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

Na Qin; Yuancheng LI; Cheng Wang; Meng Zhu; Juncheng Dai; Tongtong Hong; Demetrius Albanes; Stephen Lam; Adonina Tardon; Chu Chen; Gary Goodman; Stig E Bojesen; Maria Teresa Landi; Mattias Johansson; Angela Risch; H-erich Wichmann; Heike Bickeboller; Gadi Rennert; Susanne Arnold; Paul Brennan; John K Field; Sanjay Shete; Loic LE Marchand; Olle Melander; Hans Brunnstrom; Geoffrey Liu; Rayjean J Hung; Angeline Andrew; Lambertus A Kiemeney; Shan Zienolddiny; Kjell Grankvist; Mikael Johansson; Neil Caporaso; Penella Woll; Philip Lazarus; Matthew B Schabath; Melinda C Aldrich; Victoria L Stevens; Guangfu Jin; David C Christiani; Zhibin HU; Christopher I Amos; Hongxia MA; Hongbing Shen

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

Author: Na QIN ¹ ; Yuancheng LI ¹ ; Cheng WANG ¹ ; Meng ZHU ¹ ; Juncheng DAI ¹ ; Tongtong HONG ¹ ; Demetrius ALBANES ² ; Stephen LAM ³ ; Adonina TARDON ⁴ ; Chu CHEN ⁵ ; Gary GOODMAN ⁶ ; Stig E BOJESEN ⁷ ; Maria Teresa LANDI ⁸ ; Mattias JOHANSSON ⁹ ; Angela RISCH ¹⁰ ; H-Erich WICHMANN ¹¹ ; Heike BICKEBOLLER ¹² ; Gadi RENNERT ¹³ ; Susanne ARNOLD ¹⁴ ; Paul BRENNAN ⁹ ; John K FIELD ¹⁵ ; Sanjay SHETE ¹⁶ ; Loic LE MARCHAND ¹⁷ ; Olle MELANDER ¹⁸ ; Hans BRUNNSTROM ¹⁸ ; Geoffrey LIU ¹⁹ ; Rayjean J HUNG ²⁰ ; Angeline ANDREW ²¹ ; Lambertus A KIEMENEY ²² ; Shan ZIENOLDDINY ²³ ; Kjell GRANKVIST ²⁴ ; Mikael JOHANSSON ²⁵ ; Neil CAPORASO ²⁶ ; Penella WOLL ²⁷ ; Philip LAZARUS ²⁸ ; Matthew B SCHABATH ²⁹ ; Melinda C ALDRICH ³⁰ ; Victoria L STEVENS ³¹ ; Guangfu JIN ¹ ; David C CHRISTIANI ³² ; Zhibin HU ¹ ; Christopher I AMOS ³³ ; Hongxia MA ³⁴ ; Hongbing SHEN ³⁵
Author Information

1. Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
2. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892-9304, USA.
3. Department of Integrative Oncology, British Columbia Cancer Agency, Vancouver, BC, V5Z 1L3, Canada.
4. Faculty of Medicine, University of Oviedo and CIBERESP, Oviedo, 33006, Spain.
5. Program in Epidemiology, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA.
6. Public Health Sciences Division, Swedish Cancer Institute, Seattle, WA, 98026, USA.
7. Department of Clinical Biochemistry, Copenhagen University Hospital, Copenhagen, DK-1017, Denmark.
8. National Cancer Institute, Bethesda, MD, 20892-9304, USA.
9. Genetic Epidemiology Group, International Agency for Research on Cancer, Lyon, 69372, France.
10. Cancer Center Cluster Salzburg at PLUS, Department of Molecular Biology, University of Salzburg, Heidelberg, 5020, Austria.
11. Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig Maximilians University, Munich, Bavaria, 80539, Germany.
12. Department of Genetic Epidemiology, University Medical Center Goettingen, Goettingen, 37075, Germany.
13. Technion Faculty of Medicine, Carmel Medical Center, Haifa, 3448516, Israel.
14. Markey Cancer Center, University of Kentucky, Lexington, KY, 40506-0054, USA.
15. 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.
16. Department of Epidemiology, The University of Texas, MD Anderson Cancer Center, Houston, TX, 77079, USA.
17. Department of Epidemiology, University of Hawaii Cancer Center, Honolulu, HI, 96813, USA.
18. Department of Clinical Sciences, Lund University, BMC F12, 221 84, Lund, Sweden.
19. Epidemiology Division, Princess Margaret Cancer Center, Toronto, ON, M4Y 2H8, Canada.
20. Epidemiology Division, Lunenfeld-Tanenbuaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada.
21. Department of Neurology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, 03756, USA.
22. Department of Health Evidence, Radboud University Medical Center, Nijmegen, 9101 6500, HB, Germany.
23. National Institute of Occupational Health (STAMI), Oslo, Pb 5330, Norway.
24. Department of Medical Biosciences, Umeå University, Umea, 901 87, Sweden.
25. Department of Radiation Sciences, Umeå University, Umea, 901 87, Sweden.
26. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.
27. Academic Unit of Clinical Oncology, University of Sheffield, Sheffield, S10 2TN, UK.
28. College of Pharmacy, Washington State University, Spokane, WA, 99210, USA.
29. Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 12902, USA.
30. Department of Thoracic Surgery, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
31. Department of Epidemiology Research Program, American Cancer Society, Atlanta, GA, 30303, USA.
32. China International Cooperation Center for Environment and Human Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
33. Baylor College of Medicine, Institute for Clinical and Translational Research, Houston, TX, 21202, USA.
34. Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China. hongxiama@njmu.edu.cn.
35. Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China. hbshen@njmu.edu.cn.
Publication Type:Meta-Analysis
Keywords: function annotation; genetic heterogeneity; genome-wide association study; homologous recombination repair deficiency; immune; lung cancer
MeSH: Adenocarcinoma of Lung/genetics*; Carcinoma, Non-Small-Cell Lung/genetics*; Carcinoma, Squamous Cell/genetics*; Genetic Heterogeneity; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Lung Neoplasms/genetics*; Polymorphism, Single Nucleotide
From: Frontiers of Medicine 2021;15(2):275-291
CountryChina
Language:English
Abstract: 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, P = 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.