Telomere length, telomere maintenance genes and cancer risk

描述（由申请人提供）：已发现外周血淋巴细胞中的端粒缩短与头颈癌风险增加6倍相关，并且当与烟草使用史相结合时，比值比增加至25。然而，尽管有希望的发现，表明端粒长度变化之间的关系在酿酒酵母和端粒维持基因的多态性，这些关系在人类的性质还没有被研究。这也没有在一般癌症中，特别是在CRC患者中进行严格的研究。我们试图了解端粒维持基因、端粒长度和癌症风险之间的关系。我们提出了一个实证研究，以检查端粒维持基因，端粒长度和癌症风险之间的因果关系。我们的研究将集中在年轻人（d 50岁）与CRC显示微卫星稳定（MSS）肿瘤。这样的关注是重要的，因为首先，使年轻个体成为我们研究的中心将提高我们检测与CRC本身相关而不是与其他年龄相关的合并症（例如，高血压、心血管疾病）与端粒长度缩短相关。第二，大多数CRC病例中的肿瘤实际上是微卫星稳定的（MSS）。第三，MSS CRC表现出大多数端粒维持基因遵循的端粒酶依赖性途径。我们的具体目标是确定：（1）体质端粒长度与年轻发病的CRC的风险相关;（2）端粒维持基因的多态性与人类体质端粒长度变异相关;（3）端粒维持基因多态性与癌症风险增加相关。我们的方法的基本假设是端粒缩短有助于MSS CRC的发展，并且端粒稳态基因的多态性将有助于端粒长度变异，并最终导致CRC的发展。如果是真的，我们的研究结果可能有助于确定与端粒维持相关的遗传途径，这反过来可能为我们提供潜在的化学预防和治疗策略，并阐明与CRC和其他癌症发展相关的潜在遗传事件。公共卫生相关性：虽然结直肠癌通常在65岁时发生，但今年美国将有近20，000名50岁的年轻人被诊断出患有结直肠癌。端粒是染色体上的帽子，随着年龄的增长而缩短，端粒缩短与包括癌症在内的许多衰老疾病有关。我们将研究端粒缩短在血液样本DNA中的作用和端粒维持基因中的遗传缺陷，以确定这些年轻人是否因为端粒缩短所表现的加速老化而发展为CRC。

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.