majority of changes consisted of a reduction in telomere length. Patients harboring shorter telomeres had a significantly adverse outcome (P = 0.015). Chromosomal instability was identified in 65% of tumors, significantly correlating with short telomeres (P = 0.0094). Using multivariate analysis, telomere length remained the only significant prognostic variable (P = 0.034). Patients with short telomeres had a 5.3-fold risk of relapse as compared to those with unchanged or longer telomeres. CONCLUSION: We have shown that tumors with telomere length reduction result in genomic instability. In addition, telomere length reduction was the only significant predictor of outcome. We suggest that reduction of telomere length in tumor cells at diagnosis could serve as a prognostic marker in Ewing sarcoma.     

Telomere dynamics in myelodysplastic syndromes and acute leukemic transformation.

Myelodysplastic syndromes (MDS) are characterized by cytopenias in the blood and dysplastic features in the hematopoietic cells. Although the impact of cytogenetic abnormalities is considerable for prognosis, the exact genetic mechanism of MDS remains undetermined. In this study we assessed cytogenetic changes, microsatellite alterations, and telomere dynamics in order to obtain further insight into the pathogenesis of MDS. Thirty-three percentage of MDS patients and 60% of post-MDS acute leukemia (post-MDS AML) had de novo microsatellite changes. In the MDS phase, however, > 60% of patients showed reduction of telomere lengths without microsatellite changes, indicating that telomere reduction in most MDS patients does not seem to be directly linked to genome instability, or that reduction of telomere length does not induce microsatellite changes in the MDS phase. Some MDS patients had microsatellite changes without telomerase elevation, indicating that genome instability might accumulate during the disease progression in some MDS patients, and this condition (cellular senescence) may be related to ineffective hemopoiesis in MDS patients. In contrast, 40% of post-MDS AML patients had elevated telomerase activity with microsatellite changes, indicating that approximately 40% of patients with post-MDS AML patients had accumulation of genome instability resulting in elevated telomerase activity in an attempt to obtain genetic stability. However, the remaining MDS patients had microsatellite changes without telomerase up-regulation, suggesting that some MDS had genome instability even after leukemic transformation. Most MDS patients with elevated telomerase activity in the AML phase had elevated telomerase activity even in the MDS phase without apparent change in telomere length before and after leukemic transformation. These findings indicate that telomerase activity in the MDS phase may be independent of telomere length, although telomere shortening seems to be related to genomic instability, and this process may be linked to apoptosis of MDS cells.     

Telomere length,c-myc and mad-1 expression could represent prognosis markers of myelodysplastic syndrome

Telomere dysfunction might generate genomic instability leading to the progression of myelodysplastic syndromes (MDS) into acute myeloid leukemia (AML). We investigated telomere length (TL), telomerase activity (TA) and hTERT, c-myc, mad1, and p53 expression in the bone marrow of patients with MDS (n = 109), AML (n = 47) and in controls (n = 24). TL was lower in MDS patients than in controls (p < 0.001) and higher in L-MDS (low, intermediate-1 IPSS, p < 0.01) respect H-MDS (high, intermediate-2 IPSS, p < 0.01) patients. Mad-1 expression was higher in MDS patients than in controls (p < 0.01), c-myc expression was highest in AML and in H-MDS patients. Our results show that the telomere dynamics might be useful for stratifying patients according to a risk scoring system.     

Telomere stability is frequently impaired in high-risk groups of patients with myelodysplastic syndromes.

