Telomeres and lung cancer incidence and survival

端粒与肺癌的发病率和生存率

• 批准号: 8538889
• 负责人: Jennifer A. Doherty
• 金额: $ 52.89万
• 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/8538889
• 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

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）：肺癌是全球癌症发病率和死亡的主要原因。一旦被诊断为肺癌，只有15%的人能活过5年。据估计，85% - 90%的肺癌病例是由吸烟引起的，但只有不到20%的吸烟者患肺癌，这表明其他因素可能起着诱发作用。最近，一些大规模的全基因组关联研究报道了端粒酶逆转录酶（TERT）基因的snp与肺癌风险密切相关。TERT是端粒维持基因，常是肺肿瘤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。随着细胞的每一次分裂，它们逐渐缩短，当长度达到临界短时，细胞就会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。三个病例对照研究发现，较短的端粒长度与肺癌风险相关，而较长的端粒长度（在肺癌诊断前测量）与肺癌风险增加有关。鉴于这四项研究的差异但具有启发性的发现，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的增加有关，尽管这在以前还没有被研究过。此外，到目前为止，还没有研究检测淋巴细胞端粒长度与肺癌生存率之间的关系。在胡萝卜素和视黄醇疗效试验中的巢式病例对照研究（n=790例，1558例对照）中，一组前瞻性采集血样的重度吸烟者，我们建议检查：肺癌诊断前采集样本中测量的整体和染色体臂特异性端粒长度是否与肺癌风险相关；TERT和其他端粒维持相关基因中大约400个标签和假定的功能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有关。一项针对吸烟者的大型前瞻性研究将提供证据，有助于澄清端粒长度是否与肺癌风险和/或生存有关。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，那么这种测量方法可能被用于识别高危吸烟者中肺癌风险特别高的个体亚群。