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：
8721859
负责人：
Jennifer A. Doherty
金额：
$ 48万
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 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8721859
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 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 screening 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.

描述（由申请人提供）：肺癌是全世界癌症发病和死亡的主要原因。一旦诊断出患有肺癌，只有 15% 的人存活时间超过五年。据估计，85-90% 的肺癌病例是由吸烟引起的，但只有不到 20% 的吸烟者患上肺癌，这表明其他因素也可能起到诱发作用。最近，几项大规模全基因组关联研究报告称，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位点。端粒位于染色体末端，保护细胞的遗传完整性。它们随着每次细胞分裂而逐渐缩短，当它们达到极短的长度后，细胞将发生凋亡或细胞衰老。另外，极短的端粒会导致染色体不稳定和融合，从而导致有利于致癌的遗传变化的积累。虽然三项病例对照研究观察到较短的端粒长度与肺癌风险相关，但在一项巢式病例对照研究中，较长的端粒长度（在肺癌诊断前测量）与肺癌风险增加相关。鉴于这四项研究的结果存在差异但具有启发性，因此需要进行更多研究来阐明端粒长度在肺癌发展中的作用。特定染色体的缩短可能与肺癌风险增加有关，尽管之前尚未对此进行过研究。此外，迄今为止还没有研究检查淋巴细胞端粒长度和肺癌存活率。在胡萝卜素和视黄醇功效试验中的一项巢式病例对照研究（n = 790 例，1,558 名对照）中，前瞻性地收集了一组重度吸烟者的血液样本，我们建议检查：是否是全局的和染色体臂特异性的，在肺癌诊断前收集的样本中测量的端粒长度与肺癌风险相关； TERT 和其他端粒维持相关基因中大约 400 个标签和推定功能 SNP 是否与肺癌风险相关；以及端粒长度和端粒维持基因的变异是否与肺癌患者的生存相关。一项针对吸烟者的大型前瞻性研究（例如所提议的研究）将提供证据，有助于澄清端粒长度是否与肺癌风险和/或生存相关。如果整体端粒长度或染色体特异性端粒长度与肺癌风险相关，则可以开发这种测量方法来识别吸烟者高危人群中肺癌风险特别高的个体子集。