Epidemiologic evidence for a role of telomere dysfunction in cancer etiology

Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis (Impact Factor: 3.68). 07/2011; 730(1-2):75-84. DOI: 10.1016/j.mrfmmm.2011.06.009
Source: PubMed


Telomeres, the dynamic nucleoprotein structures at the ends of linear chromosomes, maintain the genomic integrity of a cell. Telomere length shortens with age due to the incomplete replication of DNA ends with each cell division as well as damage incurred by oxidative stress. Patterns of telomere shortening, genomic instability, and telomerase expression in many cancer tissues compared to adjacent normal tissue implicate telomere crisis as a common crucial event in malignant transformation. In order to understand the role of telomere length in cancer etiology, most epidemiologic studies have measured average telomere length of peripheral blood or buccal cell DNA as a surrogate tissue biomarker of telomere dysfunction and cancer risk. In this review, we present the results from epidemiologic investigations conducted of telomere length and cancer risk. We note differences in reported associations based on study design, which may be due to biases intrinsic to retrospective studies. Finally, we conclude with study design considerations as future investigations are needed to elucidate the relationship between telomere length and a number of cancer sites.

Download full-text


Available from: Sharon A Savage,
  • Source
    • "Telomeres are a repetitive sequence of nucleotides rich in guanidine, synthesized by the enzyme telomerase, that cap the ends of chromosomes to prevent chromosomes from deterioration (Blackburn and Gall, 1978). Usually telomeres shorten during each round of DNA replication but in advanced cancers telomerase is reactivated to maintain telomere length allowing many more cell divisions (Artandi and DePinho, 2010; Prescott et al., 2012). Downregulation of 14-3-3s protein in keratinocytes maintains telomerase activity allowing them to escape replicative senescence (Dellambra et al., 2000). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The incidence of ocular surface squamous neoplasia (OSSN) is strongly associated with solar ultraviolet (UV) radiation, HIV and human papilloma virus (HPV). Africa has the highest incidence rates in the world. Most lesions occur at the limbus within the interpalpebral fissure particularly the nasal sector. The nasal limbus receives the highest intensity of sunlight. Limbal epithelial crypts are concentrated nasally and contain niches of limbal epithelial stem cells in the basal layer. It is possible that these are the progenitor cells in OSSN. OSSN arises in the basal epithelial cells spreading towards the surface which resembles the movement of corneo-limbal stem cell progeny before it later invades through the basement membrane below. UV radiation damages DNA producing pyrimidine dimers in the DNA chain. Specific CC -> TT base pair dimer transformations of the p53 tumour-suppressor gene occur in OSSN allowing cells with damaged DNA past the G1-S cell cycle checkpoint. UV radiation also causes local and systemic photo-immunosuppression and reactivates latent viruses such as HPV. The E7 proteins of HPV promote proliferation of infected epithelial cells via the retinoblastoma gene while E6 proteins prevent the p53 tumour suppressor gene from effecting cell-cycle arrest of DNA-damaged and infected cells. Immunosuppression from UV radiation, HIV and vitamin A deficiency impairs tumour immune surveillance allowing survival of aberrant cells. Tumour growth and metastases are enhanced by; telomerase reactivation which increases the number of cell divisions a cell can undergo; vascular endothelial growth factor for angiogenesis and matrix metalloproteinases (MMPs) that destroy the intercellular matrix between cells. Despite these potential triggers, the disease is usually unilateral. It is unclear how HPV reaches the conjunctiva. (C) 2014 The Authors. Published by Elsevier Ltd.
    Experimental Eye Research 10/2014; 129. DOI:10.1016/j.exer.2014.10.015 · 2.71 Impact Factor
  • Source
    • "Nevertheless, most of those results came from case-control studies that make it difficult to establish definitive causal relationships. To solve this problem, different prospective studies have been carried out showing statistically significant inverse relationships between telomere length and both cancer incidence and mortality, as the Bruneck Study in Italy [14] and others summarized in the recent review from Prescot et al. [26]. Nevertheless, those cancers more influenced by smoking and inflammatory processes show closer associations than, e.g., breast cancer, indicating a complex background. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Telomere length is considered to be a risk factor in adults due to its proved association with cancer incidence and mortality. Since newborn present a wide interindividual variation in mean telomere length, it is relevant to demonstrate if these differences in length can act also as an early risk indicator. To answer this question, we have measured the mean telomere length of 74 samples of cord blood from newborns and studied its association with the basal genetic damage, measured as the frequency of binucleated cells carrying micronuclei. In addition, we have challenged the cells of a subgroup of individuals (N = 35) against mitomycin-C (MMC) to establish their sensitivity to induced genomic instability. Results indicate that newborn with shorter telomeres present significantly higher levels of genetic damage when compared to those with longer telomeres. In addition, the cellular response to MMC was also significantly higher among those samples from subjects with shorter telomeres. Independently of the causal mechanisms involved, our results show for the first time that telomere length at delivery influence both the basal and induced genetic damage of the individual. Individuals born with shorter telomeres may be at increased risk, especially for those biological processes triggered by genomic instability as is the case of cancer and other age-related diseases.
    PLoS ONE 03/2014; 9(3):e91753. DOI:10.1371/journal.pone.0091753 · 3.23 Impact Factor
  • Source
    • "Epidemiologic data using peripheral blood mononuclear cells and buccal mucosa cells also strongly indicate that telomere shortening is associated with aging in humans, mainly by studying agingrelated traits as cancer (Prescott et al., 2012) and inherited bone marrow failure syndromes (Gadalla et al., 2010) (among several other traits that have been studied in this regard). Nowadays it is clearly understood that telomere dysfunction, caused by telomere shortening during aging, is one of the main mechanisms underlying physiological cell senescence. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dyskeratosis congenita (DC) encompasses a large spectrum of diseases and clinical manifestations generally related to premature aging, including bone marrow failure and cancer predisposition. The major risk factor for DC is to carry germline telomere-related mutations-in telomerase or telomere shelterin genes-which results in premature telomere dysfunction, thus increasing the risk of premature aging impairments. Despite the advances that have been accomplished in DC research, the molecular aspects underlying the phenotypic variability of the disease remain poorly understood. Here different aspects of telomere biology, concerning adult stem cells senescence, tumor suppression and cancer are considered in the context of DC, resulting in two translational models: late onset of DC symptoms in telomere-related mutations carriers is a potential indicator of increased cancer risk and differences in tumor suppression capacities among the genetic subgroups are (at least partial) causes of different clinical manifestations of the disease. The limitations of both models are presented, and further experiments for their validation, as well as clinical implications, are discussed.
    Ageing research reviews 03/2013; 12(2). DOI:10.1016/j.arr.2013.03.003 · 4.94 Impact Factor
Show more