Deciphering associations between three RNA splicing-related genetic variants and lung cancer risk

Wenjun Yang; Hongliang Liu; Ruoxin Zhang; Jennifer A Freedman; Younghun Han; Rayjean J Hung; Yonathan Brhane; John McLaughlin; Paul Brennan; Heike Bickeboeller; Albert Rosenberger; Richard S Houlston; Neil E Caporaso; Maria Teresa Landi; Irene Brueske; Angela Risch; David C Christiani; Christopher I Amos; Xiaoxin Chen; Steven R Patierno; Qingyi Wei

doi:10.1038/s41698-022-00281-9

Deciphering associations between three RNA splicing-related genetic variants and lung cancer risk

NPJ Precis Oncol. 2022 Jun 30;6(1):48. doi: 10.1038/s41698-022-00281-9.

Authors

Wenjun Yang^#^{1

2

3}, Hongliang Liu^#^{2

4}, Ruoxin Zhang^#^{2

4

5

6}, Jennifer A Freedman^{2

7}, Younghun Han⁸, Rayjean J Hung⁹, Yonathan Brhane⁹, John McLaughlin¹⁰, Paul Brennan¹¹, Heike Bickeboeller¹², Albert Rosenberger¹², Richard S Houlston¹³, Neil E Caporaso¹⁴, Maria Teresa Landi¹⁴, Irene Brueske¹⁵, Angela Risch¹⁶, David C Christiani^{17

18}, Christopher I Amos¹⁹, Xiaoxin Chen²⁰, Steven R Patierno^{21

22}, Qingyi Wei^{23

24

25

26}

Affiliations

¹ International Center for Aging and Cancer, Pathology Department of the First Affiliated Hospital, Hainan Medical University, Haikou, 571199, China.
² Duke Cancer Institute, Duke University Medical Center, Durham, NC, 27710, USA.
³ Ningxia Human Stem Cell Research Institute, the General Hospital of Ningxia Medical University, Yinchuan, 750004, China.
⁴ Department of Population Health Sciences, Duke University School of Medicine, Durham, NC, 27710, USA.
⁵ School of Public Health, Fudan University; Key Laboratory of Public Health Safety, Ministry of Education, Shanghai, 200032, China.
⁶ Yiwu Research Institute of Fudan University, Yiwu, Zhejiang, 322000, China.
⁷ Department of Medicine, Division of Medical Oncology, Duke University School of Medicine, Durham, NC, 27710, USA.
⁸ Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, 77030, USA.
⁹ Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.
¹⁰ Public Health Ontario, Toronto, ON, M5T 3L9, Canada.
¹¹ International Agency for Research on Cancer, World Health Organization, Lyon, 69372, France.
¹² Department of Genetic Epidemiology, University Medical Center Göttingen, Göttingen, 37073, Germany.
¹³ Division of Genetics and Epidemiology, the Institute of Cancer Research, London, SW7 3RP, UK.
¹⁴ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
¹⁵ Helmholtz Centre Munich, German Research Centre for Environmental Health, Institute of Epidemiology, Neuherberg, 85764, Germany.
¹⁶ Department of Molecular Biology, University of Salzburg, Salzburg, 5020, Austria.
¹⁷ Massachusetts General Hospital, Boston, MA, 02114, USA.
¹⁸ Department of Environmental Health, Harvard School of Public Health, Boston, MA, 02115, USA.
¹⁹ Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA.
²⁰ Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, 27707, USA.
²¹ Duke Cancer Institute, Duke University Medical Center, Durham, NC, 27710, USA. steven.patierno@duke.edu.
²² Department of Medicine, Division of Medical Oncology, Duke University School of Medicine, Durham, NC, 27710, USA. steven.patierno@duke.edu.
²³ Duke Cancer Institute, Duke University Medical Center, Durham, NC, 27710, USA. qingyi.wei@duke.edu.
²⁴ Department of Population Health Sciences, Duke University School of Medicine, Durham, NC, 27710, USA. qingyi.wei@duke.edu.
²⁵ Department of Medicine, Division of Medical Oncology, Duke University School of Medicine, Durham, NC, 27710, USA. qingyi.wei@duke.edu.
²⁶ Duke Global Health Institute, Duke University Medical Center, Durham, NC, 27710, USA. qingyi.wei@duke.edu.

^# Contributed equally.

Abstract

Limited efforts have been made in assessing the effect of genome-wide profiling of RNA splicing-related variation on lung cancer risk. In the present study, we first identified RNA splicing-related genetic variants linked to lung cancer in a genome-wide profiling analysis and then conducted a two-stage (discovery and replication) association study in populations of European ancestry. Discovery and validation were conducted sequentially with a total of 29,266 cases and 56,450 controls from both the Transdisciplinary Research in Cancer of the Lung and the International Lung Cancer Consortium as well as the OncoArray database. For those variants identified as significant in the two datasets, we further performed stratified analyses by smoking status and histological type and investigated their effects on gene expression and potential regulatory mechanisms. We identified three genetic variants significantly associated with lung cancer risk: rs329118 in JADE2 (P = 8.80E-09), rs2285521 in GGA2 (P = 4.43E-08), and rs198459 in MYRF (P = 1.60E-06). The combined effects of all three SNPs were more evident in lung squamous cell carcinomas (P = 1.81E-08, P = 6.21E-08, and P = 7.93E-04, respectively) than in lung adenocarcinomas and in ever smokers (P = 9.80E-05, P = 2.70E-04, and P = 2.90E-05, respectively) than in never smokers. Gene expression quantitative trait analysis suggested a role for the SNPs in regulating transcriptional expression of the corresponding target genes. In conclusion, we report that three RNA splicing-related genetic variants contribute to lung cancer susceptibility in European populations. However, additional validation is needed, and specific splicing mechanisms of the target genes underlying the observed associations also warrants further exploration.

Abstract

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