Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia

Journal name:
Nature Genetics
Volume:
44,
Pages:
1330–1335
Year published:
DOI:
doi:10.1038/ng.2456
Received
Accepted
Published online

To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10−6) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10−18), 6q22.2 (rs9387478, P = 4.14 × 10−10) and 6p21.32 (rs2395185, P = 9.51 × 10−9). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking.

At a glance

Figures

  1. Association results from a GWAS of never-smoking women in Asia.
    Figure 1: Association results from a GWAS of never-smoking women in Asia.

    Manhattan plot based on P values derived from 1-degree-of-freedom tests of genotype trend effect in unconditional logistic regression analysis adjusted for study, age and three eigenvectors in a GWAS of lung cancer in never-smoking Asian females, including 5,510 lung cancer cases and 4,544 controls. The x axis represents chromosomal location, and the y axis shows P values on a negative logarithmic scale. The red horizontal line represents the genome-wide significance threshold of P = 5 × 10−8. Labeled are two previously associated loci (TERT at 5p15.33 and TP63 at 3q28) together with three newly identified loci (VTI1A on chromosome 10 and ROS1-DCBLD1 and the HLA class II region on chromosome 6).

  2. Association results, recombination hotspots and LD plots for the regions newly associated with lung cancer in never-smoking Asian females.
    Figure 2: Association results, recombination hotspots and LD plots for the regions newly associated with lung cancer in never-smoking Asian females.

    Top, association results are shown with −log10 (P values) (left y axis). Overlaid are the likelihood ratio statistics (right y axis) to estimate putative recombination hotspots across the region on the basis of 3 sets of 100 randomly selected control samples representing Han Chinese, Japanese and Korean (connected lines in green, blue and red, respectively) individuals. Bottom, LD heatmap based on pairwise r2 values from total control populations for all SNPs included in the GWAS. (a) A 229.7-kb region at 10q25.2 spanning the VTI1A gene. (b) A 223.4-kb region at 6q22.2 spanning the ROS1, DCBLD1 and GOPC genes. (c) A 279.6-kb region at 6p21.32 spanning multiple genes in the HLA class II region. Because a TaqMan assay could not be designed for rs2395185, we instead genotype rs28366298, its perfect surrogate (r2 = 1.0), by TaqMan. The reported P value is based on meta-analysis of the rs2395185 results in the GWAS and the rs28366298 results in the TaqMan set. Genomic coordinates are based on NCBI Human Genome Build 36. Schematic gene structures are taken from the UCSC Genome Browser and are scaled to the x axis.

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Author information

  1. These authors contributed equally to this work.

    • Qing Lan,
    • Chao A Hsiung,
    • Keitaro Matsuo,
    • Yun-Chul Hong,
    • Adeline Seow,
    • Zhaoming Wang,
    • H Dean Hosgood III,
    • Kexin Chen &
    • Jiu-Cun Wang
  2. These authors jointly directed this work.

    • Tangchun Wu,
    • Yi-Long Wu,
    • Pan-Chyr Yang,
    • Baosen Zhou,
    • Min-Ho Shin,
    • Joseph F Fraumeni Jr,
    • Dongxin Lin,
    • Stephen J Chanock &
    • Nathaniel Rothman

Affiliations

  1. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

    • Qing Lan,
    • H Dean Hosgood III,
    • Nilanjan Chatterjee,
    • Wei Hu,
    • Neil Caporaso,
    • Maria Teresa Landi,
    • Bryan A Bassig,
    • Margaret Tucker,
    • Charles C Chung,
    • Sonja I Berndt,
    • Christopher Kim,
    • Wong-Ho Chow,
    • Bu-Tian Ji,
    • Joseph F Fraumeni Jr,
    • Stephen J Chanock &
    • Nathaniel Rothman
  2. Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.

    • Chao A Hsiung,
    • Chin-Fu Hsiao,
    • Wen-Chang Wang,
    • Yen-Li Lo,
    • Ying-Hsiang Chen &
    • Hsien-Chih Lin
  3. Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.

    • Keitaro Matsuo
  4. Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.

    • Yun-Chul Hong
  5. Saw Swee Hock School of Public Health, National University of Singapore, Singapore.

    • Adeline Seow,
    • Ying Chen &
    • Wei-Yen Lim
  6. Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

    • Zhaoming Wang,
    • Laurie Burdett,
    • Meredith Yeager,
    • Jeffrey Yuenger,
    • Kevin B Jacobs &
    • Amy Hutchinson
  7. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, USA.

    • H Dean Hosgood III
  8. Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.

    • Kexin Chen,
    • Biyun Qian,
    • Hong Zheng &
    • Haixin Li
  9. Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.

    • Jiu-Cun Wang,
    • Daru Lu,
    • Xueying Zhao,
    • Zhenhong Zhao,
    • Junjie Wu,
    • Hongyan Chen &
    • Li Jin
  10. State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.

