Telomeres and lung cancer incidence and survival

端粒与肺癌的发病率和生存率

• 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
• 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

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%的人存活时间超过五年。据估计，吸烟导致85- 90%的肺癌病例，但只有不到20%的吸烟者患上肺癌，这表明其他因素可能起着诱发作用。最近，几个大规模的全基因组关联研究报告，在端粒酶逆转录酶（TERT）基因的SNPs与肺癌的风险密切相关。端粒酶逆转录酶是一种端粒维持基因，通常是肺肿瘤中染色体异常的一个位点。端粒位于染色体的末端，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，并且在它们达到临界短长度后，细胞将经历凋亡或细胞衰老。或者，极端短的端粒可以导致染色体不稳定和融合，允许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不一致，但具有启发性，需要进一步的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，尽管以前没有研究过。此外，迄今为止还没有研究检查淋巴细胞端粒长度和肺癌生存率。在一项巢式病例对照研究中，（n=790例，1，558例对照）在胡萝卜素和视黄醇疗效试验中，一个前瞻性收集血液样本的重度吸烟者队列，我们建议检查：在肺癌诊断前收集的样本中测量的总体和染色体臂特异性端粒长度是否与肺癌风险相关;在端粒酶逆转录酶和其他端粒维持相关基因中的大约400个标签和推定的功能性单核苷酸多态性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率相关。在吸烟者中进行的一项大型前瞻性研究，如所提出的研究，将提供证据，有助于澄清端粒长度是否与肺癌风险和/或生存率相关。如果整体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高危吸烟人群中肺癌风险特别高的个体子集。 公共卫生关系：端粒是染色质-蛋白质复合物，其覆盖染色体末端并保护染色体免于降解和彼此融合。随着端粒缩短，它们保护染色体的能力减弱。在这项研究中，我们将研究短端粒长度和调节端粒长度的基因变异是否与肺癌风险和生存率相关。