Alterations In Telomere Length Research Articles

Network cultivation, diurnal cortisol and biological ageing: The rejuvenation hypothesis

A stronger motivation to cultivate social ties in older adults (ages range from 62 to 86 years) has been associated with a cortisol profile similar to that observed in undergraduate students, who are decades younger. We have shown the cultivation of social networks buffers against increases in diurnal cortisol common in old age. Cortisol is crucial for the response to stress and the process of ageing, and a recent study has demonstrated that a lower cortisol level is associated with longevity. We link the findings of social network cultivation and cortisol profile to the processes of biological ageing through DNA telomere length. Telomeres are repeated DNA sequences that cap and protect the ends of chromosomes, and telomere length is considered a potential biomarker for biological age because it is closely related to the cellular process of ageing and chronic stress and is inversely related to chronological age. Studies examining biological ageing have shown an association between an altered cortisol profile and telomere length dynamics. Together, these findings on social networks, cortisol profiles and telomere length suggest that seniors who are motivated to maintain social ties are biologically younger. We therefore propose the ‘rejuvenation hypothesis’, which posits that seniors with a stronger motivation for social network cultivation are biologically younger, as measured by cortisol levels and telomere length, than their peers who are less motivated to pursue social relationships. This idea suggests a new perspective and potentially fruitful direction for geriatric research. The focus on social network cultivation adds an important psychosocial dimension to rejuvenation therapies that so far have been dominated by biomedical approaches. The rejuvenation hypothesis also has important implications for social policy by supporting the viability of promoting network cultivation among the elderly to facilitate healthy ageing.

Shorter telomere length in schizophrenia: Evidence from a real-world population and meta-analysis of most recent literature

Schizophrenia is a severe, chronic mental disorder. Schizophrenia is visualized as an accelerated cellular aging syndrome characterized by early onset of cardiovascular disease causing premature mortality. In human aging involves alterations in telomere length (TL). To investigate the presence of TL shortening in schizophrenia and psychiatric syndromes associated, this condition was studied in leukocytes (LTL) of a sample of patients suffering from schizophrenia and other psychotic disorders, and compared with a group of non-psychiatric controls. We explored the relationship between LTL and age, gender, and smoking habit with the aim to control whether these potential confounding factors may influence the rate of telomeres shortening. We also performed a new comprehensive meta-analysis including studies on LTL in schizophrenia patients compared to healthy subjects published in the last two years and the results of the present study. Our results suggest that a diagnosis of schizophrenia, more than gender, age, cigarette smoking or alcohol drinking, is the most important condition responsible of the LTL shortening. A strong LTL shortening was observed in patients affected by schizophrenia, Schizoaffective disorder, and Psychosis not otherwise specified when they were younger than 50 years, while in the group of older subjects no major differences were observed. Additional evidence supporting the causal link of schizophrenia with accelerated telomeres shortening came from the analysis of the updated meta-analysis. The availability of a personalized profile of mechanistic pathways, risk factors, and clinical features may pose the basis for a rehabilitative treatment addressing individual needs of the psychiatric patients.

Abstract LB-158: Longitudinal associations of lifetime adiposity with leukocyte telomere length and mitochondrial DNA copy number

Abstract Adiposity may cause adverse health outcomes by increasing oxidative stress and systemic inflammation, which can be reflected by altered telomere length (TL) and mitochondrial DNA copy number (mtCN) in peripheral blood leukocytes. However, little is known about the influence of lifetime adiposity on TL and mtCN in later life. This study was performed to investigate the associations of lifetime adiposity with leukocyte TL and mtCN in 9613 participants from the Nurses' Health Study. A group-based trajectory modelling approach was used to create trajectories of body shape from age 5 through 60 years, and a genetic risk score (GRS) was created based on 97 known adiposity susceptibility loci. Associations of body shape trajectories and GRS with dichotomized TL and mtCN were assessed by logistic regression models. After adjustment for lifestyle and dietary factors, compared with the lean-stable group, the lean-marked increase group had higher odds of having below-median TL (OR = 1.18, 95% CI: 1.04, 1.35; P = 0.01), and the medium-marked increase group had higher odds of having below-median mtCN (OR = 1.28, 95% CI:1.00,1.64; P = 0.047). There was a suggestive trend toward lower mtCN across the GRS quartiles (P for trend = 0.07). In conclusion, telomere attrition may be accelerated by marked weight gain in middle life, whereas mtCN is likely to be reduced persistently by adiposity over the life course. The findings indicate the importance of lifetime weight management to preserve functional telomeres and mitochondria. Citation Format: Dong Hang, Hongmei Nan, Ane Sørlie Kværner, Immaculata De Vivo, Andrew T. Chan, Zhibin Hu, Hongbing Shen, Edward Giovannucci, Mingyang Song. Longitudinal associations of lifetime adiposity with leukocyte telomere length and mitochondrial DNA copy number [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-158.