Genomic instability induces an accumulation of genetic changes and may play a role in the pathogenesis of myelodysplastic syndromes (MDS). To clarify the possible association between genomic instability and clinical outcome in MDS patients, we compared telomere dynamics to the recently established International Prognostic Scoring System (IPSS) risk groups for MDS. We measured the terminal restriction fragments (TRFs) of 93 patients with MDS at the time of diagnosis, and telomerase activity was analyzed in 62 patients with MDS using the PCR-based telomeric repeat amplification protocol (TRAP) assay. A total of 53 of 93 MDS patients had TRFs within the age-matched normal range, and the remaining patients showed shortened TRFs (35 patients) or elongated TRFs (5 patients). MDS patients with shortened TRFs had a significantly low hemoglobin concentration (P = 0.04), a high percentage of marrow blasts (P = 0.02), and a high incidence of cytogenetic abnormalities (P < 0.05). The incidence of leukemic transformation was significantly high in patients with shortened TRF length (P < 0.05). In addition, patients with shortened TRF length were frequently seen in the IPSS high-risk group (P < 0.01). Most of the MDS patients had normal-to-low levels of telomerase activity, suggesting that changes in TRF length rather than telomerase activity may more accurately reflect the pathophysiology of MDS. MDS patients with shortened TRF length had a very poor prognosis (P < 0.01), suggesting that telomere dynamics may be linked to clinical outcome in MDS patients. Thus, an abnormal mechanism of telomere maintenance in subgroups of MDS patients may be an early indication of genomic instability. This study demonstrates that telomere stability is frequently impaired in a high-risk group of MDS patients and suggests that, in combination with the IPSS classification system, measurement of TRFs may be useful in the future to stratify MDS patients according to risk and manage the care of MDS patients.     

Telomere length and telomerase subunits as diagnostic and prognostic biomarkers in Barrett carcinoma

BACKGROUND: Maintenance of telomeres has been identified as an essential regulator of proliferative capacity and genomic integrity in malignant tumors. The authors evaluated telomere length and telomerase subunits, hTR and hTERT, as prognostic markers in patients with Barrett carcinoma. METHODS: Telomere length was measured by Southern blot analysis and hTR expression and hTERT expression by real-time polymerase chain reaction in both cancer tissue and adjacent noncancerous Barrett mucosa in resection specimens from 46 patients with Barrett carcinoma (International Union Against Cancer [UICC] stages I-III). The median follow-up time of the surviving patients was 79 months. RESULTS: Cancer tissue expressed more hTERT-mRNA than noncancerous mucosa (P < .05). Telomere lengths in cancer tissue and in noncancerous mucosa increased with higher pT category (P = .08 and P = .05, respectively). Twenty-one patients who died of tumor recurrence showed significantly longer telomeres in cancer tissue compared with 25 patients without tumor-related deaths (P < .05). Telomere length in both cancer tissue and in noncancerous mucosa and the telomere-length ratio cancer:noncancerous tissue were correlated with overall survival. In multivariate analysis, the telomere-length ratio proved to be an independent prognostic parameter (P < .02; relative risk of death 3.4; confidence interval, 1.3-8.9). Ten patients with telomere-length ratios >1.17 had a significantly poorer overall survival compared with 36 patients with telomere-length ratios 相似文献   

Association of circulating leukocyte telomere length with survival in patients with colorectal cancer

IntroductionTelomere shortening, as seen with aging, can cause chromosomal instability and promote cancer progression. We investigated the association between circulating telomere length and overall and disease-free survival in a sub-cohort of patients with colorectal cancer.MethodsBaseline genomic DNA from blood leukocytes was extracted from N = 92 newly diagnosed stage I-IV patients with colorectal cancer enrolled at the ColoCare Study site in Heidelberg, Germany. Detailed information on clinicodemographic (including age) and lifestyle risk factors, and clinical outcomes (including recurrence and survival) was collected. Telomere length was measured in DNA using multiplex quantitative polymerase chain reaction. Kaplan Meier survival curves were generated comparing shorter to longer telomere lengths with log-rank testing.ResultsThe mean T/S ratio for study patients was 0.5 (range: 0.3–0.9). Shorter telomeres were associated with older age at baseline. Patients with shorter telomeres experienced a worse overall and disease-free survival, although this association did not reach statistical significance. Kaplan-Meier survival curves for those with circulating telomere length below vs. above the median showed poorer overall (log-rank p = 0.31) and disease-free survival (long-rank p = 0.23).ConclusionsOur results suggest that individuals with shorter telomeres, as seen with aging, may experience a worse overall and disease-free survival after colorectal cancer diagnosis. Larger sample sizes with longer follow-up are needed to further evaluate telomere length as a prognostic biomarker in colorectal cancer progression.     

