Association Analysis of Driver Gene-Related Genetic Variants Identified Novel Lung Cancer Susceptibility Loci with 20,871 Lung Cancer Cases and 15,971 Controls.
- Department of Epidemiology, International Joint Research Center on Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
- Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
- Department of Integrative Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
- Department of Public Health IUOPA, University of Oviedo, ISPA and CIBERESP, Oviedo, Spain.
- Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
- Public Health Sciences Division, Swedish Cancer Institute, Seattle, Washington.
- Department of Clinical Biochemistry, Copenhagen University Hospital, Copenhagen, Denmark.
- National Cancer Institute, Bethesda, Maryland.
- Genetic Epidemiology Group, International Agency for Research on Cancer, Lyon, France.
- University of Salzburg, Department of Biosciences, Allergy-Cancer-BioNano Research Centre, Salzburg, Austria.
- Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig Maximilians University, Munich, Bavaria, Germany.
- Department of Genetic Epidemiology, University Medical Center Goettingen, Goettingen, Germany.
- Departments of Environmental Health and Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
- Technion Faculty of Medicine, Carmel Medical Center, Haifa, Israel.
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky.
- Molecular and Clinical Cancer Medicine, Roy Castle Lung Cancer Research Programme, The University of Liverpool Institute of Translational Medicine, Liverpool, United Kingdom.
- Department of Epidemiology, The University of Texas, MD Anderson Cancer Center, Houston, Texas.
- Epidemiology Program, University of Hawai'i Cancer Center, Honolulu, Hawai'i.
- Clinical Sciences, Lund University, Lund, Sweden.
- Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
- Prosseman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.
- Department of Neurology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
- Department for Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands.
- National Institute of Occupational Health (STAMI), Oslo, Norway.
- Department of Medical Biosciences, Umeå University, Umea, Sweden.
- Department of Radiation Sciences, Umeå University, Umea, Sweden.
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
- Academic Unit of Clinical Oncology, University of Sheffield, Sheffield, United Kingdom.
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington.
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
- Department of Medicine (Division of Genetic Medicine), Vanderbilt University Medical Center, Nashville, Tennessee.
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia.
- Department of Medicine, Epidemiology Section, Institute for Clinical and Translational Research, Baylor Medical College, Houston, Texas. hbshen@njmu.edu.cn chris.amos@bcm.edu.
- Department of Epidemiology, International Joint Research Center on Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. hbshen@njmu.edu.cn chris.amos@bcm.edu.
BACKGROUND: A substantial proportion of cancer driver genes (CDG) are also cancer predisposition genes. However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated.
METHODS: We selected expression-related single-nucleotide polymorphisms (eSNP) and nonsynonymous variants of lung CDGs, and tested their associations with lung cancer risk in two large-scale genome-wide association studies (20,871 cases and 15,971 controls of European descent). Conditional and joint association analysis was performed to identify independent risk variants. The associations of independent risk variants with somatic alterations in lung CDGs or recurrently altered pathways were investigated using data from The Cancer Genome Atlas (TCGA) project.
RESULTS: We identified seven independent SNPs in five lung CDGs that were consistently associated with lung cancer risk in discovery (P < 0.001) and validation (P < 0.05) stages. Among these loci, rs78062588 in TPM3 (1q21.3) was a new lung cancer susceptibility locus (OR = 0.86, P = 1.65 × 10-6). Subgroup analysis by histologic types further identified nine lung CDGs. Analysis of somatic alterations found that in lung adenocarcinomas, rs78062588[C] allele (TPM3 in 1q21.3) was associated with elevated somatic copy number of TPM3 (OR = 1.16, P = 0.02). In lung adenocarcinomas, rs1611182 (HLA-A in 6p22.1) was associated with truncation mutations of the transcriptional misregulation in cancer pathway (OR = 0.66, P = 1.76 × 10-3).
CONCLUSIONS: Genetic variants can regulate functions of lung CDGs and influence lung cancer susceptibility.
IMPACT: Our findings might help unravel biological mechanisms underlying lung cancer susceptibility.
- 2007-0004: A Whole Genome Association Study (WGAS) of Lung Cancer and Smoking (Neil Caporaso - 2007)