Telomere length alterations in microsatellite stable colorectal cancer and association with the immune response

Telomeres are repetitive sequences (TTAGGG) located at the end of chromosomes. Telomeres progressively shorten with each cell replication cycle, ultimately leading to chromosomal instability and loss of cell viability. Telomere length anomaly appears to be one of the earliest and most prevalent genetic alterations in malignant transformation. Here we aim to estimate telomere length from whole-exome sequencing data in colon tumors and normal colonic mucosa, and to analyze the potential association of telomere length with clinical factors and gene expression in colon cancer.Reads containing at least five repetitions of the telomere sequence (TTAGGG) were extracted from the raw sequences of 42 adjacent normal-tumor paired samples. The number of reads from the tumor sample was normalized to build the Tumor Telomere Length Ratio (TTLR), considered an estimation of telomere length change in the tumor compared to the paired normal tissue. We evaluated the associations between TTLR and clinical factors, gene expression and copy number (CN) aberrations measured in the same tumor samples.Colon tumors showed significantly shorter telomeres than their paired normal samples. No significant association was observed between TTLR and gender, age, tumor location, prognosis, stromal infiltration or molecular subtypes. The functional gene set enrichment analysis showed pathways related to immune response significantly associated with TLLR.By extracting a relative measure of telomere length from whole-exome sequencing data, we have assessed that colon tumor cells predominantly shorten telomeres, and this alteration is associated with expression changes in genes related to immune response and inflammation in tumor cells.

Evaluatıon of health effects, genetıc damage and telomere length ın children exposed to arsenic in West Bengal, İndia

Increasing evidence of arsenic contamination in ground water and its associated adverse health outcomes affects millions of people worldwide. However, arsenic toxicity studies in children have gained impetus very recently due to the non-prominence of the hallmarks of arsenic toxicity i.e skin lesions. We recognized the need to evaluate the status of genetic damage brought about by early life exposure to arsenic in children as measured by micronucleus (MN) assay for three cell types namely buccal mucosa, urothelial cells and lymphocytes. A thorough health checkup and complete haematogram of the study participants was performed to measure overall health effects and changes in the blood profile in children exposed to arsenic through drinking water in West Bengal, India. Since telomere length alteration has been identified as a good indicator of arsenic toxicity in adults, we measured the telomere length of the arsenic exposed and unexposed children. We found that all the three cell types had significantly higher (P < 0.0001) MN frequency in the arsenic exposed children when compared to the unexposed. Blood profiling showed significantly altered neutrophil, eosinophil, lymphocyte and haemoglobin levels in the arsenic exposed children than their unexposed counterparts. Telomere length in the arsenic exposed children was slightly higher than the unexposed. This is a firsthand report of the genetic damage observed in children exposed to arsenic through drinking water in West Bengal, India.

Green tea supplementation promotes leukocyte telomere length elongation in obese women.

inflammation and oxidative stress are factors that may play a substantial role in telomere attrition. In line of this, obesity is associated with telomere shortening. Green tea had anti-inflammatory and antioxidant effects and may alter telomere length (TL). we evaluated the effect of decaffeinated green tea supplementation in obese women on TL. we conducted a cross-sectional interventional study with ten obese (body mass index [BMI] > 40 kg/m²) and eight normal weight (BMI > 18.5 and < 24.9 kg/m²) women (age between 27 and 48 years). The supplementation was carried out with capsules (each contained 450.7 mg of epigallocatechin-3-gallate) during eight weeks. Anthropometric and dietary intake assessment, and blood collection (for biochemical and TL analysis by quantitative PCR) were performed before and after supplementation. Normal weight patients were evaluated at a single moment. we observed a significant increase on TL after supplementation (1.57 ± 1.1 to 3.2 ± 2.1 T/Sratio; p < 0.05). Moreover, we found shorter TL in obese patients (day 0) when compared to normal weight individuals (3.2 ± 1.9 T/Sratio; p < 0.05) and an inverse association between TL and BMI, even after age adjustment (beta = -0.527; r² = 0.286; IC = -0.129, -0.009). obesity is related to shorter telomeres. Green tea supplementation during eight weeks promotes telomere elongation in obese women.

Longitudinal associations of lifetime adiposity with leukocyte telomere length and mitochondrial DNA copy number.

