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Mutations in the promoter of the telomerase reverse transcriptase ( TERT) and fibroblast growth factor receptor 3 ( FGFR3) genes constitute the most recurrent somatic alterations in urothelial carcinoma of bladder. In this study, we screened DNA from 327 urothelial bladder carcinomas from well-documented patients, with different stages and grades and known TERT promoter mutational status, for FGFR3 alterations and measured relative telomere length (RTL). Although, the frequency of the TERT promoter mutations was higher than those in FGFR3; however, the alterations at the two loci occurred together more frequently than per chance [Odds ratio (OR) = 4.93, 95% CI = 2.72-8.92, p < 0.0001]. While tumors with TERT promoter and FGFR3 mutations had shorter RTL than those without mutations ( p < 0.0001), the TERT promoter mutations in conjunction with the common allele of the rs2853669 polymorphism defined sub-group of patients with an observed decreased overall survival (OR = 2.15, 95% CI = 1.00-4.61) and increased recurrence in patients with TaG1+TaG2 disease categories (OR = 3.68, 95%CI = 1.12-12.05). The finding of shorter telomeres in tumors with TERT promoter and/or FGFR3 mutations than without mutations implies mechanistic relevance of telomere biology in cancer progression. The observed association with recurrence and survival shows that the TERT promoter mutations can potentially be used as markers to refine selection of patients for different treatments. The overwhelming frequency of the TERT promoter mutations also represents a case for development of an eventual therapeutic target. [ABSTRACT FROM AUTHOR]

Abstracts from the conference "Effects of Traumatic Stress: Molecular and Hormonal Mechanism," held in New York, September 11–14, 2012 are presented.

Rationale/statement of the problem : Major depressive disorder (MDD) and other serious mental illnesses are associated with high rates of comorbid medical illnesses. Many of these comorbid conditions are more typically seen in the aged, raising the possibility that these psychiatric illnesses are associated with accelerated aging. An emerging biomarker of cell aging and of increased risk of medical illness is leukocyte telomere length, and several studies have now characterized leukocyte telomere length in MDD and other psychiatric illnesses. Fewer psychiatric studies have characterized the activity of telomerase, an enzyme that can elongate and preserve telomeric DNA, or have investigated the biochemical mediators of accelerated telomere shortening. Methods : Seven studies examining telomere length in MDD, three studies in schizophrenia, two studies in bipolar illness, two studies in PTSD, and one study in generalized anxiety disorder were reviewed, as were one study of telomerase activity in MDD and one study in schizophrenia. Additional studies in chronically stressed individuals and in individuals with histories of childhood adversity were also reviewed. Results : Shortened leukocyte telomeres have been demonstrated in MDD, bipolar illness, schizophrenia, anxiety disorders, and post-traumatic stress disorder, although in some studies, only subgroups of patients (e.g., those with longer lifetime exposure to the illness, those with poor responses to treatment, or those with preexisting histories of childhood adversity) showed shortened telomeres. Leukocyte telomere shortening is correlated with peripheral indices of increased oxidative stress and increased immune activation. Two studies (one in caregivers with high depression ratings and one in unmedicated patients with MDD) reported elevated peripheral blood mononuclear cell (PBMC) telomerase activity, perhaps representing a compensatory attempt by the body to preserve endangered telomeres. Preliminary data in MDD suggest that relatively low telomerase activity before treatment, and greater treatment-associated increases in telomerase activity, are associated with better antidepressant responses. This, plus the preliminary observation that PBMC telomerase activity is directly correlated with hippocampal volume (by MRI) in MDD, support emerging preclinical data that telomerase has intrinsic neurotrophic and antidepressant effects. Conclusion : Telomere shortening in MDD and certain other psychiatric conditions may, at least partially, reflect chronic exposure to inflammation and oxidation. As such, it may be a bellwether of increased medical risk, or it may play a more direct causal role in accelerated aging. The interplay of telomere integrity and telomerase activity may be an important determinant of psychiatric and medical outcome. Overall, the data are consistent with the view that MDD and certain other psychiatric illnesses have systemic manifestations beyond the brain and call into question the dichotomy of “mental” vs. “physical” illnesses.

Rationale/statement of the problem : Substantial evidence suggests conditions in intrauterine life may play a critical role in subsequent health and disease susceptibility related outcomes (i.e., the concept of fetal or developmental programming of health and disease). The elucidation of biological mechanisms underlying these effects is an area of active investigation. We suggest that telomere biology may represent a novel mechanism underlying the effects of a disparate set of suboptimal intrauterine exposures on various health and disease risk phenotypes. From an evolutionary-developmental perspective, energy substrate availability (i.e., nutrition) and challenges that have the potential to impact the structural or functional integrity and survival of the organism (i.e., stress) likely represent the most important environmental considerations underlying natural selection and developmental plasticity. Maternal stress and nutrition in pregnancy therefore represent attractive candidate processes in the context of fetal programming of telomere biology. Our previous work has established an important role for prenatal stress and stress-related processes in adult telomere biology Methods : In two longitudinal birth cohorts, stress- and nutrition-related processes were assessed during pregnancy and telomere length (TL) was subsequently measured in newborns (cord blood) and infants (buccal cells). Results : (1) Among the nutrition-related factors, maternal lower folate levels (an essential methyl donor) and higher triglyceride concentrations in early pregnancy were significantly and independently associated with shorter newborn TL. (2) Among psychosocial stress-related measures, higher maternal pregnancy-specific stress was associated with shorter newborn TL. (3) Maternal estrogen (E3) levels during early pregnancy were associated with longer infant TL. Conclusion : Taken together, our findings provide the first evidence in humans that maternal nutrition and stress-related processes during pregnancy may exert a programming effect on the newborn and infant telomere biology system. In utero telomere biology represents a potential molecular mechanism whereby different exposures in this critical developmental period before birth could impact subsequent health and disease susceptibility related outcomes over the life span, including aging and longevity