    • Jiu-Cun Wang,
    • Daru Lu,
    • Xueying Zhao,
    • Zhenhong Zhao,
    • Junjie Wu,
    • Hongyan Chen &
    • Li Jin
  11. Department of Pathology, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

    • Maria Pik Wong
  12. Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Institute for Medicine and Public Health, Vanderbilt University, Nashville, Tennessee, USA.

    • Wei Zheng,
    • Xiao-Ou Shu &
    • Qiuyin Cai
  13. Lung Cancer Center, Kyungpook National University Medical Center, Daegu, Republic of Korea.

    • Jae Yong Park
  14. Genomic Research Center, Taipei, Taiwan.

    • Chien-Jen Chen &
    • Yao-Jen Li
  15. Department of Internal Medicine, Division of Oncology/Hematology, College of Medicine, Korea University Anam Hospital, Seoul, Republic of Korea.

    • Yeul Hong Kim,
    • Jae Sook Sung &
    • Kyong Hwa Park
  16. Department of Thoracic and Cardiovascular Surgery, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.

    • Young Tae Kim,
    • Yoo Jin Jung,
    • Chang Hyun Kang &
    • In Kyu Park
  17. Ministry of Education Key Laboratory of Modern Toxicology, Nanjing Medical University, Nanjing, China.

    • Hongbing Shen,
    • Zhibin Hu,
    • Lingmin Hu,
    • Jing Dong &
    • Minjie Chu
  18. Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, China.

    • Hongbing Shen,
    • Zhibin Hu,
    • Lingmin Hu,
    • Jing Dong &
    • Minjie Chu
  19. Westat, Rockville, Maryland, USA.

    • Charles Lawrence
  20. National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan.

    • I-Shou Chang &
    • Chung-Hsing Chen
  21. Division of Thoracic Surgery, Kinki University School of Medicine, Sayama, Japan.

    • Tetsuya Mitsudomi
  22. Genome Research Center for Hematopoietic Diseases, Chonnam National University Hwasun Hospital, Hwasun-eup, Republic of Korea.

    • Hee Nam Kim
  23. Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.

    • Gee-Chen Chang &
    • Yuh-Min Chen
  24. Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.

    • Gee-Chen Chang,
    • Tsung-Ying Yang &
    • Kun-Chieh Chen
  25. Division of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut, USA.

    • Bryan A Bassig
  26. China National Environmental Monitoring Center, Beijing, China.

    • Fusheng Wei &
    • Guoping Wu
  27. Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China.

    • Zhihua Yin,
    • Wei Wu,
    • Peng Guan,
    • Qincheng He &
    • Baosen Zhou
  28. Department of Etiology & Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

    • Chen Wu,
    • Jiang Chang,
    • Wen Tan &
    • Dongxin Lin
  29. State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

    • Chen Wu,
    • Jiang Chang,
    • Wen Tan &
    • Dongxin Lin
  30. Guangdong Lung Cancer Institute, Medical Research Center and Cancer Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.

    • She-Juan An,
    • Xu-Chao Zhang,
    • Jian Su &
    • Yi-Long Wu
  31. Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

    • Victor Ho Fun Lee
  32. Department of Human Genetics, Genome Institute of Singapore, Singapore.

    • Jianjun Liu &
    • Yuqing Li
  33. School of Life Sciences, Anhui Medical University, Hefei, China.

    • Jianjun Liu
  34. Cancer Research Center, Kyungpook National University Medical Center, Daegu, Republic of Korea.

    • Hyo-Sung Jeon,
    • Jin Eun Choi &
    • Yi Young Choi
  35. Institute of Environmental Medicine, Seoul National University Medical Research Center, Seoul, Republic of Korea.

    • Jin Hee Kim
  36. Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.

    • Yu-Tang Gao &
    • Yong-Bing Xiang
  37. Department of Respiratory Therapy, Chang Gung Memorial Hospital, Chiayi, Taiwan.

    • Ying-Huang Tsai
  38. Institute of Occupational Medicine and Ministry of Education Key Laboratory for Environment and Health, School of Public Health, Huazhong University of Science and Technology, Wuhan, China.

    • Huan Guo &
    • Tangchun Wu
  39. Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Robert Klein
  40. Lung and Esophageal Cancer Clinic, Chonnam National University Hwasun Hospital, Hwasun-eup, Republic of Korea.

    • In-Jae Oh &
    • Young-Chul Kim
  41. Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.

    • In-Jae Oh &
    • Young-Chul Kim
  42. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

    • Kuan-Yu Chen &
    • Chong-Jen Yu
  43. Chinese Center for Disease Control and Prevention, Beijing, China.

    • Xingzhou He
  44. Department of Internal Medicine, Kaohsiung Medical University Hospital, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

    • Ming-Shyan Huang &
    • Jen-Yu Hung
  45. Department of Biochemistry, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

    • Junwen Wang
  46. Centre for Genomic Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

    • Junwen Wang
  47. Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

    • Wu-Chou Su &
    • Chien-Chung Lin
  48. Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.

    • Sook Whan Sung
  49. Chest Department, Taipei Veterans General Hospital, Taipei, Taiwan.

    • Yuh-Min Chen &
    • Reury-Perng Perng
  50. Cancer Center, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.