Adiposity may cause adverse health outcomes by increasing oxidative stress and systemic inflammation, which can be reflected by altered telomere length (TL) and mitochondrial DNA copy number (mtCN) in peripheral blood leukocytes. However, little is known about the influence of lifetime adiposity on TL and mtCN in later life. This study was performed to investigate the associations of lifetime adiposity with leukocyte TL and mtCN in 9613 participants from the Nurses' Health Study. A group-based trajectory modelling approach was used to create trajectories of body shape from age 5 through 60years, and a genetic risk score (GRS) was created based on 97 known adiposity susceptibility variants. Associations of body shape trajectories and GRS with dichotomized TL and mtCN were assessed by logistic regression models. After adjustment for lifestyle and dietary factors, compared with the lean-stable group, the lean-marked increase group had higher odds of having below-median TL (OR = 1.18, 95% CI 1.04, 1.35; P = 0.01), and the medium-marked increase group had higher odds of having below-median mtCN (OR = 1.28, 95% CI 1.00, 1.64; P = 0.047). There was a suggestive trend toward lower mtCN across the GRS quartiles (P for trend = 0.07). In conclusion, telomere attrition may be accelerated by marked weight gain in middle life, whereas mtCN is likely to be reduced persistently by adiposity over the life course. The findings indicate the importance of lifetime weight management to preserve functional telomeres and mitochondria.

High dietary fat and sucrose result in an extensive and time-dependent deterioration in health of multiple physiological systems in mice

Obesity is associated with metabolic dysfunction, including insulin resistance and hyperinsulinemia, and with disorders such as cardiovascular disease, osteoporosis, and neurodegeneration. Typically, these pathologies are examined in discrete model systems and with limited temporal resolution, and whether these disorders co-occur is therefore unclear. To address this question, here we examined multiple physiological systems in male C57BL/6J mice following prolonged exposure to a high-fat/high-sucrose diet (HFHSD). HFHSD-fed mice rapidly exhibited metabolic alterations, including obesity, hyperleptinemia, physical inactivity, glucose intolerance, peripheral insulin resistance, fasting hyperglycemia, ectopic lipid deposition, and bone deterioration. Prolonged exposure to HFHSD resulted in morbid obesity, ectopic triglyceride deposition in liver and muscle, extensive bone loss, sarcopenia, hyperinsulinemia, and impaired short-term memory. Although many of these defects are typically associated with aging, HFHSD did not alter telomere length in white blood cells, indicating that this diet did not generally promote all aspects of aging. Strikingly, glucose homeostasis was highly dynamic. Glucose intolerance was evident in HFHSD-fed mice after 1 week and was maintained for 24 weeks. Beyond 24 weeks, however, glucose tolerance improved in HFHSD-fed mice, and by 60 weeks, it was indistinguishable from that of chow-fed mice. This improvement coincided with adaptive β-cell hyperplasia and hyperinsulinemia, without changes in insulin sensitivity in muscle or adipose tissue. Assessment of insulin secretion in isolated islets revealed that leptin, which inhibited insulin secretion in the chow-fed mice, potentiated glucose-stimulated insulin secretion in the HFHSD-fed mice after 60 weeks. Overall, the excessive calorie intake was accompanied by deteriorating function of numerous physiological systems.

Association of Telomere Length With Chromosomal Damage Among Chinese Workers Exposed to Vinyl Chloride Monomer.

To explore the relationship between relative telomere length (RTL) and chromosomal damage represented by micronucleus (MN) frequencies among vinyl chloride monomer (VCM) -exposed workers. A group of 126 VCM-exposed workers, 60 internal controls, and 25 external controls were examined for RTL by Quantitative polymerase chain reaction and MN frequencies by cytokinesis-block micronucleus test. Cumulative exposure dose was used to estimate the exposure of VCM-exposed workers. The RTL were significantly shorter in exposed workers and internal controls than in external controls. The exposed workers had significantly increased MN frequencies than both control groups. Additionally, MN frequencies were negatively associated with RTL in VCM-exposed group. VCM exposure may alter telomere length, which could be a potential biomarker of susceptibility to chromosomal damage.

Silica inhalation altered telomere length and gene expression of telomere regulatory proteins in lung tissue of rats

Exposure to silica can cause lung fibrosis and cancer. Identification of molecular targets is important for the intervention and/or prevention of silica-induced lung diseases. Telomeres consist of tandem repeats of DNA sequences at the end of chromosomes, preventing chromosomal fusion and degradation. Regulator of telomere length-1 (RTEL1) and telomerase reverse transcriptase (TERT), genes involved in telomere regulation and function, play important roles in maintaining telomere integrity and length. The goal of this study was to assess the effect of silica inhalation on telomere length and the regulation of RTEL1 and TERT. Lung tissues and blood samples were collected from rats at 4, 32, and 44 wk after exposure to 15 mg/m3 of silica × 6 h/d × 5 d. Controls were exposed to air. At all-time points, RTEL1 expression was significantly decreased in lung tissue of the silica-exposed animals compared to controls. Also, significant increases in telomere length and TERT were observed in the silica group at 4 and 32 wk. Telomere length, RTEL1 and TERT expression may serve as potential biomarkers related to silica exposure and may offer insight into the molecular mechanism of silica-induced lung disease and tumorigeneses.

