Telomere Loss as a Mechanism for Chromosome Instability in Human Cancer

Department of Radiation Oncology, University of California San Francisco, San Francisco, CA 94143-1331, USA.
Cancer Research (Impact Factor: 9.33). 06/2010; 70(11):4255-9. DOI: 10.1158/0008-5472.CAN-09-4357
Source: PubMed


Cancer cells commonly have a high rate of telomere loss, even when expressing telomerase, contributing to chromosome instability and tumor cell progression. This review addresses the hypothesis that this high rate of telomere loss results from a combination of four factors. The first factor is an increase in the frequency of double-strand breaks (DSB) at fragile sites in cancer cells due to replication stress. The second factor is that telomeres are fragile sites. The third factor is that subtelomeric regions are highly sensitive to DSBs, so that DSBs near telomeres have an increased probability of resulting in chromosome instability. The fourth factor is that cancer cells may be deficient in chromosome healing, the de novo addition of telomeres to the sites of DSBs, a mechanism that prevents chromosome instability resulting from DSBs near telomeres. Understanding these factors and how they influence telomere loss will provide important insights into the mechanisms of chromosome instability and the development of novel approaches for anti-cancer therapy. Cancer Res; 70(11); 4255-9. (c)2010 AACR.

Download full-text


Available from: John Murnane, Jul 21, 2014
  • Source
    • "Counter et al. [24] demonstrated that transfecting human fibroblasts with viral proteins led to the inactivation of p53 and p16 pathways. Deficiency of p53/p16 proteins leads to ''crisis'' which is characterized by a high rate of telomere loss and instability in chromosome structure [25] [26] [27] [28]. Crisis serves as another line of defense against the development of cancer because the resulting genome instability and DNA-damage signaling induce the death of the vast majority of cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Radiotherapy plays a key role in cancer treatments, but tumor cell death differs from one tumor to another. The response of patients to radiotherapy varies considerably and adverse side effects are difficult to prevent. The mechanisms involved in the heterogeneity of this response are not well understood. In order to enhance the efficacy and safety of radiotherapy, it is important to identify subpopulations most at risk of developing a late adverse response to radiotherapy. Telomeres are composed of multiple repeats of a unique sequence of nucleotides forming a TTAGGG pattern. They protect chromosomes from end-to-end fusion and maintain genomic stability. Telomeres have been shown to be extremely sensitive to radiotherapy especially because of their atypical DNA damage repair response, which includes partial inhibition of the non-homologous end joining repair pathway. Ionizing Radiation (IR)-induced damage to telomere DNA could lead to chromosome instability and the initiation or progression of tumor processes. Telomeres could thus be a reliable marker of IR exposure and as such become a new parameter for predicting radiosensitivity. Furthermore, short telomeres are more sensitive to radiotherapy, which could partially explain differences in tumor cell death and in inter-individual sensitivity to radiotherapy. Telomere length could be used to identify subpopulations of patients who could benefit from higher or lower doses per fraction. Finally, pharmacological interference with tumor-cell telomere biology to reduce telomere length and/or telomere stability could also enhance the effectiveness and safety of radiotherapy. Telomeres could play a key role in radiotherapy in the era of personalized medicine. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Feb 2015 · Cancer Treatment Reviews
  • Source
    • "Telomeres are repetitive structures at the end of chromosomes that are essential for maintaining and protecting the chromosomes from degradation and end-to-end fusion [1] [2]. Many studies suggest that the loss of telomere function leads to genomic instability [3] [4] [5] [6] [7]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Defects in telomere maintenance can result in telomere fusions that likely play a causative role in carcinogenesis by promoting genomic instability. However, this proposition remains to be fully understood in human colon carcinogenesis. In the present study, the temporal sequence of telomere dysfunction dynamics was delineated by analyzing telomere fusion, telomere length, telomerase activity, hotspot mutations in KRAS or BRAF, and TP53 of tissue samples obtained from 18 colon cancer patients. Our results revealed that both the deficiency of p53 and the shortening of mean telomere length were not necessary for producing telomere fusions in colon tissue. In five cases, telomere fusion was observed even in tissue adjacent to cancerous lesions, suggesting that genomic instability is initiated in pathologically non-cancerous lesions. The extent of mean telomere attrition increased with lymph node invasiveness of tumors, implying that mean telomere shortening correlates with colon cancer progression. Telomerase activity was relatively higher in most cancer tissues containing mutation(s) in KRAS or BRAF and/or TP53 compared to those without these hotspot mutations, suggesting that telomerase could become fully active at the late stage of colon cancer development. Interestingly, the majority of telomere fusion junctions in colon cancer appeared to be a chromatid-type containing chromosome 7q or 12q. In sum, this meticulous correlative study not only highlights the concept that telomere fusion is present in the early stages of cancer regardless of TP53/KRAS mutation status, mean telomere length, and telomerase activity, but also provides additional insights targeting key telomere fusion junctions which may have significant implications for colon cancer diagnoses.
    Preview · Article · Oct 2014 · Neoplasia (New York, N.Y.)
  • Source
    • "Although the role of the deletion of this region in tumorigenesis is not known, telomere loss in general is observed frequently in cancer cells and it is suggested to play an important role in driving the chromosome instability associated with cancer. The telomere loss on the chromosome leads to chromosome fusions between two sister chromatids during mitosis facilitating the accumulation of genetic changes [24,25]. The list of genes included in these regions is provided in the Additional file 1. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent developments in high-throughput genomic technologies make it possible to have a comprehensive view of genomic alterations in tumors on a whole genome scale. Only a small number of somatic alterations detected in tumor genomes are driver alterations which drive tumorigenesis. Most of the somatic alterations are passengers that are neutral to tumor cell selection. Although most research efforts are focused on analyzing driver alterations, the passenger alterations also provide valuable information about the history of tumor development. In this paper, we develop a method for estimating the age of the tumor lineage and the timing of the driver alterations based on the number of passenger alterations. This method also identifies mutator genes which increase genomic instability when they are altered and provides estimates of the increased rate of alterations caused by each mutator gene. We applied this method to copy number data and DNA sequencing data for ovarian and lung tumors. We identified well known mutators such as TP53, PRKDC, BRCA1/2 as well as new mutator candidates PPP2R2A and the chromosomal region 22q13.33. We found that most mutator genes alter early during tumorigenesis and were able to estimate the age of individual tumor lineage in cell generations. This is the first computational method to identify mutator genes and to take into account the increase of the alteration rate by mutator genes, providing more accurate estimates of the tumor age and the timing of driver alterations.
    Full-text · Article · Dec 2013 · BMC Bioinformatics
Show more