Short Communication Telomere Length in the Colon Declines with Age: a Relation to Colorectal Cancer? Jacintha O’Sullivan, 1 Rosa Ana Risques, 1 Margaret T. Mandelson, 3,4 Lu Chen, 3 Teresa A. Brentnall, 2 Mary P. Bronner, 6 Melissa P. MacMillan, 1 Ziding Feng, 3 Joseph R. Siebert, 1,5 John D. Potter, 3 and Peter S. Rabinovitch 1,3 Departments of 1 Pathology and 2 Medicine, University of Washington; 3 Fred Hutchinson Cancer Research Center; 4 Center for Health Studies, Group Health Cooperative; 5 Children’s Hospital and Regional Medical Center, Seattle, Washington; and 6 Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, Ohio Abstract Telomeres shorten with age, which may be linked to genomic instability and an increased risk of cancer. To explore this association, we analyzed telomere length in normal colorectal tissue of individuals at different ages using quantitative-fluorescence in situ hybridization (Q- FISH) and quantitative-PCR (Q-PCR). Using Q-FISH, we also examined the histologically normal epithelium adjacent to, or distant from, colon adenomas and cancers, in addition to the neoplasms. Q-FISH and Q-PCR showed that telomere length was inversely associated with age until fages 60 to 70; surprisingly, beyond this age, telomere length was positively associated with age. This association was found exclusively in epithelial, and not in stromal, cells. Peripheral blood lymphocytes showed an inverse association between telomere length and age, but without any apparent increase in telomere length in the oldest individuals. Telomere length in larger adenoma lesions (>2 cm) was significantly shorter than in normal adjacent (P = 0.004) or normal distant (P = 0.05) tissue from the same individuals. However, telomere length in histologically normal epithelium adjacent to cancers or in adenomas <2 cm was not statistically different from that of the normal distant mucosa or from normal controls, evidence that a telomere-shortening field effect was not present. We suggest that the positive association between telomere length and age in the oldest patients is a consequence of selective survival of elderly patients with long colonocyte telomeres. (Cancer Epidemiol Biomarkers Prev 2006;15(3):573 – 7) Introduction Telomeres are repetitive DNA sequences (TTAGGG) found at the end of each chromosome. They provide stability and protect chromosomes from end-to-end fusions, degradation, and recombination (1). Telomere attrition can expose chromosome ends, activating cell cycle checkpoints and cellular senescence (2), and promoting cycles of bridge- breakage-fusion (3). The enzyme telomerase allows the synthesis of new telomeric DNA, thus maintaining prolifer- ative capacity (4). An age-related decline in telomere length may promote genetic instability and increase the risk of malignancy. Peripheral blood telomere lengths measured in individuals in their 7th decade of life is predictive of survival (5), although the strongest correlate of telomere length was mortality from cardiac and infectious disease. We have previously shown that telomere dysfunction is an early event in neoplastic progres- sion in ulcerative colitis (6), and is related to chromosomal instability and anaphase bridge formation. This may facilitate the molecular evolution of tumorigenesis in cells by acceler- ating chromosomal instability (6). We analyzed telomere length in normal colonic mucosa in individuals ages 0 to 93 years using two techniques: quantitative-fluorescence in situ hybridization (Q-FISH), which measures telomere length separately in epithelial and stromal cells in tissue sections, and quantitative-PCR (Q-PCR), which accurately measures telomere length using small amounts of DNA. We also examined telomere length in normal mucosa adjacent to adenomas and colorectal carcinomas in order to investigate whether a telomere-erosion field effect was evident in sporadic colorectal tumorigenesis, similar to that previously shown in ulcerative colitis (6). Materials and Methods Patients and Samples. Three sets of specimens were obtained. The first consisted of normal colorectal mucosa (the majority of which were rectal) from 136 subjects ranging from 0 to 93 years (55 males and 81 females) and with no history of colorectal malignancy. Diagnoses included trauma, appendi- citis, diverticular disease, solitary rectal ulcer syndrome, mucosal prolapse, rectal prolapse, focal active colitis, and lymphoid tissue. Normal colonic mucosal specimens from neonates were obtained at autopsy. All analyses in this group were done on formalin-fixed tissue using Q-FISH. The second set included peripheral blood lymphocytes (PBL) and frozen normal colon biopsies from 47 patients with nonneoplastic histology, as above; 22 of these cases were from the same patients as set 1. Patients ranged from 34 to 79 years old (11 males and 36 females). Information on smoking, use of aspirin and other nonsteroidal antiinflammatory medications (NSAID), and prior gastrointestinal disease was available for 57 of 136 cases in the first set, and in 42 of 47 cases in the 573 Cancer Epidemiol Biomarkers Prev 2006;15(3). March 2006 Received 7/22/05; revised 1/11/06; accepted 1/11/06. Grant support: NIH grants P30 AG13280 (P.S. Rabinovitch), P20 CA103728 (P.S. Rabinovitch), PO1 CA74184 (J.D. Potter), and RO1 CA68124-10 (T.A. Brentnall). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: J. O’Sullivan and R.A. Risques contributed equally to this work. J. O’Sullivan is currently at the Center for Colorectal Disease, Education, and Research Center, St. Vincent’s University Hospital, Dublin 4, Ireland. Requests for reprints: Peter S. Rabinovitch, Department of Pathology, University of Washington, Seattle, WA. E-mail: petersr@u.washington.edu Copyright D 2006 American Association for Cancer Research. doi:10.1158/1055-9965.EPI-05-0542 Research. on October 23, 2016. © 2006 American Association for Cancer cebp.aacrjournals.org Downloaded from