Telomere quantification in frontal and temporal brain tissue of patients with schizophrenia

Recent imaging studies have suggested that accelerated aging occurs in schizophrenia. However, the exact cause of these findings is still unclear. In this study we measured telomere length, a marker for cell senescence, in gray and white matter brain tissue from the medial frontal gyrus (MFG) and superior temporal gyrus (STG) of 9 patients with schizophrenia and 11 controls. No alterations in telomere length were found in MFG gray and white matter and in STG gray matter. A significant reduction in telomere length was observed in STG white matter of patients with schizophrenia as compared to controls (fold change of −0.42, U = 5, P = 0.008). Our results support previous findings that telomere length in gray matter is not affected, whereas they suggest that increased cell senescence may affect white matter temporal brain tissue.

Abstract 511: Chromosome instability mechanisms in breast cancer among African Americans and Caucasians

Abstract Significant disparities exist in breast cancer among African Americans (AAs) women compared to Caucasians. Even though AAs are less likely to undergo regular mammograms due to access barriers, it is unlikely that differences in screen based detection accounts entirely for outcome disparities. While the current guidelines recommend women begin mammography at age 40 or 50, AA women may be at increased risk for delayed diagnosis since &amp;gt;10% of breast cancer cases in AAs are diagnosed in women younger &amp;lt;40 years compared with 5% of Caucasians. This highlights the importance of defining optimal ethnically appropriate age of screening especially given the disproportionate mortality among younger black women patients. Therefore, an alternative approach using biomarkers should be considered in order to develop ethnically appropriate measures for detecting the disease in the earliest stages. Genomic instability has long been recognized as a major driver of carcinogenesis occurring early on and increasing in complexity with disease progression. However, to date little is known about the underlying mechanisms associated with such instability among the different ethnic groups. In this study we hypothesized that alterations in telomere length and dysfunctional centrosome apparatus are underlying mechanisms associated with ethnic-based genomic instability. We investigated alterations in centrosome apparatus, misaligned chromosomes and spindle angle orientation in AA [HCC 70] and Caucasian [HCC1395] cell lines using confocal microscopy. Our results demonstrated significant differences in structural (30%) and numerical alterations (60%) in centrosome apparatus between AA and Caucasian cell lines (p&amp;lt;0.001). We also noticed a significant increase of misaligned chromosomes (35%) and (68 %) in the metaphase of Caucasians and AA’s respectively (p&amp;lt;0.002). In addition, a significant difference in spindle orientation was observed among AAs and Caucasians suggesting that mitotic phase abnormalities may be, in part, responsible for the underlying genetic instabilities associated with breast cancer. Using ingenuity pathway analysis, we compared gene expressions in both AAs and Caucasian cell lines and observed a significant change in telomerase signaling expression between the cell lines, suggesting a role for telomere lengths in the generation of genetic instability. Together, identifying the specific mechanisms that drive tumorigenesis may provide opportunities for future targeted prevention efforts among high risk cohorts. (This work is supported in part by CA189240) Citation Format: Jose Thaiparambil, Oula Mansour, Susan Haley, Randa EL-Zein. Chromosome instability mechanisms in breast cancer among African Americans and Caucasians [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 511. doi:10.1158/1538-7445.AM2017-511

Abstract 3468: Comprehensive analysis of telomere length and telomere maintenance mechanisms across 31 human cancer types

Abstract Telomeres cap chromosome ends and prevent chromosomal fusions. In the majority of somatic cells telomere shortens with each cell division. Cancer cells, on the other hand, maintain telomere length (TL) through reactivation of telomerase or alternative lengthening of telomere (ALT). Though closely related to cancer hallmarks such as chromosomal instability, telomere length has not been systematically analyzed in cancer. We used DNA sequencing to infer TL in 18,430 samples across 31 cancer types. Tumor TL was shorter compared to normal TL but tended to be longer in testicular germ cell tumors, sarcomas and gliomas. TL in non-neoplastic leukocyte and solid tissue samples was negatively correlated with patient age and varied between lineages, with kidney samples showing the longest TL and leukocytes the shortest. Amongst tumors, 73% expressed telomerase reverse transcriptase (TERT), which was associated with mutations of the TERT promoter (23%), focal amplifications (6%), gene fusions (1%) and structural variants of the promoter (4%) and gene body (3%). Isoform analysis revealed that the full-length TERT transcript was dominantly expressed compared to the enzymatically inactive minus beta variant in all cancer types. TERT expression was positively associated with predicted telomerase activity, inferred from comparison of known ALT and non-ALT tumor samples. Distal breakpoint positions involved in TERT promoter structural variants demonstrated increased levels of H3K27ac and H3K4me1, suggesting displaced enhancer elements. We additionally detected hypermethylation of the TERT promoter in 69%, and found an unexpected association with TERT expression. Combined, 95% of TERT expressing tumors was found positive for at least one potential genomic or epigenetic regulatory event. Six percent of tumors did not express TERT and harbored somatic mutations, deletions, gene fusions or structural variants in ATRX or DAXX, both of which have been shown to be tightly associated with ALT. These tumors demonstrated decreased of ATRX expression in combination with significantly longer TL and expression of telomeric repeat containing RNA (TERRA). Interestingly, 21% of the cohort did not express TERT and was ATRX wild-type. In this double wild-type group, unsupervised analysis identified positive correlations between telomere length, TP53 and RB1 alterations. Predicted telomerase activity in the double wild type and ATRX or DAXX altered groups was significantly lower compared to TERT expressing tumors. Gene expression was found to be TL dependent, with genes nearby telomeres showing a negative correlation (increased expression with shorter TL) whereas genes far away from telomeres showed a positive correlation and (increased expression with longer TL). Our analysis provides insights into the various modalities associated with TERT expression and provides a landscape of determinants of telomere length in cancer. Citation Format: Floris P. Barthel, Siyuan Zheng, Roel G. Verhaak. Comprehensive analysis of telomere length and telomere maintenance mechanisms across 31 human cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3468. doi:10.1158/1538-7445.AM2017-3468

Abstract 2264: Telomere biology gene methylation and cancer risk

Abstract Background: Telomeres maintain genomic stability and regulate cellular senescence. Numerous studies have examined blood telomere length (BTL) and cancer risk, including our own which previously identified a dynamic relationship between BTL and cancer risk over time: Relative to subjects who remained cancer-free, those who later developed cancer experienced accelerated telomere shortening until 3-4 years prior to cancer diagnosis/censoring, at which point BTL in the incident cancer group stabilized. Other studies have suggested that cancer cells are able to hijack telomere maintenance mechanisms (e.g., telomerase) in order to circumvent the Hayflick limit, which will otherwise induce senescence and limit cancer cells’ ability to multiply. As DNA methylation dysregulation is a known epigenetic hallmark of cancer, our objective was to understand whether DNA methylation of telomere biology genes is associated with cancer risk and BTL. Methods: We studied 915 blood measurements from 491 subjects in the Normative Aging Study taken between 1999 and 2013, who were cancer free in 1999 and randomly selected for whole-epigenome DNA methylation profiling using the Illumina 450K BeadChip array. Among these subjects, 125 cases developed cancer and 366 controls remained cancer free for our entire follow up (median 10.1 years). Our analysis focused on 2,731 CpG sites on 142 genes related to telomere length maintenance. We used linear models to identify CpGs differentially methylated by cancer status at the first blood draw only, followed by mixed models using our full data to determine the final CpG sites of interest for Cox models of cancer risk, and another set of mixed models to compare trajectories over time of methylation in cancer patients vs. controls. Finally an additional mixed model explored the temporal relationship between methylation measured at the first visit and BTL measured at the second visit. Results: Our screening identified 167 CpG sites, 10 of which were associated with time-dependent cancer risk at FDR &amp;lt;0.05. Methylation of one CpG on each of CDC73, NSMCE2, and RPA1 was associated with decreased cancer risk. Methylation of one CpG on each of DCLRE1C, DDB1, H2AFY, HNRNPA2B1, and TEP1, as well as two CpGs on TERF2, was associated with increased cancer risk. DNA methylation trajectory at three CpGs was significantly different across cancer status (cg20772347 on DDB1, cg23157637 on TEP1, and cg04818274 on TERF2). One CpG on NSMCE2 and one on TERF2 were associated with BTL in cancer-free subjects, while another CpG on TERF2 was associated with BTL in subjects who later developed cancer. Conclusion: These findings suggest that methylation changes in telomere maintenance genes may be a mechanism by which cancer cells alter telomere length, thus undermining genomic stability and protecting cancer cells from senescence. Future studies should confirm these findings, and explore these CpG sites and genes as potential early detection biomarkers and therapeutic targets. Citation Format: Brian T. Joyce, Yang Li, Yinan Zheng, Lei Liu, Hushan Yang, Chad Achenbach, Pantel Vokonas, Joel Schwartz, Andrea Baccarelli, Lifang Hou. Telomere biology gene methylation and cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2264. doi:10.1158/1538-7445.AM2017-2264

Mutation of the TERT promoter leads to poor prognosis of patients with non-small cell lung cancer.

