Telomeres and lung cancer incidence and survival

端粒与肺癌的发病率和生存率

基本信息

批准号：
8107313
负责人：
Jennifer A. Doherty
金额：
$ 72.53万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-08 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8107313
关键词：
Age All-Trans-Retinol American Cancer Society Apoptosis Beta Carotene Bladder Blood Blood specimen Breast Cancer Etiology Carotene Case-Control Studies Cell Aging Cell division Cells Cessation of life Chromosomal Instability Chromosome Arm Chromosome abnormality Chromosomes DNA Repair Gene Data Development Diagnosis Esophageal Esophagus Genes Genetic Genome Hamman-Rich syndrome Head and neck structure Histologic Histology Incidence Individual Length Lung Neoplasms Lymphocyte Malignant Neoplasms Malignant neoplasm of lung Measurement Measures Mutation Nested Case-Control Study Peripheral Blood Lymphocyte Play Population Prospective Studies Recording of previous events Reporting Research Personnel Risk Risk Factors Role Sampling Screening procedure Sentinel Site Smoker Smoking Smoking History Stomach TEP1 gene TERF1 gene TERF2 gene TINF2 gene TNKS gene Telomere Maintenance Telomere Maintenance Gene Telomere Shortening Therapeutic Tobacco United States Update Variant Woman alpha Tocopherol cancer diagnosis cancer prevention cancer risk carcinogenesis chromatin protein cigarette smoking cohort cost efficacy trial genome wide association study high risk men protein complex senescence smoking cessation telomerase reverse transcriptase telomere tumor

项目摘要

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer incidence and death worldwide. Once diagnosed with lung cancer, only 15% of individuals survive longer than five years. Tobacco-smoking is estimated to be responsible for 85- 90% of lung cancer cases, but fewer than 20% of smokers develop lung cancer, suggesting that other factors may play a predisposing role. Recently, several large-scale genome-wide association studies have reported that SNPs in the telomerase reverse transcriptase (TERT) gene are strongly associated with lung cancer risk. TERT is a telomere maintenance gene, and is often a site of chromosomal abnormalities in lung tumors. Telomeres, located at the ends of chromosomes, protect the genetic integrity of cells. They progressively shorten with every cell division, and after they reach a critically short length, the cell will undergo apoptosis or cellular senescence. Alternatively, critically short telomeres can cause chromosomal instability and fusions, allowing the accumulation of genetic changes in favor of carcinogenesis. While three case-control studies have observed that shorter telomere length was associated with lung cancer risk, longer telomere length (measured prior to lung cancer diagnosis) was associated with increased lung cancer risk in a nested case- control study. Given the discrepant but suggestive findings from these four studies, additional studies are needed to elucidate the role of telomere length in lung cancer development. It is possible that shortening of specific chromosomes is associated with an increased risk of lung cancer, though this has not been studied previously. Also, no studies to date have examined lymphocyte telomere length and lung cancer survival. In a nested case-control study (n=790 cases, 1,558 controls) within the Carotene and Retinol Efficacy Trial, a cohort of heavy smokers with blood samples collected prospectively, we propose to examine: whether global, and chromosome-arm-specific, telomere length measured in samples collected prior to lung cancer diagnosis are associated with lung cancer risk; whether approximately 400 tag and putative functional SNPs in TERT and other telomere maintenance-related genes are associated with lung cancer risk; and whether telomere length and variation in telomere maintenance genes are associated with survival among individuals who develop lung cancer. A large, prospective study among smokers such as the one proposed will provide evidence that will aid in clarifying whether telomere length is associated with lung cancer risk and/or survival. If either global or chromosome-specific telomere length is associated with lung cancer risk, this measurement could possibly be developed to identify a subset of individuals at particularly high risk of lung cancer, among the high-risk population of smokers. PUBLIC HEALTH RELEVANCE: Telomeres are chromatin-protein complexes that cap chromosome ends and protect chromosomes from degradation and fusion with one another. As telomeres shorten, their ability to protect the chromosome diminishes. In this study, we will examine whether short telomere length, and variation in genes regulating telomere length, are associated with lung cancer risk and survival.

描述（由申请人提供）：肺癌是全球癌症发病率和死亡的主要原因。一旦被诊断出患有肺癌，只有15％的个体生存超过五年。据估计，烟草烟是造成85-90％的肺癌病例的原因，但不到20％的吸烟者发展了肺癌，这表明其他因素可能起易感性的作用。最近，一些大规模基因组关联研究报告说，端粒酶逆转录酶（TERT）基因中的SNP与肺癌风险密切相关。 TERT是一种端粒维持基因，通常是肺部肿瘤中染色体异常的部位。位于染色体末端的端粒保护细胞的遗传完整性。它们随着每个细胞分裂而逐渐缩短，并且在达到严重的长度后，细胞会经历凋亡或细胞衰老。另外，临界短端粒会导致染色体不稳定性和融合，从而使遗传变化积累，有利于致癌作用。虽然三项病例对照研究观察到端粒长度较短与肺癌风险有关，但在嵌套的病例对照研究中，端粒长度较长（在肺癌诊断之前测量）与肺癌风险增加有关。鉴于这四项研究的差异但暗示性的发现，需要进一步的研究来阐明端粒长度在肺癌发育中的作用。特异性染色体的缩短可能与肺癌的风险增加有关，尽管以前尚未对此进行研究。此外，迄今为止，尚无研究检查淋巴细胞端粒长度和肺癌存活。在胡萝卜素和视黄醇功效试验中的一项嵌套病例对照研究（n = 790例，1,558例对照）中，一群带有血样的大吸烟者的同类群体前景收集，我们建议检查：全球和染色体特异性的，特异性的，特异性的，特异性的，端粒的长度，在与Lung癌症诊断相关的样本中，与Lung Cancer诊断相关，是Lung Cancer Cancer的风险相关的。在TERT和其他与端粒维持相关基因中大约有400个TAG和推定的功能SNP都与肺癌风险有关；端粒维持基因的端粒长度和变化是否与发展为肺癌的个体的生存有关。在诸如拟议的烟民之类的吸烟者中进行的一项大型前瞻性研究将提供证据，有助于阐明端粒长度是否与肺癌风险和/或生存有关。如果全球或染色体特异性的端粒长度与肺癌风险有关，则可以开发这种测量以识别高风险吸烟者人群中的一部分处于特别高的肺癌风险的个体。公共卫生相关性：端粒是染色质 - 蛋白质络合物，它们的染色体结束并保护染色体免受降解和融合彼此的融合。随着端粒的缩短，它们保护染色体减小的能力。在这项研究中，我们将检查短端粒长度和调节端粒长度的基因的变化是否与肺癌风险和生存有关。