Potential utility of telomere length assessment in breast cancer in a diagnostic histopathology setting.

INTRODUCTION: Telomeres shorten with cell cycling but are restored above mortality threshold in many cancers making them potentially exploitable for differentiating malignant from benign tissues, and for cancer evaluation. MATERIALS AND METHODS: We assessed telomeres in a diagnostic histopathology setting using quantitative fluorescence in situ hybridisation on 33 fibroadenoma (FA) and 73 invasive breast carcinoma of no special type (IBC-NST) (prototypes of benign and malignant breast tumours, respectively) with paired benign, non-lesional breast tissues (BNL). Telomere lengths were expressed as telomere/chromosome-2-centromere ratio (TCR). The telomere length cut-off for malignancy was also determined. RESULTS: Mean TCR of IBC-NST was significantly shorter than FA and BNL (p<0.001). Mean TCR of FA was shorter than BNL but not significantly (p>0.05). TCR cut-off for IBC-NST based on FA was ≤0.29 (sensitivity=75.3%; specificity=78.8%), and ≤0.30 based on BNL (sensitivity=76.7%; specificity=89.0%). TCR of IBC-NST did not differ in relation to histological grade, nodal and hormonal status (p>0.05) but was significantly shorter in HER2-overexpressing cancers (p<0.05). CONCLUSION: We have demonstrated a first-step to the development of methodologybased cut-off values of mean telomere length for distinguishing benign from malignant breast tissues. Telomere length may not value-add to the standard prognostic and predictive parameters, but has potential in relation to HER2.

A scoping systematic review of social stressors and various measures of telomere length across the life course.

Numerous studies examine the relationship between social stressors and telomere length (TL). Beyond considering methods and major findings, this scoping systematic review takes a novel approach as it groups studies according to the types of social stressor considered and by age groups. Following PRISMA guidelines, we searched PubMed, Web of Science, Embase, and Scopus. We included all English-language human subject research articles that modeled any measure of TL as a dependent variable and exposure to a social stressor as an independent variable. For the sample of 105 articles, we summarized methods and findings by type of social stressor (socioeconomic stressors, stressful life events, work-related stressors, and neighborhood stressors) and by age of the study population (infants/children, middle-aged adults, older adults, and mixed samples of middle-aged and older adults). We found more variation in TL measurement methodology in studies of infants/children and older adults than in studies focusing on middle-aged adults. The most consistent finding was a relationship between early-life stressors and shorter TL. Work and neighborhood stressors, and older populations, are currently understudied. Across all stressors, limited evidence suggests that the stress-TL relationship may be moderated by characteristics such as age, sex, and race/ethnicity. We conclude with specific suggestions for future research.

Exposure to violence during childhood is associated with telomere erosion from 5 to 10 years of age: a longitudinal study.

There is increasing interest in discovering mechanisms that mediate the effects of childhood stress on late-life disease morbidity and mortality. Previous studies have suggested one potential mechanism linking stress to cellular aging, disease and mortality in humans: telomere erosion. We examined telomere erosion in relation to children's exposure to violence, a salient early-life stressor, which has known long-term consequences for well-being and is a major public-health and social-welfare problem. In the first prospective-longitudinal study with repeated telomere measurements in children while they experienced stress, we tested the hypothesis that childhood violence exposure would accelerate telomere erosion from age 5 to age 10 years. Violence was assessed as exposure to maternal domestic violence, frequent bullying victimization and physical maltreatment by an adult. Participants were 236 children (49% females; 42% with one or more violence exposures) recruited from the Environmental-Risk Longitudinal Twin Study, a nationally representative 1994-1995 birth cohort. Each child's mean relative telomere length was measured simultaneously in baseline and follow-up DNA samples, using the quantitative PCR method for T/S ratio (the ratio of telomere repeat copy numbers to single-copy gene numbers). Compared with their counterparts, the children who experienced two or more kinds of violence exposure showed significantly more telomere erosion between age-5 baseline and age-10 follow-up measurements, even after adjusting for sex, socioeconomic status and body mass index (B=-0.052, s.e.=0.021, P=0.015). This finding provides support for a mechanism linking cumulative childhood stress to telomere maintenance, observed already at a young age, with potential impact for life-long health.