Telomere length is a prognostic factor in neuroblastoma

BACKGROUND: Maintenance of telomeres, in most instances by reactivation of telomerase, is obligatory for the indefinite proliferation of tumor cells. The objective of this study was to evaluate telomere length and telomerase activity (TA) as markers for progression and prognosis in neuroblastoma. METHODS: Primary tumor samples from 51 patients were analyzed for telomere length and TA and were correlated with known prognostic parameters and outcome. RESULTS: Telomere length had a highly significant correlation with prognosis (P = .007). Short telomeres were predictive of a favorable prognosis, whereas long or unchanged telomeres were predictive of a poor outcome. For the first time to their knowledge, the authors have shown that, within the high-risk group patients, telomere length could define a favorable subgroup that had a progression-free survival (PFS) rate of 86% compared with a PFS rate of 36% for patients with more adverse disease, which is the expected PFS rate for such patients (P = .04). In a multivariate analysis, telomere length was the most significant prognostic parameter (P = .032). TA was correlated significantly with outcome and with known prognostic factors. High TA and low TA were associated with adverse and favorable outcomes, respectively (P = .01). CONCLUSION: The results of this investigation suggested that telomere length is a highly significant prognostic parameter of clinical relevance in patients with neuroblastoma. In high-risk patients, telomere length was the sole significant parameter that identified a group of patients who had a favorable prognosis. The authors suggest that telomere length should be included in the recommended diagnostic investigations for patients with neuroblastoma.     

Correlations of telomere length, telomerase activity, and telomeric-repeat binding factor 1 expression in colorectal carcinoma

BACKGROUND: Telomere maintenance has been proposed as an essential step for tumor cell immortalization. The objectives of the current study were to investigate the mechanisms implicated in telomere length in colorectal carcinoma (CRC) and to evaluate the prognostic impact of telomere status. METHODS: Ninety-one colorectal carcinoma samples that were obtained from patients who underwent surgery were analyzed to investigate the factors related to telomere function. The authors studied telomerase activity, terminal restriction fragment (TRF) length, and telomeric-repeat binding factor (TRF1) expression and analyzed the prognostic implications of those factors. RESULTS: Most tumors (81.3%) displayed telomerase activity. Overall, telomeres in CRC specimens were significantly shorter compared with telomeres in normal, adjacent specimens (P=0.02). Moreover, tumors that demonstrated shortened telomeres displayed higher TRF1 levels than tumors without telomere shortening. In relation to patient prognosis, a significantly poor clinical course was observed in the group of patients who had tumors with longer telomeres (P=0.02), and this finding emerged as an independent prognostic factor in a Cox proportional hazards model (P=0.04; relative risk, 6.48). Among patients with tumors classified as telomerase-positive, telomere length ratios (the ratio of tumor tissues to normal tissues)相似文献   

Telomere dysfunction and chromothripsis

Chromothripsis is a recently discovered form of genomic instability, characterized by tens to hundreds of clustered DNA rearrangements resulting from a single dramatic event. Telomere dysfunction has been suggested to play a role in the initiation of this phenomenon, which occurs in a large number of tumor entities. Here, we show that telomere attrition can indeed lead to catastrophic genomic events, and that telomere patterns differ between cells analyzed before and after such genomic catastrophes. Telomere length and telomere stabilization mechanisms diverge between samples with and without chromothripsis in a given tumor subtype. Longitudinal analyses of the evolution of chromothriptic patterns identify either stable patterns between matched primary and relapsed tumors, or loss of the chromothriptic clone in the relapsed specimen. The absence of additional chromothriptic events occurring between the initial tumor and the relapsed tumor sample points to telomere stabilization after the initial chromothriptic event which prevents further shattering of the genome.     

Telomere dynamics in myelodysplastic syndrome determined by telomere measurement of marrow metaphases.

