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Frontiers of Medicine >> 2021, Volume 15, Issue 2 doi: 10.1007/s11684-020-0779-4

Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma

. Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.. State Key Laboratory of Reproductive Medicine, Center for Global Health, Nanjing Medical University, Nanjing 211166, China.. Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing 211166, China.. Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing 211166, China.. China International Cooperation Center for Environment and Human Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892-9304, USA.. Department of Integrative Oncology, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada.. Faculty of Medicine, University of Oviedo and CIBERESP, Oviedo 33006, Spain.. Program in Epidemiology, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.. Public Health Sciences Division, Swedish Cancer Institute, Seattle, WA 98026, USA.. Department of Clinical Biochemistry, Copenhagen University Hospital, Copenhagen DK-1017, Denmark.. National Cancer Institute, Bethesda, MD 20892-9304, USA.. Genetic Epidemiology Group, International Agency for Research on Cancer, Lyon 69372, France.. Cancer Center Cluster Salzburg at PLUS, Department of Molecular Biology, University of Salzburg, Heidelberg 5020, Austria.. Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig Maximilians University, Munich, Bavaria 80539, Germany.. Department of Genetic Epidemiology, University Medical Center Goettingen, Goettingen 37075, Germany.. Technion Faculty of Medicine, Carmel Medical Center, Haifa 3448516, Israel.. Markey Cancer Center, University of Kentucky, Lexington, KY 40506-0054, USA.. Department of Molecular and Clinical Cancer Medicine, Roy Castle Lung Cancer Research Programme, The University of Liverpool Institute of Translational Medicine, Liverpool L69 7ZX, UK.. Department of Epidemiology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77079, USA.. Department of Epidemiology, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.. Department of Clinical Sciences, Lund University, BMC F12, 221 84, Sweden.. Epidemiology Division, Princess Margaret Cancer Center, Toronto, ON M4Y 2H8, Canada.. Epidemiology Division, Lunenfeld-Tanenbuaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada.. Department of Neurology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.. Department of Health Evidence, Radboud University Medical Center, Nijmegen 9101 6500 HB, Germany.. National Institute of Occupational Health (STAMI), Oslo Pb 5330, Norway.. Department of Medical Biosciences, Umeå University, Umea 901 87, Sweden.. Department of Radiation Sciences, Umeå University, Umea 901 87, Sweden.. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850, USA.. Academic Unit of Clinical Oncology, University of Sheffield, Sheffield S10 2TN, UK.. College of Pharmacy, Washington State University, Spokane, WA 99210, USA.. Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 12902, USA.. Department of Thoracic Surgery, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.. Department of Epidemiology Research Program, American Cancer Society, Atlanta, GA 30303, USA.. Department of Environmental Health, Harvard School of Public Health, Department of Medicine, Harvard Medical School/Massachusetts General Hospital, Boston, MA 02115, USA.. Baylor College of Medicine, Institute for Clinical and Translational Research, Houston, TX 21202, USA

Received: 2020-07-24 Accepted: 2020-09-09 Available online: 2020-09-09

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Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER=1.95, =0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.

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