Dataset Information

Telomere length and genetic anticipation in Lynch syndrome.

ABSTRACT: Telomere length variation has been associated with increased risk of several types of tumors, and telomere shortening, with genetic anticipation in a number of genetic diseases including hereditary cancer syndromes. No conclusive studies have been performed for Lynch syndrome, a hereditary colorectal cancer syndrome caused by germline mutations in the DNA mismatch repair genes. Here we evaluate telomere length in Lynch syndrome, both as a cancer risk factor and as a mechanism associated with anticipation in the age of cancer onset observed in successive generations of Lynch syndrome families. Leukocyte telomere length was measured in 244 mismatch repair gene mutation carriers from 96 Lynch syndrome families and in 234 controls using a monochrome multiplex quantitative PCR method. Cancer-affected mutation carriers showed significantly shorter telomeres than cancer-free mutation carriers. In addition, cancer-affected carriers showed the most pronounced shortening of telomere length with age, compared with unaffected carriers. The anticipation in the age of cancer onset observed in successive generations was not associated with telomere shortening, although, interestingly, all mother-son pairs showed telomere shortening. In conclusion, cancer-affected mismatch repair gene mutation carriers have distinct telomere-length pattern and dynamics. However, anticipation in the age of onset is not explained by telomere shortening. Pending further study, our findings suggest that telomere attrition might explain the previously reported dependence of cancer risk on the parent-of-origin of mismatch repair gene mutations.

SUBMITTER: Segui N

PROVIDER: S-EPMC3634050 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Telomere length and genetic anticipation in Lynch syndrome.

Seguí Nuria N Pineda Marta M Guinó Elisabet E Borràs Ester E Navarro Matilde M Bellido Fernando F Moreno Victor V Lázaro Conxi C Blanco Ignacio I Capellá Gabriel G Valle Laura L

PloS one 20130423 4

Telomere length variation has been associated with increased risk of several types of tumors, and telomere shortening, with genetic anticipation in a number of genetic diseases including hereditary cancer syndromes. No conclusive studies have been performed for Lynch syndrome, a hereditary colorectal cancer syndrome caused by germline mutations in the DNA mismatch repair genes. Here we evaluate telomere length in Lynch syndrome, both as a cancer risk factor and as a mechanism associated with ant ...[more]

PMID: 23637804

Similar Datasets

Project description:Background: Activation of telomere maintenance mechanisms (TMMs) is a hallmark of most cancers, and is required to prevent genome instability and to establish cellular immortality through reconstitution of capping of chromosome ends. TMM depends on the cancer type. Comparative studies linking tumor biology and TMM have potential impact for evaluating cancer onset and development. Methods: We have studied alterations of telomere length, their sequence composition and transcriptional regulation in mismatch repair deficient colorectal cancers arising in Lynch syndrome (LS-CRC) and microsatellite instable (MSI) sporadic CRC (MSI s-CRC), and for comparison, in microsatellite stable (MSS) s-CRC and in benign colon mucosa. Our study applied bioinformatics analysis of whole genome DNA and RNA sequencing data and a pathway model to study telomere length alterations and the potential effect of the "classical" telomerase (TEL-) and alternative (ALT-) TMM using transcriptomic signatures. Results: We have found progressive decrease of mean telomere length in all cancer subtypes compared with reference systems. Our results support the view that telomere attrition is an early event in tumorigenesis. TMM gets activated in all tumors studied due to concerted overexpression of a large fraction of genes with direct relation to telomere function, where only a very small fraction of them showed recurrent mutations. TEL-related transcriptional state was dominating in all CRC subtypes, showing, however, subtype-specific activation patterns; while contribution of the ALT-TMM was slightly more prominent in the hypermutated MSI s-CRC and LS-CRC. TEL-TMM is mainly activated by over-expression of DKC1 and/or TERT genes and their interaction partners, where DKC1 is more prominent in MSS than in MSI s-CRC and can serve as a transcriptomic marker of TMM activity. Conclusions: Our results suggest that transcriptional patterns are indicative for TMM pathway activation with subtle differences between TEL and ALT mechanisms in a CRC subtype-specific fashion. Sequencing data potentially provide a suited measure to study alterations of telomere length and of underlying transcriptional regulation. Further studies are needed to improve this method.