Myelodysplastic syndrome (MDS), which is known to be a preleukemic state, is a heterogeneous entity characterized by ineffective hematopoiesis and dysplastic morphological features. Most MDS patients show erosive telomeric repeats (TTAGGG)(n), without up-regulation of telomerase activity, suggesting that telomere shortening may be linked to cellular senescence in MDS. We measured telomere length in samples from 13 MDS patients and 8 healthy volunteers, based on telomere signals of individual chromosomes, using digital images of metaphases after quantitative fluorescence in situ hybridization (Q-FISH) with peptide nucleic acid probes and compared the results with results obtained with the standard method of determining terminal restriction fragment (TRF) length. In healthy volunteers, we found a significant correlation between TRF length and telomere fluorescence signals detected by Q-FISH, and a relatively wide distribution of fluorescence telomere signals was demonstrated in every sample. In contrast, we found no linear correlation between TRF length and telomere fluorescence signals in MDS, and most MDS patients showed weak telomere fluorescence signals, corresponding to short telomeres, with a narrow range compared with normal subjects. TRF length represented telomere DNA in whole marrow cells, whereas telomere fluorescence signals by Q-FISH represented only marrow metaphases corresponding to MDS-derived cells. Metaphases from most MDS patients showed homogeneous telomere shortening, irrespective of the presence of cytogenetic abnormality. In contrast, marrow metaphases from normal individuals showed a relatively wide range of telomere signals in each metaphase, indicating that in MDS cells, telomere shortening mechanisms that normally exist might be dysregulated. Therefore, analysis of telomere distribution as well as average telomere length detected by Q-FISH might be useful to clarify the telomere dynamics of MDS cells.     

Reduced telomere DNA content is correlated with genomic instability and metastasis in invasive human breast carcinoma

Telomere shortening leads to genomic instability and has been correlated with poor outcome in several types of cancer. A recently described, robust titration assay was used to quantify telomere DNA content in frozen and paraffin-embedded specimens of 49 invasive human breast carcinomas, including tumors with normal or abnormal contents of genomic DNA, which produced regional, distant, or local disease. Telomere DNA contents ranged from 53% to 370% of the content in a reference DNA purified from normal placenta. Tumors were divided into three groups of approximately equal size based on increasing telomere DNA content. All of 16 tumors in the group with the least telomere DNA (Group I), were aneuploid compared to 9/17 tumors in the group with the most telomere DNA (Group III). The Chi-square test for trend indicated that tumors with the least telomere DNA were significantly more likely to be aneuploid than tumors with the most telomere DNA (p<0.002). Twelve of 14 tumors in Group I also produced metastatic disease compared to 8/15 tumors in Group III. The Fischer Exact Test indicated that tumors with the least telomere DNA were significantly more likely to be metastatic than tumors with the most telomere DNA (p<0.05). There was no association between telomere DNA content and patients age, tumors size, grade, stage, or fraction of cells in S-phase. The correlation of reduced telomere DNA content with aneuploidy and metastasis, both of which are associated with poor outcome in invasive breast carcinoma, implies that telomere DNA content also could have prognostic value.     

Telomere length in haemopoietic stem cells can be determined from that of mononuclear blood cells or whole blood

Telomere length can be used to predict the replicative capacity of haematological progenitor cells and may be an important prognostic factor for the onset of cellular immune dysfunction. However, such measurements require invasive bone marrow (BM) biopsies and laborious stem cell isolations that are impractical in a clinical setting. Previous studies have used peripheral blood (PB) cells as an indicator of stem cell telomere length without demonstrating a correlation. In this study, we examined the telomere length in PB, isolated mononuclear cells (MNC) and BM aspirates from each of 19 patients ranging in age from 45 to 81 years. Correlation analysis confirmed that mean telomere length of BM aspirates was equivalent to that of PB (r = 0.85, P < 0.001), or MNC (r = 0.94, P < 0.001). Since BM is a heterogeneous population of cells, we have also shown in 13 separate patients that the mean telomere length in isolated peripheral blood stem cell (PBSC) harvests was equivalent to that of isolated CD34+ stem cells (r = 0.83, P < 0.001). Thus, telomere length in haemopoietic stem cells can be determined from that of whole or fractionated PB in future studies of haematological disorders.     

