DESCRIPTION (provided by applicant): Telomere shortening in peripheral blood lymphocytes has been found to be associated with a six fold increased risk for head and neck cancer and increases to an odds ratio of 25 when combined with a history of tobacco use. Yet, despite the promising finding that shows a relationship between telomere length variation in Saccharomyces cerevisiae and polymorphisms in telomere maintenance genes, the nature of these relationships in humans has not been studied. Nor has this been rigorously studied in cancer in general and in CRC patients in particular. We seek to understand the relationship between telomere maintenance genes, telomere length, and cancer risk. We propose an empirical study to examine the causal relationship between telomere maintenance genes, telomere length, and cancer risk. Our study will focus on young individuals (d 50 years old) with CRC that show microsatellite stable (MSS) tumor. Such a focus is important because, first, making young individuals the center of our study will enhance our ability to detect telomere length changes that are related to CRC itself rather than to other age-related co-morbidities (e.g., hypertension, cardiovascular disease) associated with telomere length shortening. Second, the tumors in the majority of CRC cases are in fact microsatellite stable (MSS). Third, MSS CRC exhibits the telomerase dependent pathway that the majority of telomere maintenance genes follow. Our specific objectives are to determine whether: (1) constitutional telomere length is associated with the risk of young onset CRC; (2) polymorphisms in telomere maintenance genes are associated with constitutional telomere length variation in humans and (3) telomere maintenance gene polymorphism are associated with an increased risk for cancer. The underlying hypotheses of our approach is that telomere shortening contributes to the development of MSS CRC and that polymorphisms in telomere homeostasis genes will contribute to telomere length variability, and ultimately to the development of CRC. If true, the results from our study may help identify genetic pathways related to telomere maintenance which in turn may provide us with insight into potential chemo-preventive and therapeutic strategies as well as elucidate the underlying genetic events related to the development of CRC and other cancers. PUBLIC HEALTH RELEVANCE: Though colorectal cancer usually develops at e 65 years old, nearly 20,000 young adults d 50 years of age will be diagnosed with colorectal cancer in the United States this year. Telomeres are the caps on the chromosomes that shorten as we age, and telomere shortening has been associated with many diseases of aging including cancer. We will study the role of telomere shortening in DNA from blood samples and genetic defects in telomere maintenance genes to determine if these young adults develop CRC because of accelerated aging that is manifested by telomere shortening.
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