Project description:Summary Many epidemiologic studies have identified important relationships between leukocyte telomere length (LTL) with genetics and health. Most of these studies have been significantly limited in scope by focusing predominantly on individual diseases or restricted to GWAS analysis. Using two large patient populations derived from Vanderbilt University and Marshfield Clinic biobanks linked to genomic and phenomic data from medical records, we investigated the inter-relationship between LTL, genomics, and human health. Our GWAS confirmed 11 genetic loci previously associated with LTL and two novel loci in SCNN1D and PITPNM1. PheWAS of LTL identified 67 distinct clinical phenotypes associated with both short and long LTL. We demonstrated that several diseases associated with LTL were related to one another but were largely independent from LTL genetics. Age of death was correlated with LTL independent of age. Those with very short LTL (<−1.5 standard deviation [SD]) died 10.4 years (p < 0.0001) younger than those with average LTL (±0.5 SD; mean age of death = 74.2 years). Likewise, those with very long LTL (>1.5 SD) died 1.9 years (p = 0.0175) younger than those with average LTL. This is consistent with the PheWAS results showing diseases associating with both short and long LTL. Finally, we estimated that the genome (12.8%) and age (8.5%) explain the largest proportion of LTL variance, whereas the phenome (1.5%) and sex (0.9%) explained a smaller fraction. In total, 23.7% of LTL variance was explained. These observations provide the rationale for expanded research to understand the multifaceted correlations between TL biology and human health over time, leading to effective LTL usage in medical applications. Most studies studying telomere length are limited in scope by focusing on an individual disease or genomic analysis. Using two large patient populations derived from Vanderbilt University and Marshfield Clinic biobanks we provide one of the first comprehensive studies that examine the inter-relationship between telomere length, genomics, and human health.

Project description:BackgroundTelomeres at the ends of eukaryotic chromosomes play a critical role in maintaining the integrity and stability of the genome and participate in the initiation of DNA damage/repair responses.MethodsWe performed a case-control study to evaluate the role of three SNPs (TERT-07, TERT-54 and POT1-03) in telomere maintenance genes previously found to be significantly associated with breast cancer risk. We used sister-sets obtained from the New York site of the Breast Cancer Family Registry (BCFR). Among the 313 sister-sets, there were 333 breast cancer cases and 409 unaffected sisters who were evaluated in the current study. We separately applied conditional logistic regression and generalized estimating equations (GEE) models to evaluate associations between the three SNPs and breast cancer risk within sister-sets. We examined the associations between genotype, covariates and telomere length among unaffected sisters using a GEE model.ResultsWe found no significant associations between the three SNPs in telomere maintenance genes and breast cancer risk by both conditional logistic regression and GEE models, nor were these SNPs significantly related to telomere length. Among unaffected sisters, shortened telomeres were statistically significantly correlated with never hormone replacement therapy (HRT) use. Increased duration of HRT use was significantly associated with reduced telomere length. The means of telomere length were 0.77 (SD = 0.35) for never HRT use, 0.67 (SD = 0.29) for HRT use < 5 yrs and 0.59 (SD = 0.24) for HRT use ≥ 5 yrs after adjusting for age of blood donation and race and ethnicity.ConclusionsWe found that exogenous hormonal exposure was inversely associated with telomere length. No significant associations between genetic variants and telomere length or breast cancer risk were observed. These findings provide initial evidence to understand hormonal exposure in the regulation of telomere length and breast cancer risk but need replication in prospective studies.

Project description:Background: Previous studies have revealed associations between psychiatric disorder diagnosis and shorter telomere length. Here, we attempt to discern whether genetic risk for psychiatric disorders, or use of pharmacological treatments (i.e., antidepressants), predict shorter telomere length and risk for aging-related disease in a United Kingdom population sample. Methods: DNA samples from blood were available from 351 participants who were recruited as part of the South East London Community Health (SELCoH) Study, and for which whole-genome genotype data was available. Leukocyte telomere length was characterized using quantitative polymerase chain reactions. Individualized polygenic risk scores for major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) were calculated using Psychiatric Genomics Consortium summary statistics. We subsequently performed linear models, to discern the impact polygenic risk for psychiatric disorders (an etiological risk factor) and antidepressant use (common pharmacological treatment) have on telomere length, whilst accounting for other lifestyle/health factors (e.g., BMI, smoking). Results: There were no significant associations between polygenic risk for any of the psychiatric disorders tested and telomere length (p > 0.05). Antidepressant use was significantly associated with shorter telomere length and this was independent from a depression diagnosis or current depression severity (p ? 0.01). Antidepressant use was also associated with a significantly higher risk of aging-related disease, which was independent from depression diagnosis (p ? 0.05). Conclusion: Genetic risk for psychiatric disorders is not associated with shorter telomere length. Further studies are now needed to prospectively characterize if antidepressant use increases risk for aging-related disease and telomere shortening, or whether people who age faster and have aging-related diseases are just more likely to be prescribed antidepressants.

Dataset Information

Telomere length and genetic anticipation in Lynch syndrome.

Publications

Telomere length and genetic anticipation in Lynch syndrome.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets