Telomere length, telomere maintenance genes and cancer risk

端粒长度、端粒维持基因和癌症风险

• 批准号: 7893838
• 负责人: LISA Allyn BOARDMAN
• 金额: $ 57.41万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-18 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7893838
• 关键词: Age; Age-Years; Aging; Alcohols; Apoptosis; Blood specimen; Body mass index; Cancer Patient; Cardiovascular Diseases; Cell Aging; Cell division; Cells; Chromosomal Stability; Chromosomes; Clinical; Colorectal Cancer; Comorbidity; Constitutional; Control Groups; DNA; Data; Development; Diagnosis; Disease; Event; Exhibits; Folate; Frequencies; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Geographic Locations; Head and Neck Cancer; Homeostasis; Hormones; Human; Hypertension; Individual; Length; Life Style; Lymphocyte; Malignant Neoplasms; Measures; Meat; Microsatellite Repeats; Mismatch Repair; Mutation; Nature; Non-Insulin-Dependent Diabetes Mellitus; Non-Steroidal Anti-Inflammatory Agents; Odds Ratio; Pathway interactions; Peripheral; Peripheral Blood Lymphocyte; Preventive; Radiation therapy; Recording of previous events; Risk; Role; Saccharomyces cerevisiae; Smoking; Somatic Cell; Telomerase; Telomere Capping; Telomere Length Maintenance; Telomere Maintenance; Telomere Maintenance Gene; Telomere Shortening; Testing; Therapeutic; Tobacco use; United States; Variant; Yeasts; age related; aged; calcium intake; cancer risk; case control; colon cancer family registry; design; fruits and vegetables; gene repair; human old age (65+); insight; public health relevance; repaired; sex; telomere; tumor; young adult

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.

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六倍相关，并且与吸烟史相结合时，优势比增加至 25。然而，尽管这一令人鼓舞的发现显示了酿酒酵母端粒长度变异与端粒维持基因多态性之间的关系，但人类中这些关系的性质尚未得到研究。对于一般癌症，特别是结直肠癌患者，也没有对此进行严格研究。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。我们提出一项实证研究来检验端粒维持基因、端粒长度和癌症风险之间的因果关系。我们的研究将重点关注患有结直肠癌且显示微卫星稳定 (MSS) 肿瘤的年轻个体（年龄 50 岁）。这样的关注很重要，因为首先，将年轻人作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相关，而不是与其他与年龄相关的并发症（例如高血压、心血管疾病）相关。与端粒长度缩短有关。其次，大多数结直肠癌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) 体质端粒长度是否与年轻发病的 CRC 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，端粒稳态基因的多态性将有助于端粒长度变异，并最终促进 CRC 的发展。如果属实，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，这反过来又可能使我们深入了解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。公共卫生相关性：虽然结直肠癌通常在 65 岁左右发病，但今年美国将有近 20,000 名 50 岁以下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。我们将研究血液样本 DNA 中端粒缩短的作用以及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。