EDITORIAL

Walking the Telomere Plank Into Cancer

Kwok-Kin Wong, Ronald A. DePinho

Affiliations of authors: K.-K. Wong, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; R. A. DePinho, Department of Medical Oncology, Dana Farber Cancer Institute and Departments of Medicine and Genetics, Harvard Medical School, Boston.

Correspondence to: Ronald A. DePinho, MD, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney St., M413, Boston, MA 02115 (e-mail: ron_depinho{at}dfci.harvard.edu).

Our knowledge of the basic biology of telomeres is now beginning to yield fundamental insights into the pathophysiology of complex human diseases including cancer. Telomeres cap chromosome ends and thereby prevent the ends from being recognized as free DNA double-stranded breaks, which activate p53-dependent DNA damage response systems and could produce illegitimate chromosomal fusions. Studies in model organisms, including the mouse, have demonstrated that loss of telomeric sequences results in increased chromosomal instability, activation of telomere checkpoint responses (e.g., cellular growth arrest and apoptosis), multisystem degeneration, and premature aging (14). The tumor suppressor p53 plays a key role in sensing and mediating the telomere checkpoint response. Analyses of the telomerase-deficient mouse system have established that p53 inactivation enhances the survival of cells with short, dysfunctional telomeres but generates wholesale genomic changes that drive the neoplastic process (57). These observations in the mouse are complemented by analyses of staged human colon and pancreatic cancers, showing an association between the onset of telomere dysfunction and chromosomal instability during early carcinogenesis, consistent with a role for telomere dysfunction in cancer initiation (812).

Given the pivotal impact of telomeres in degenerative and neoplastic diseases, recent studies have assessed whether telomere length was associated with the risk of developing these diseases and/or might serve as a prognostic marker for established disease. To date, telomere length determinations in the study of cancer have been performed directly on the neoplastic tissue, focusing on its value as a predictor of benign-to-malignant progression, as a diagnostic marker for cancer, and as a marker for prognosis (1315). Several studies of non-neoplastic medical conditions have begun to explore the utility of determining telomere length in accessible peripheral blood lymphocytes (PBLs) rather than the diseased tissue. Such studies (1620) have shown that PBL telomere lengths are associated with the risk of developing atherosclerosis, premature myocardial infarctions, and coronary artery disease; with Alzheimer’s disease status; and with overall mortality. In this issue of the Journal, Wu et al. (20a) provide evidence that the presence of short telomeres in PBLs is associated with an increased risk for the development of carcinomas of the head and neck, kidney, bladder, and lung. Analysis of telomere lengths in PBLs from 313 patients diagnosed with these carcinomas and an equal number of matched cancer-free control subjects revealed statistically significantly shorter telomeres in cancer patients than in control subjects. Shorter telomeres were strongly associated with an increased risk for all four cancers (odds ratio = 4.51), independent of other well-recognized cancer risk factors. This study also demonstrated that telomere lengths were inversely associated with baseline and mutagen-induced genomic instability as measured in vitro by comet assays in PBLs from the case patients and control subjects. Finally, stratified analysis pointed to a greater-than-additive association for these cancers between a particular mutagen, tobacco smoke, and shortened telomeres, although the molecular nature of this interaction cannot be determined from this analysis.

This provocative study raises a number of intriguing possibilities that relate to how telomeres influence tumorigenesis in the aged. First, the relatively shorter telomeres in PBLs of cancer patients may indicate that telomeres inherited by cancer patients were shorter than those inherited by control subjects. If we assume that rates of telomere shortening per cell division are similar in different organ systems, then the PBL telomere reserves at a given age could provide an approximation of telomere status in other renewing tissues including epithelium. This possibility seems unlikely, however, in light of the vastly different rates of cell renewal in various tissues, distinct exposure histories to stress factors that could affect rates of telomere attrition, and subtle differences in telomerase activity between hematopoietic and epithelial lineages. Second, genetic differences in telomere degradation kinetics or cell turnover rates in renewing organs could be associated with the risk of cancer, i.e., individuals with sustained accelerated rates of telomere shortening would be at greater risk for cancer than those with normal rates. Another not mutually exclusive possibility is that environmental stress (e.g., smoking) may drive an equivalent level of telomere shortening and/or accelerated renewal in both hematopoietic and epithelial compartments. The greater predisposition toward epithelial, as opposed to hematopoietic, cancers could be rationalized on the basis of a more robust telomere checkpoint response in hematopoietic lineages than in epithelial lineages. Other possibilities are that decreased telomere length in PBLs from cancer patients reflects an increased rate of immunocyte proliferation as a result of associated inflammatory processes that promote carcinogenesis or that it reflects the immune response to the cancer itself (2125). Finally, an intriguing mechanism driving increased cancer incidence may be diminished immune surveillance of nascent cancers as a consequence of immunocyte senescence elicited by short telomeres (2628). Unfortunately, causality between short telomeres and cancer cannot be established by using the case–control format alone. These provocative data, however, now warrant a large prospective epidemiologic study designed to determine whether telomere length, measured in early life or at a minimum before the onset of cancer, was associated with the risk of developing cancer.

Data from Wu et al. also lend support to the hypothesis that environmental stressors may operate through the telomere to increase disease susceptibility. Specifically, PBLs derived from cancer patients sustained increased baseline DNA damage and displayed higher sensitivity to ionizing radiation and other DNA-damaging agents. This finding is consistent with observations that cells possessing short dysfunctional telomeres show impaired DNA damage repair and increased genomic instability (2931). If we extrapolate these findings to epithelial cells, it is possible that shorter telomeres would place these cells at greater risk for genomic instability after exposure to various intrinsic and extrinsic DNA damaging factors. It should be noted, however, that Wu et al. did not detect an association between telomere length in PBLs and smoking status in either case patients or control subjects and yet report a greater-than-additive association for the development of cancer between shorter PBL telomeres and tobacco smoking. Thus, there seems to be a very complex interplay between these two factors that has yet to be fully elucidated. One possibility is that tobacco smoke, which contains more than 5000 compounds, might stimulate telomere shortening in epithelial cells but not in hematopoietic cells. Further research to elucidate the precise mechanisms by which tobacco smoke promotes tumorigenesis and influences telomere kinetics is needed to understand this interaction.

We believe that telomere length will prove a valuable biomarker for a variety of diseases affecting different organ systems. One area of clinical promise is the clinical management of various hematopoietic proliferative disorders with a propensity toward malignant transformation (e.g., monoclonal gammopathy of unknown significance and myleodysplasia). A large body of basic science knowledge indicates that serial telomere length measurements during the course of such premalignant conditions may provide useful information to more accurately stratify these high-risk patients (3239). For patients with solid tumors, further proof of the utility of using PBLs as a reliable surrogate tissue to determine telomere lengths in the epithelial lineages is needed before its clinical application as a screening tool. This issue, however, may be rendered moot by breathtaking advances in nanotechnology and molecular imaging that may make possible the determination of telomere length in vivo in a single cell. In the years ahead, we can anticipate that basic scientific discoveries, such as those in the telomere field, will continue to yield mechanistic insights into the pathogenesis of a broad spectrum of human diseases and transform the clinical management of these diseases. Given that advancing age is the most potent of all ‘carcinogens’ and the aged population is rapidly expanding, continued translational efforts are needed to enhance the health management of age-associated disorders, particularly cancer.

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