Telomere length, telomere maintenance genes and cancer risk

描述(申请人提供)：外周血淋巴细胞端粒缩短已被发现与患头颈癌的风险增加6倍有关，当与吸烟史结合时，优势比增加到25。然而，尽管有很有希望的发现表明酿酒酵母的端粒长度变异与端粒维持基因的多态之间存在联系，但这些关系在人类中的性质还没有得到研究。在一般癌症中，尤其是在结直肠癌患者中，这一点也没有得到严格的研究。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。我们建议进行一项实证研究，以检验端粒维持基因、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表现为微卫星稳定(MSS)肿瘤的年轻结直肠癌患者(d 50岁)。这种关注很重要，因为首先，使年轻人成为我们研究的中心将增强我们检测端粒长度变化的能力，这些变化与结直肠癌本身有关，而不是与端粒长度缩短相关的其他与年龄相关的共病(例如高血压、心血管疾病)。其次，大多数结直肠癌的肿瘤实际上是微卫星稳定的(MSS)。第三，MSS CRC展示了大多数端粒维持基因遵循的端粒酶依赖途径。我们的具体目标是确定：(1)结构性端粒长度是否与年轻发病的CRC的风险有关；(2)端粒维持基因的多态是否与人类的结构性端粒长度变异有关；(3)端粒维持基因的多态是否与癌症风险增加有关。我们的方法的基本假设是端粒缩短有助于MSS CRC的发展，端粒稳态基因的多态将有助于端粒长度的变异，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识别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，并阐明与结直肠癌和其他癌症发展相关的潜在遗传事件。与公共卫生相关：虽然结直肠癌通常在65岁时发病，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，随着年龄的增长端粒缩短，端粒缩短与包括癌症在内的许多衰老疾病有关。我们将研究血液样本DNA中端粒缩短的作用和端粒维持基因的遗传缺陷，以确定这些年轻人是否因为端粒缩短所表现的加速衰老而患上结直肠癌。

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.