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Carcinogenesis Advance Access published online on May 19, 2005
Carcinogenesis, doi:10.1093/carcin/bgi126
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received December 20, 2004
Revised May 3, 2005
Accepted May 10, 2005

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Roles of tumor suppressor and telomere maintenance genes in cancer and aging - an epidemiological study

Jian Gu 1, Margaret R. Spitz 1, Hua Zhao 1, Jie Lin 1, H. Barton Grossman 2, Colin P. Dinney 2, and Xifeng Wu 1*

1 Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
2 Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas

* To whom correspondence should be addressed.
Xifeng Wu, E-mail: xwu{at}mdanderson.org


  Abstract

Advanced age is strikingly linked to increased incidence of cancer. To gain insight into the mechanism underlying the association between increased cancer incidence and aging in normal human physiological conditions, we used a case-control design and measured the mRNA expression levels of p53, ATM, hTERT, and TRF2, four major protectors of genomic integrity, in isolated peripheral blood lymphocytes from 202 confirmed bladder cancer (BC) patients and 199 healthy controls. Significant age effects on expression levels were observed. When we divided the study subjects into three age groups (<57, 57 to 65, and ≥65), the expressions of p53, ATM, and TRF2 significantly decreased with advancing age in cases (P for trend ≤0.001, 0.01 and 0.01 for p53, ATM, and TRF2, respectively). In controls, however, p53 expression significantly increased with advancing age (P for trend = 0.05). Among subjects ≥65 years old, the expressions of p53, ATM, and TRF2 was significantly lower in cases than in controls (P = 0.003, 0.04, and 0.05 for p53, ATM, and TRF2, respectively), suggesting that attenuated genomic maintenance mechanisms lead to increased cancer risk in older individuals. When we dichotomized our study population at the median age of study subjects (61 years old), low p53 expression was associated with a significantly increased BC risk in older people (OR = 2.27, 95% CI = 1.00 - 5.16). In addition, older subjects without detectable hTERT expression had a significantly reduced BC risk (OR = 0.41, 95% = 0.17 - 0.99). Our study provides the first epidemiologic evidence that the increased genomic instability resulting from the combination of telomere dysfunction, impaired ATM- and p53-mediated DNA damage, and/or telomere dysfunction response pathway contributes to increased cancer incidence in the elderly population.

Keywords: cancer; aging; p53; ATM; mRNA expression; telomere dysfunction.
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