Telomeres and lung cancer incidence and survival

描述(申请人提供)：肺癌是全球癌症发病率和死亡率的主要原因。一旦被诊断出患有肺癌，只有15%的人能活过五年。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到诱因作用。最近，一些大规模的全基因组关联研究报道，端粒酶逆转录酶(TERT)基因中的SNPs与肺癌风险密切相关。TERT是一种端粒维持基因，在肺癌中经常是染色体异常的部位。位于染色体末端的端粒保护细胞的遗传完整性。它们随着每一次细胞分裂而逐渐缩短，当它们达到临界短长度后，细胞将经历凋亡或细胞衰老。或者，端粒过短会导致染色体不稳定和融合，从而导致有利于癌症发生的基因变化的积累。虽然三项病例对照研究已经观察到较短的端粒长度与肺癌风险相关，但在一项嵌套的病例对照研究中，较长的端粒长度(在肺癌诊断前测量)与肺癌风险增加相关。考虑到这四项研究的不同但具有启发性的发现，还需要更多的研究来阐明端粒长度在肺癌发生中的作用。特定染色体的缩短可能与肺癌风险的增加有关，尽管以前还没有研究过这一点。此外，到目前为止，还没有研究检查淋巴细胞端粒长度与肺癌生存率的关系。在胡萝卜素和视黄醇疗效试验中进行的一项嵌套病例对照研究(n=790例，1,558例对照)中，我们提议检测：在肺癌诊断前收集的样本中测量的全球和特定染色体臂的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约400个标签和推测功能的SNPs是否与肺癌风险相关；以及端粒维护基因的端粒长度和变异是否与肺癌患者的生存相关。在吸烟者中进行的一项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。如果全球或特定于染色体的端粒长度与肺癌风险相关，这种测量可能被开发出来，以在吸烟者的高危人群中识别出患肺癌风险特别高的一部分人。

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.