Mutations in the promoter region of telomerase reverse transcriptase (TERT) and alterations in telomere length (TL) have been the focus of research in various types of cancer. In the present study, the frequency and clinical characteristics of TERT promoter mutations and TL were studied in non-small cell lung cancers (NSCLC). TERT promoter mutations and TL were analyzed in 188 patients using DNA sequencing and the reverse transcription-quantitative polymerase chain reaction, respectively. The TERT promoter mutation rate was observed to be 2.2% (4/188 NSCLC cases), and it was significantly associated with regional lymph node invasion (P<0.001). No significant difference in TL was observed between the patients with and without TERT promoter mutations. TL was decreased in males (P=0.058 vs. females) and smokers (P=0.008 vs. non-smokers). Survival analyses demonstrated poor prognoses for patients with NSCLC with TERT promoter mutations (P<0.001). Multivariate survival analyses demonstrated that TERT promoter mutations were an independent prognostic marker for poor overall survival (P=0.045). The results of the present study demonstrated that TERT promoter mutation was not frequent in NSCLC; however, it may have value as a prognostic marker in NSCLC.

Abstract P3-09-02: Unhealthy lifestyle patterns are prevalent in unaffected BRCA mutation carriers &amp; are associated with increased oxidative stress and telomere length alterations

The lifetime-risk of breast-cancer is greatly increased in women carrying a deleterious mutation in the BRCA1 or BRCA2 genes . Recently, there has been increased penetrance of BRCA1 and BRCA2 mutations which may be due to lifestyle influences. There is a need to identify approaches to reduce the penetrance of BRCA 1/2 mutations. Understanding how modifiable lifestyle-factors affect cancer-risk in BRCA-mutation carriers may have implications for risk-reduction in this group. At the molecular level, oxidative-stress and telomere dysfunction are early events in cancer development and these processes may be considered surrogate markers of cancer-risk. It has been reported that BRCA-mutation carriers are more susceptible to these pro-carcinogenic processes that non-carriers. The aim of this pilot study was to objectively measure lifestyle factors in unaffected BRCA-mutation carriers and to assess the impact of these lifestyle-factors on oxidative-stress profiles and telomere length. Participants (n=75) were recruited from breast-cancer family-risk clinics and cancer-genetics clinics. Body-composition (BMI, waist-circumference), metabolic profiles and physical-activity (triaxial accelerometry) were measured for each participant. Serum levels of the oxidative-stress markers 8-oxo-7,8-dihydro-29-deoxyguanosine (8-oxo-DG) and 4-hydroxynonenal (4-HNE) were measured in a subset of participants (n=30) by ELISA. Telomere length was measured in a subset of participants (n=30) by quantitative PCR (qPCR). Participants demonstrated poor adherence to physical-activity guidelines with 94% not reaching physical-activity levels recommended by the American College of Sports Medicine. The majority of participants were overweight (39%) or obese (32%) with 73% exhibiting abdominal obesity. 21% of participants had the metabolic syndrome (MetS) at the time of study enrolment with the majority of participants (80%) presenting with at least one feature of the MetS. Circulating levels of 8-oxo-DG did not appear to be affected by body composition or MetS status, however, serum levels of the lipid peroxidation marker 4-HNE were significantly higher in participants with the MetS (p This work has provided compelling evidence that in this cohort of BRCA-mutation carriers, unhealthy lifestyle-patterns are prevalent. In addition, these results suggest that the potential may exist to modify pro-carcinogenic processes in this cohort by modifying physical activity levels and targeting the metabolic syndrome and its component features lifestyle interventions and/or medication.The lifetime-risk of breast-cancer is greatly increased in women carrying a deleterious mutation in the BRCA1 or BRCA2 genes . Recently, there has been increased penetrance of BRCA1 and BRCA2 mutations which may be due to lifestyle influences. There is a need to identify approaches to reduce the penetrance of BRCA 1/2 mutations. Understanding how modifiable lifestyle-factors affect cancer-risk in BRCA-mutation carriers may have implications for risk-reduction in this group. At the molecular level, oxidative-stress and telomere dysfunction are early events in cancer development and these processes may be considered surrogate markers of cancer-risk. It has been reported that BRCA-mutation carriers are more susceptible to these pro-carcinogenic processes that non-carriers. The aim of this pilot study was to objectively measure lifestyle factors in unaffected BRCA-mutation carriers and to assess the impact of these lifestyle-factors on oxidative-stress profiles and telomere length. Participants (n=75) were recruited from breast-cancer family-risk clinics and cancer-genetics clinics. Body-composition (BMI, waist-circumference), metabolic profiles and physical-activity (triaxial accelerometry) were measured for each participant. Serum levels of the oxidative-stress markers 8-oxo-7,8-dihydro-29-deoxyguanosine (8-oxo-DG) and 4-hydroxynonenal (4-HNE) were measured in a subset of participants (n=30) by ELISA. Telomere length was measured in a subset of participants (n=30) by quantitative PCR (qPCR). Participants demonstrated poor adherence to physical-activity guidelines with 94% not reaching physical-activity levels recommended by the American College of Sports Medicine. The majority of participants were overweight (39%) or obese (32%) with 73% exhibiting abdominal obesity. 21% of participants had the metabolic syndrome (MetS) at the time of study enrolment with the majority of participants (80%) presenting with at least one feature of the MetS. Circulating levels of 8-oxo-DG did not appear to be affected by body composition or MetS status, however, serum levels of the lipid peroxidation marker 4-HNE were significantly higher in participants with the MetS (p This work has provided compelling evidence that in this cohort of BRCA-mutation carriers, unhealthy lifestyle-patterns are prevalent. In addition, these results suggest that the potential may exist to modify pro-carcinogenic processes in this cohort by modifying physical activity levels and targeting the metabolic syndrome and its component features lifestyle interventions and/or medication. Citation Format: McGarrigle SA, Guinan EM, Hussey J, O9Sullivan J, Boyle T, Hanhauser Y, Al-azawi D, Kennedy MJ, Gallagher DJ, Connolly EM. Unhealthy lifestyle patterns are prevalent in unaffected BRCA mutation carriers & are associated with increased oxidative stress and telomere length alterations [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-09-02.