    • Li Liu
  51. Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • William Pao
  52. School of Public Health, The University of Hong Kong, Hong Kong, China.

    • Jun Xu
  53. Departmentof Pulmonary and Critical Care, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

    • Chih-Liang Wang
  54. Department of Surgery, Division of Cardiothoracic Surgery, Queen Mary Hospital, Hong Kong, China.

    • Alan Dart Loon Sihoe
  55. Department of Internal Medicine, Division of Medical Oncology, College of Medicine, Korea University Guro Hospital, Seoul, Republic of Korea.

    • Jun Suk Kim
  56. Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.

    • Ho-Il Yoon
  57. Department of Oncology, Wuhan Iron and Steel Corporation Staff Worker Hospital, Wuhan, China.

    • Ping Xu
  58. Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.

    • Takashi Kohno &
    • Kouya Shiraishi
  59. Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun-eup, Republic of Korea.

    • Sun-Seog Kweon
  60. Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.

    • Sun-Seog Kweon &
    • Min-Ho Shin
  61. Cancer Center, China Medical University and Hospital, Taichung, Taiwan.

    • Chih-Yi Chen
  62. Division of Environmental Epidemiology, Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, The Netherlands.

    • Roel Vermeulen
  63. Department of Pathology, Queen Elizabeth Hospital, Hong Kong, China.

    • John K C Chan
  64. Division of Multistep Carcinogenesis, National Cancer Center Research Institute, Tokyo, Japan.

    • Jun Yokota
  65. Qujing Center for Diseases Control and Prevention, Sanjiangdadao, Qujing, China.

    • Jihua Li
  66. Department of Respiratory Medicine, Mitsui Memorial Hospital, Tokyo, Japan.

    • Hideo Kunitoh
  67. Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.

    • Pan-Chyr Yang

Contributions

Q.L., N.R., S.J.C., D. Lin, C.A.H., Y.-C.H., K.M., A.S., H.D.H., J.Y.P., C.-J.C., Y.H.K., Y.T.K., C.L., Y.-L.W., P.-C.Y., B.Z., M.-H.S., J.F.F., K.C., W.Z., T.W., H.S., I.-S.C., D. Lu, N. Caporaso, W.P., R.K., J. Liu, M.T.L., N. Chatterjee, M.T. and M.Y. organized and designed the study. S.J.C., D. Lin, R.K., J. Liu, C.A.H., K.M., T.W., L.B., M.Y., J. Yuenger, Z.Y., C.W., H.G., A.H., W.W., Y.L., W.P., H.-C.L. and B.Z. conducted and supervised the genotyping of samples. Z.W., K.B.J., N.R., Q.L., S.J.C., N. Chatterjee, C.A.H., H.D.H., W.H., M.Y., I.-S.C., C.-F.H., W.-C.W., C.C.C., S.I.B., C.-H.C., R.V. and Y.-H.C. contributed to the design and execution of statistical analysis. Q.L., N.R., S.J.C., Z.W., W.H., C.C.C., C.A.H., K.M., Y.-C.H., A.S., H.D.H., N. Chatterjee, N. Caporaso, C.L., M.Y., B.A.B., M.T., S.-J.A., S.I.B., M.T.L., C.K., R.V., Y.-L.W., J.F.F. and I.-S.C. wrote the first draft of the manuscript. C.A.H., Q.L., B.Z., Y.-C.H., K.M., A.S., K.C., J.-C.W., M.P.W., W.Z., J.Y.P., W.H., C.-J.C., Y.H.K., Y.T.K., T.W., H.S., I.-S.C., T.M., H.N.K., F.W., Z.Y., C.W., S.-J.A., G.-C.C., B.Q., V.H.F.L., D. Lu, H.-S.J., J.S.S., J.H.K., Y.-T.G., Y.-H.T., Y.J.J., H.G., Z.H., I.-J.O., K.-Y.C., X.H., W.W., J.C., X.-C.Z., M.-S.H., H.Z., J. Wang, X.Z., J.E.C., W.-C.S., K.H.P., S.W.S., X.-O.S., Y.-M.C., L.L., C.H.K., L.H., Y.-C.K., T.-Y.Y., J.X., P.G., W.T., J.S., C.-L.W., H.L., A.D.L.S., Z.Z., Y.C., Y.Y.C., J.-Y.H., J.S.K., H.-I.Y., Q.C., C.-C.L., I.K.P., P.X., J.D., Q.H., R.-P.P., T.K., S.-S.K., C.-Y.C., R.V., J. Wu, W.-Y.L., K.-C.C., W.-H.C., B.-T.J., J.K.C.C., M.C., Y.-J.L., J. Yokota, J. Li, H.C., Y.-B.X., C.-J.Y., H.K., G.W., L.J., Y.-L.L., K.S., Y.-L.W., P.-C.Y., M.-H.S., J.F.F., D. Lin, S.J.C. and N.R. conducted the epidemiological studies and contributed samples to the GWAS and/or follow-up genotyping. All authors contributed to the writing of the manuscript.

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