Telomerase activity in myelodysplastic syndromes

Myelodysplastic syndromes are clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis and peripheral cytopenias. Telomeres are thought to be critical in maintaining normal hematopoiesis. In this study, we assessed telomere dynamics in order to obtain further insight into the pathogenesis of MDS. We studied telomerase activity (TA) in mononuclear cells from peripheral blood (PB) and bone marrow (BM) from patients with myelodysplastic syndrome (MDS; n=24), acute myeloid leukemia (AML; n=14), chronic myeloid leukemia (CML; n=12) and 11 normal controls using a polymerase chain reaction-based telomeric repeat amplification assay. Telomerase activities (mean+/-S.D.) were found as 0.199+/-0.09, 0.414+/-0.55, 0.253+/-0.26 and 0.181+/-0.05 pg/ml in PB mononuclear cells, respectively (P>0.05). Comparison of TA of BM mononuclear cells from 19 MDS patients versus 10 BM samples from normal controls revealed no significant difference (P=0.3). There was no correlation between the levels of TA and clinical and prognostic parameters of the patients with MDS, such as degree of anemia, platelet counts on presentation, gender, presence of organomegaly, bone marrow fibrosis and BM blast percentages. Patients who had higher TA had significantly inferior survival compared with patients who had lower TA (P=0.005). Consistent with previous data, our results suggest that in patients with MDS, telomerase activity might be insufficient to compensate for the telomere shortening. Furthermore, TA might be prognostically important in patients with MDS. Measurements of enzymatic activity in association with telomere length studies may help to understand the prognostic role of telomere dynamics in patients with myelodysplastic syndromes more reliably.     

Telomere maintenance and the etiology of adult glioma

A growing body of epidemiologic and tumor genomic research has identified an important role for telomere maintenance in glioma susceptibility, initiation, and prognosis. Telomere length has long been investigated in relation to cancer, but whether longer or shorter telomere length might be associated with glioma risk has remained elusive. Recent data address this question and are reviewed here. Common inherited variants near the telomerase-component genes TERC and TERT are associated both with longer telomere length and increased risk of glioma. Exome sequencing of glioma patients from families with multiple affected members has identified rare inherited mutations in POT1 (protection of telomeres protein 1) as high-penetrance glioma risk factors. These heritable POT1 mutations are also associated with increased telomere length in leukocytes. Tumor sequencing studies further indicate that acquired somatic mutations of TERT and ATRX are among the most frequent alterations found in adult gliomas. These mutations facilitate telomere lengthening, thus bypassing a critical mechanism of apoptosis. Although future research is needed, mounting evidence suggests that glioma is, at least in part, a disease of telomere dysregulation. Specifically, several inherited and acquired variants underlying gliomagenesis affect telomere pathways and are also associated with increased telomere length.     

Telomere shortening is associated with poor prognosis and telomerase activity correlates with DNA repair impairment in non-small cell lung cancer

BACKGROUND AND PURPOSE: Telomere function and DNA damage response pathways are frequently inactivated in cancer. Moreover, some telomere-binding proteins have been implicated in DNA repair. The purpose of this work consists of evaluating the prognostic impact of telomere dysfunction and its relationship with DNA repair systems in non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: We analysed 83 NSCLCs and their corresponding control samples obtained from patients submitted to surgery. Telomere function was evaluated by determining telomerase activity and telomere length. DNA repair expression assays were established by using cDNA arrays containing 96 DNA-repair genes and by Real Time Quantitative PCR. RESULTS: Our data indicated that telomere attrition was significantly associated with poor clinical outcome of patients (P=0.02), being this parameter a significant prognostic factor independent of tumour stage (P=0.012; relative risk=1.887; 95% CI: 1.147-3.102). DNA-repair gene expression studies showed down regulation of DCLRE1C and GTF2H1 and a clear FLJ10858 up regulation in tumour tissues, as compared to controls. In addition, a number of genes related to DNA-repair were significantly down regulated in tumours that reactivated telomerase (DCLRE1C, GTF2H1, PARP-3, MLH1, and TRF2). CONCLUSIONS: Telomere shortening emerged as a poor clinical evolution parameter in NSCLC. Moreover, results from this work suggest a relationship between the loss of several DNA repair genes and telomerase activity, which may be of relevance in the pathogenesis of non-small lung cancer.     