Systematic analysis of telomere length and somatic alterations in 31 cancer types.

Cancer cells survive cellular crisis through telomere maintenance mechanisms. We report telomere lengths in 18,430 samples, including tumors and non-neoplastic samples, across 31 cancer types. Telomeres were shorter in tumors than in normal tissues and longer in sarcomas and gliomas than in other cancers. Among 6,835 cancers, 73% expressed telomerase reverse transcriptase (TERT), which was associated with TERT point mutations, rearrangements, DNA amplifications and transcript fusions and predictive of telomerase activity. TERT promoter methylation provided an additional deregulatory TERT expression mechanism. Five percent of cases, characterized by undetectable TERT expression and alterations in ATRX or DAXX, demonstrated elongated telomeres and increased telomeric repeat-containing RNA (TERRA). The remaining 22% of tumors neither expressed TERT nor harbored alterations in ATRX or DAXX. In this group, telomere length positively correlated with TP53 and RB1 mutations. Our analysis integrates TERT abnormalities, telomerase activity and genomic alterations with telomere length in cancer.

Oxidative guanine base damage regulates human telomerase activity.

Changes in telomere length are associated with degenerative diseases and cancer. Oxidative stress and DNA damage have been linked to both positive and negative alterations in telomere length and integrity. Here we examined how the common oxidative lesion 8-oxo-7,8-dihydro-2′-deoxyguanine (8-oxoG) regulates telomere elongation by telomerase. When present in the deoxynucleoside triphosphate pool as 8-oxodGTP, telomerase utilization of the oxidized nucleotide during telomere extension is mutagenic and terminates further elongation. Depletion of the enzyme that removes oxidized dNTPs, MTH1, increases telomere dysfunction and cell death in telomerase positive cancer cells harboring shortened telomeres. In contrast, a pre-existing 8-oxoG within the telomeric DNA sequence promotes telomerase activity by destabilizing G-quadruplex structure in the DNA. We show that the mechanism by which 8-oxoG arises in the telomere, either by insertion of oxidized nucleotides or by direct reaction with free radicals, dictates whether telomerase is inhibited or stimulated and thereby, mediates the biological outcome.

