Machiela Mitchell J, Hsiung Chao Agnes, Shu Xiao-Ou, Seow Wei Jie, Wang Zhaoming, Matsuo Keitaro, Hong Yun-Chul, Seow Adeline, Wu Chen, Hosgood H Dean, Chen Kexin, Wang Jiu-Cun, Wen Wanqing, Cawthon Richard, Chatterjee Nilanjan, Hu Wei, Caporaso Neil E, Park Jae Yong, Chen Chien-Jen, Kim Yeul Hong, Kim Young Tae, Landi Maria Teresa, Shen Hongbing, Lawrence Charles, Burdett Laurie, Yeager Meredith, Chang I-Shou, Mitsudomi Tetsuya, Kim Hee Nam, Chang Gee-Chen, Bassig Bryan A, Tucker Margaret, Wei Fusheng, Yin Zhihua, An She-Juan, Qian Biyun, Lee Victor Ho Fun, Lu Daru, Liu Jianjun, Jeon Hyo-Sung, Hsiao Chin-Fu, Sung Jae Sook, Kim Jin Hee, Gao Yu-Tang, Tsai Ying-Huang, Jung Yoo Jin, Guo Huan, Hu Zhibin, Hutchinson Amy, Wang Wen-Chang, Klein Robert J, Chung Charles C, Oh In-Jae, Chen Kuan-Yu, Berndt Sonja I, Wu Wei, Chang Jiang, Zhang Xu-Chao, Huang Ming-Shyan, Zheng Hong, Wang Junwen, Zhao Xueying, Li Yuqing, Choi Jin Eun, Su Wu-Chou, Park Kyong Hwa, Sung Sook Whan, Chen Yuh-Min, Liu Li, Kang Chang Hyun, Hu Lingmin, Chen Chung-Hsing, Pao William, Kim Young-Chul, Yang Tsung-Ying, Xu Jun, Guan Peng, Tan Wen, Su Jian, Wang Chih-Liang, Li Haixin, Sihoe Alan Dart Loon, Zhao Zhenhong, Chen Ying, Choi Yi Young, Hung Jen-Yu, Kim Jun Suk, Yoon Ho-Il, Cai Qiuyin, Lin Chien-Chung, Park In Kyu, Xu Ping, Dong Jing, Kim Christopher, He Qincheng, Perng Reury-Perng, Kohno Takashi, Kweon Sun-Seog, Chen Chih-Yi, Vermeulen Roel C H, Wu Junjie, Lim Wei-Yen, Chen Kun-Chieh, Chow Wong-Ho, Ji Bu-Tian, Chan John K C, Chu Minjie, Li Yao-Jen, Yokota Jun, Li Jihua, Chen Hongyan, Xiang Yong-Bing, Yu Chong-Jen, Kunitoh Hideo, Wu Guoping, Jin Li, Lo Yen-Li, Shiraishi Kouya, Chen Ying-Hsiang, Lin Hsien-Chih, Wu Tangchun, Wong Maria Pik, Wu Yi-Long, Yang Pan-Chyr, Zhou Baosen, Shin Min-Ho, Fraumeni Joseph F, Zheng Wei, Lin Dongxin, Chanock Stephen J, Rothman Nathaniel, Lan Qing
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.
Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.
Int J Cancer. 2015 Jul 15;137(2):311-9. doi: 10.1002/ijc.29393. Epub 2014 Dec 29.
Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of seven telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of seven telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI = 1.34-1.69) for upper vs. lower quartile of the weighted GRS, p value = 4.54 × 10(-14) ) even after removing rs2736100 (p value = 4.81 × 10(-3) ), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk.
近期来自前瞻性队列中几个相对较小的巢式病例对照研究的证据表明，在外周血白细胞（WBC）DNA中通过表型测量的较长端粒长度与肺癌风险增加之间存在关联。我们试图通过在一项对5457名从不吸烟的亚洲女性肺癌病例和4493名从不吸烟的亚洲女性对照的大型研究中，检测一组七个与端粒长度相关的基因变异，来进一步探究这种关系，该研究使用了先前报道的全基因组关联研究的数据。在上海女性健康前瞻性研究中，我们对1536名白细胞端粒长度通过表型测量的个体进行研究，证明了七个与端粒长度相关变异组成的遗传风险评分（GRS）在预测亚洲人群端粒长度方面的效用。然后我们发现，用作预测较长端粒长度的工具变量的GRS与肺癌风险增加相关（加权GRS的上四分位数与下四分位数相比，OR = 1.51（95%CI = 1.34 - 1.69），p值 = 4.54×10⁻¹⁴），即使去除rs2736100（p值 = 4.81×10⁻³）后也是如此，rs2736100是TERT基因座中的一个单核苷酸多态性，在先前的关联研究中与肺癌风险密切相关。分层分析表明，端粒相关GRS的效应在较年轻个体中最强。我们发现腺癌和鳞状细胞亚型之间的GRS效应没有差异。我们的结果表明，有利于较长端粒长度的遗传背景可能会增加肺癌风险，这与早期将较长端粒长度与肺癌风险增加相关联的前瞻性研究一致。