Telomere length in blood cells and breast cancer risk: investigations in two case–control studies

Telomere dysfunction, which leads to genomic instability, is hypothesized to play a causal role in the development of breast cancer. However, the few epidemiologic studies that assessed the relationship between telomere length in blood cells and breast cancer risk have been inconsistent. We conducted two case–control studies to further understand the role of telomere length and breast cancer risk. Overall telomere lengths were measured by telomere quantitative fluorescent in situ hybridization (TQ-FISH) and telomere quantitative real-time PCR (TQ-PCR). The associations between telomere length in blood leukocytes and risk of breast cancer were examined in two breast cancer case–control studies that were conducted at Roswell Park Cancer Institute (RPCI) and Lombardi Comprehensive Cancer Center (LCCC). Using the 50th percentile value in controls as a cut point, women who had shorter telomere length were not at significantly increased risk of breast cancer compared with women who had longer telomere length in the RPCI study (odds ratio [OR] = 1.34, 95% confidence interval [CI] = 0.84–2.12), in the LCCC study (OR = 1.18, 95% CI = 0.73–1.91), or in the combined RPCI and LCCC studies (OR = 1.23, 95% CI = 0.89–1.71). There was no significant dose–response relationship across quartiles of telomere length and no significant difference when comparing women in the lowest to highest quartile of telomere length. Overall telomere length in blood leukocytes was not significantly associated with the risk of breast cancer.     

Loss of the Association between Telomere Length and Mitochondrial DNA Copy Number Contribute to Colorectal Carcinogenesis

Positive association between telomere length and mitochondrial DNA (mtDNA) copy number were introduced in healthy and patients with psychiatric disorder. Based on frequent genetic changes of telomere and mitochondria in colorectal carcinomas (CRC), we studied their clinical characteristics and their association in colorectal carcinogenesis. DNA was extracted from 109 CRCs, 64 colorectal tubular adenomas (TAs), and 28 serrated polyps (SPs), and then, telomere length and mtDNA copy number were analyzed in these legions by using a real-time PCR assay. Telomere length and mtDNA copy number (mean ± S.D) in CRCs was 1.87 ± 1.52 and 1.61 ± 1.37, respectively. In TAs and SPs, relative mtDNA copy number was 0.92 ± 0.71 and 1.84 ± 1.06, respectively, shoing statistical difference (p = 0.017). However, telomere length was similar in these precancerous legions. Telomere length and mtDNA copy number did not show clinical and prognostic values in CRCs, however, positive correlation between telomere length and mitochondrial DNA copy number were found in CRC (r = 0.408, p < 0.001). However, this association was not shown in precancerous lesions (r = ?0.031, p = 0.765). This result suggests that loss of co-regulation between telomeres and mitochondrial function may induce the initiation or play a role as trigger factor of colorectal carcinogenesis.     

Telomere length in the colon declines with age: a relation to colorectal cancer?

Telomeres shorten with age, which may be linked to genomic instability and an increased risk of cancer. To explore this association, we analyzed telomere length in normal colorectal tissue of individuals at different ages using quantitative-fluorescence in situ hybridization (Q-FISH) and quantitative-PCR (Q-PCR). Using Q-FISH, we also examined the histologically normal epithelium adjacent to, or distant from, colon adenomas and cancers, in addition to the neoplasms. Q-FISH and Q-PCR showed that telomere length was inversely associated with age until approximately ages 60 to 70; surprisingly, beyond this age, telomere length was positively associated with age. This association was found exclusively in epithelial, and not in stromal, cells. Peripheral blood lymphocytes showed an inverse association between telomere length and age, but without any apparent increase in telomere length in the oldest individuals. Telomere length in larger adenoma lesions (>2 cm) was significantly shorter than in normal adjacent (P = 0.004) or normal distant (P = 0.05) tissue from the same individuals. However, telomere length in histologically normal epithelium adjacent to cancers or in adenomas <2 cm was not statistically different from that of the normal distant mucosa or from normal controls, evidence that a telomere-shortening field effect was not present. We suggest that the positive association between telomere length and age in the oldest patients is a consequence of selective survival of elderly patients with long colonocyte telomeres.