Association of telomere length in peripheral leukocytes with chronic hepatitis B and hepatocellular carcinoma

Background & Objectives:Telomere plays a critical role in the maintenance of genomic stability in eukaryotic chromosomes. More and more findings have shown that alteration in telomere length may involve in normal somatic cells and some diseases, however, whether the telomere length is associated with the development and/or progression of hepatic diseases remains poorly understood.Methods:A case–control study was employed to illustrate the correlation of relative telomere length (RTL) with chronic hepatitis B (CHB) and hepatocellular carcinoma (HCC). In this study, 152 patients with HCC, 212 patients with CHB, and 184 healthy controls were recruited. Genomic deoxyribonucleic acid (DNA) was extracted from the peripheral blood leukocytes, and fluorescence quantitative polymerase chain reaction (FQ-PCR) was used to detect telomere repeated numbers and 36B4 copy numbers. The RTL was calculated by telomere repeat copy number to single-copy gene number ratio in each sample compared with a reference DNA sample.Results:We found that the RTL in HCC group was the longest, followed by CHB group, and healthy control group was the shortest, showing significant statistical differences. When participants were categorized into longer and shorter group according to medium value in healthy controls, individuals who had longer RTL had a significant increased risk of CHB (odds ratio [OR]: 1.83, 95% confidence interval [CI]: 1.22–2.73) when the healthy control was used as the reference groups; furthermore, longer RTL also showed higher incidence of HCC (OR: 3.22, 95% CI: 2.01–5.17; OR: 1.58, 95% CI:1.03–2.41) when healthy control and CHB were used as the reference groups, respectively. When participants were categorized further into 4 groups according to quartile values of RTL in healthy controls, it showed that the longest RTL was also associated with an increased risk of CHB (OR: 2.09, 95% CI: 1.17–3.74) and HCC (OR: 4.31, 95% CI: 2.18–8.52; OR: 2.86, 95% CI: 1.53–5.34) when control and control/CHB group were used as the reference groups, respectively.Conclusion:Our results suggest that the alteration of telomere length in peripheral leukocytes might be involved in the hepatitis B virus infection and HCC events, and RTL might be a potential useful predictor of CHB and HCC.

Alterations of telomere length and mtDNA copy number are associated with overall survival in hepatocellular carcinoma patients treated with transarterial chemoembolization.

Increasing evidence suggests that alterations in mitochondrial DNA (mtDNA) copy number (mtDNAcn) and relative telomere length (RTL) may be implicated in the tumorigenesis of several malignancies. Alterations of both RTL and mtDNAcn are generally accepted as independent biomarkers for predicting risk and prognosis in various cancers. The aim of this study was to evaluate the prognostic value of combining leukocyte RTL with mtDNAcn (RTL-mtDNAcn) in hepatocellular carcinoma (HCC). RTL and mtDNAcn in peripheral blood leukocytes (PBLs) were measured using a real-time PCR-based method in a total of 250 HCC patients treated with transcatheter arterial chemoembolization (TACE). We evaluated the associations between RTL and/or mtDNAcn and HCC overall survival using Kaplan-Meier curve analysis and Cox proportional hazards regression model. We found that patients with longer leukocyte RTL or lower mtDNAcn had shorter overall survival time. The univariate analysis (HR1.63, 95% CI 1.23-2.17, P=7.7×10(-4)) and multivariate analysis (HR1.78, 95% CI 1.31-2.42, P=2.4×10(-4)) indicated that longer leukocyte RTL was significantly associated with poorer OS in HCC patients. Kaplan-Meier curve analysis showed that patients with longer RTL had shorter overall survival time than those with shorter RTL (log-rank P=0.001). Patients with lower mtDNA copy number was significantly associated with poorer OS by Cox proportional hazards model using both univariate (HR1.60, 95% CI 1.21-2.13, P=0.001) and multivariate analyses (HR1.77, 95% CI 1.30-2.41, P=2.8×10(-4)). Kaplan-Meier curve analysis showed that patients with lower mtDNA content had significantly shorter overall survival time than those with higher mtDNA content (log-rank P=0.001). Furthermore, combination of leukocyte RTL and mtDNAcn significantly improved the efficacy of predicting HCC prognosis. Patients with longer RTL and lower mtDNAcn exhibited a significantly poorer overall survival in both the univariate analysis (HR2.21, 95% CI 1.52-3.22, P=3.5×10(-5)) and multivariate analysis (HR2.60, 95% CI 1.73-3.90, P=4.3×10(-6)). The effect on patient prognosis was more evident in patients with longer RTL and lower mtDNAcn than in those with shorter RTL and lower mtDNA (HR2.11, 95% CI 1.34-3.32, P=0.001) or in those with longer RTL and higher mtDNA (HR2.10, 95% CI 1.34-3.27, P=0.001). Our data suggest that combination of leukocyte RTL-mtDNAcn may be a potential efficient prognostic marker for HCC patients receiving the TACE treatment.