Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never-smoking women in Asia: A report from the female lung cancer consortium in Asia

Mitchell J. Machiela, Chao Agnes Hsiung, Xiao Ou Shu, Wei Jie Seow, Zhaoming Wang, Keitaro Matsuo, Yun Chul Hong, Adeline Seow, Chen Wu, H. Dean Hosgood, Kexin Chen, Jiu Cun Wang, Wanqing Wen, Richard Cawthon, Nilanjan Chatterjee, Wei Hu, Neil E. Caporaso, Jae Yong Park, Chien Jen Chen, Yeul Hong KimYoung Tae Kim, Maria Teresa Landi, Hongbing Shen, Charles Lawrence, Laurie Burdett, Meredith Yeager, I. Shou Chang, Tetsuya Mitsudomi, Hee Nam Kim, Gee Chen Chang, Bryan A. Bassig, Margaret Tucker, Fusheng Wei, Zhihua Yin, She Juan An, Biyun Qian, Victor Ho Fun Lee, Daru Lu, Jianjun Liu, Hyo Sung Jeon, Chin Fu Hsiao, Jae Sook Sung, Jin Hee Kim, Yu Tang Gao, Ying Huang Tsai, Yoo Jin Jung, Huan Guo, Zhibin Hu, Amy Hutchinson, Wen Chang Wang, Robert J. Klein, Charles C. Chung, In Jae Oh, Kuan Yu Chen, Sonja I. Berndt, Wei Wu, Jiang Chang, Xu Chao Zhang, Ming Shyan Huang, Hong Zheng, Junwen Wang, Xueying Zhao, Yuqing Li, Jin Eun Choi, Wu Chou Su, Kyong Hwa Park, Sook Whan Sung, Yuh Min Chen, Li Liu, Chang Hyun Kang, Lingmin Hu, Chung Hsing Chen, William Pao, Young Chul Kim, Tsung Ying Yang, Jun Xu, Peng Guan, Wen Tan, Jian Su, Chih Liang Wang, Haixin Li, Alan Dart Loon Sihoe, Zhenhong Zhao, Ying Chen, Yi Young Choi, Jen Yu Hung, Jun Suk Kim, Ho Il Yoon, Qiuyin Cai, Chien Chung Lin, In Kyu Park, Ping Xu, Jing Dong, Christopher Kim, Qincheng He, Reury Perng Perng, Takashi Kohno, Sun Seog Kweon, Chih Yi Chen, Roel C H Vermeulen, Junjie Wu, Wei Yen Lim, Kun Chieh Chen, Wong Ho Chow, Bu Tian Ji, John K C Chan, Minjie Chu, Yao Jen Li, Jun Yokota, Jihua Li, Hongyan Chen, Yong Bing Xiang, Chong Jen Yu, Hideo Kunitoh, Guoping Wu, Li Jin, Yen Li Lo, Kouya Shiraishi, Ying Hsiang Chen, Hsien Chih Lin, Tangchun Wu, Maria Pik Wong, Yi Long Wu, Pan Chyr Yang, Baosen Zhou, Min Ho Shin, Joseph F. Fraumeni, Wei Zheng, Dongxin Lin, Stephen J. Chanock, Nathaniel Rothman, Qing Lan

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Abstract

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.

Original languageEnglish
Pages (from-to)311-319
Number of pages9
JournalInternational Journal of Cancer
Volume137
Issue number2
DOIs
Publication statusPublished - Jul 15 2015
Externally publishedYes

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Keywords

  • association study
  • genetic risk score
  • genetics
  • lung cancer
  • telomere length

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Machiela, M. J., Hsiung, C. A., Shu, X. O., Seow, W. J., Wang, Z., Matsuo, K., Hong, Y. C., Seow, A., Wu, C., Hosgood, H. D., Chen, K., Wang, J. C., Wen, W., Cawthon, R., Chatterjee, N., Hu, W., Caporaso, N. E., Park, J. Y., Chen, C. J., ... Lan, Q. (2015). Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never-smoking women in Asia: A report from the female lung cancer consortium in Asia. International Journal of Cancer, 137(2), 311-319. https://doi.org/10.1002/ijc.29393