Absence of subtelomeric rearrangements in selected patients with mental retardation as assessed by multiprobe T FISH.

BACKGROUND: Mental retardation (MR) is a heterogeneous condition that affects 2-3% of the general population and is a public health problem in developing countries. Chromosomal abnormalities are an important cause of MR and subtelomeric rearrangements (STR) have been reported in 4-35% of individuals with idiopathic MR or an unexplained developmental delay, depending on the screening tests and patient selection criteria used. Clinical checklists such as that suggested by de Vries et al. have been used to improve the predictive value of subtelomeric screening. FINDINGS: Fifteen patients (1-20 years old; five females and ten males) with moderate to severe MR from a genetics outpatient clinic of the Gaffrée and Guinle Teaching Hospital (HUGG) of the Federal University of Rio de Janeiro State (UNIRIO) were screened with Multiprobe T FISH after normal high resolution karyotyping. No subtelomeric rearrangements were detected even though the clinical score of the patients ranged from four to seven. CONCLUSION: In developing countries, FISH-based techniques such as Multiprobe T FISH are still expensive. Although Multiprobe T FISH is a good tool for detecting STR, in this study it did not detect STR in patients with unexplained MR/developmental delay even though these patients had a marked chromosomal imbalance. Our findings also show that clinical scores are not reliable predictors of STR.

Nuclear size measurement is a simple method for the assessment of hepatocellular aging in non-alcoholic fatty liver disease: Comparison with telomere-specific quantitative FISH and p21 immunohistochemistry.

Telomere-specific quantitative fluorescent in situ hybridization (Q-FISH) accurately evaluates hepatocellular aging on histological sections, but it requires appropriate tissue processing. To establish a more simple method for the assessment of hepatocellular aging, the usefulness of nuclear size measurement was clarified using biopsy liver samples from 64 patients with non-alcoholic fatty liver disease (NAFLD), a model for oxidative stress-associated hepatocellular aging, and 11 control individuals. Relative telomere intensity (RTI) was measured on Q-FISH, and the relative nuclear size (RNS) was calculated as the average nuclear size of the hepatocytes divided by that of lymphocytes. In normal individuals and NAFLD patients, the RTI and RNS were negatively correlated. The degree of nuclear enlargement in NAFLD patients was larger than that in normal individuals with the same telomere length, possibly reflecting telomere-independent senescence. In NAFLD patients with RNS >2.0, the regenerative responses, indicated by the ratio of Ki-67-positive index to serum alanine aminotransferase level, were significantly reduced. The RNS positively correlated with the p21 expression, another marker of senescence. This all indicates that nuclear enlargement progresses in parallel with reduced regenerative responses, telomere shortening, and p21 upregulation. Nuclear size measurement is an effective method for estimation of hepatocellular aging.

Comparative assessment of telomere length before and after hematopoietic SCT: role of grafted cells in determining post-transplant telomere status.

Our objective was to characterize the role of grafted cells in determining telomere length (TL) after hematopoietic SCT (HSCT). A total of 20 patients undergoing autografts had PBSC collected after two sequential mobilization courses: TL in the first collection was significantly longer than in the second. For their autografts, 10 patients used PBSC from the first collection and 10 from the second. TL was also investigated before and after HSCT and on the graft in 10 allogeneic HSCT. After autografting, patients receiving PBSC from the first collection had BM TL reflecting that of grafted cells (median bp: 7730 on PBSC vs 7610 on post-HSCT BM, P=NS) and significantly longer than TL of the second collection; analogously, patients autografted with PBSC from the second collection had BM TL reflecting that of grafted cells (7360 on PBSC vs 7120 on post-HSCT BM, P=NS) and significantly shorter compared with the first collection. In the allograft setting, eight patients had their pre-transplant TL significantly shorter than donor PBSC (5960 vs 7110; P=0.0005); following HSCT, BM TL (median 7380 bp) was identical to that of the graft (P=NS). We conclude that grafted cells have a major role in determining TL after HSCT.