A Large-Scale Genome-Wide Gene-Gene Interaction Study of Lung Cancer Susceptibility in Europeans With a Trans-Ethnic Validation in Asians
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Introduction: Although genome-wide association studies have been conducted to investigate genetic variation of lung tumorigenesis, little is known about gene-gene (G × G) interactions that may influence the risk of non-small cell lung cancer (NSCLC). Methods: Leveraging a total of 445,221 European-descent participants from the International Lung Cancer Consortium OncoArray project, Transdisciplinary Research in Cancer of the Lung and UK Biobank, we performed a large-scale genome-wide G × G interaction study on European NSCLC risk by a series of analyses. First, we used BiForce to evaluate and rank more than 58 billion G × G interactions from 340,958 single-nucleotide polymorphisms (SNPs). Then, the top interactions were further tested by demographically adjusted logistic regression models. Finally, we used the selected interactions to build lung cancer screening models of NSCLC, separately, for never and ever smokers. Results: With the Bonferroni correction, we identified eight statistically significant pairs of SNPs, which predominantly appeared in the 6p21.32 and 5p15.33 regions (e.g., rs521828C6orf10 and rs204999PRRT1, ORinteraction = 1.17, p = 6.57 × 10−13; rs3135369BTNL2 and rs2858859HLA-DQA1, ORinteraction = 1.17, p = 2.43 × 10−13; rs2858859HLA-DQA1 and rs9275572HLA-DQA2, ORinteraction = 1.15, p = 2.84 × 10−13; rs2853668TERT and rs62329694CLPTM1L, ORinteraction = 0.73, p = 2.70 × 10−13). Notably, even with much genetic heterogeneity across ethnicities, three pairs of SNPs in the 6p21.32 region identified from the European-ancestry population remained significant among an Asian population from the Nanjing Medical University Global Screening Array project (rs521828C6orf10 and rs204999PRRT1, ORinteraction = 1.13, p = 0.008; rs3135369BTNL2 and rs2858859HLA-DQA1, ORinteraction = 1.11, p = 5.23 × 10−4; rs3135369BTNL2 and rs9271300HLA-DQA1, ORinteraction = 0.89, p = 0.006). The interaction-empowered polygenetic risk score that integrated classical polygenetic risk score and G × G information score was remarkable in lung cancer risk stratification. Conclusions: Important G × G interactions were identified and enriched in the 5p15.33 and 6p21.32 regions, which may enhance lung cancer screening models.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Journal of Thoracic Oncology |
| Vol/bind | 17 |
| Udgave nummer | 8 |
| Sider (fra-til) | 974-990 |
| Antal sider | 17 |
| ISSN | 1556-0864 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
This study was funded by the National Natural Science Foundation of China (81820108028 to Dr. H. Shen, 81973142 to Dr. Y. Wei, 82103946 to Dr. S. Shen, 81922061 and 81973123 to Dr. H. Ma), National Key Research and Development Program of China (2016YFE0204900 to Dr. F. Chen), Natural Science Foundation of Jiangsu Province (BK20191354 to Dr. R. Zhang), China Postdoctoral Science Foundation (2020M681671 to Dr. S. Shen), Jiangsu Planned Projects for Postdoctoral Research Funds (2020Z019 to Dr. S. Shen), the U.S. National Institutes of Health (CA209414, CA092824, and ES000002 to Dr. D.C. Christiani, AG056764 to Dr. Y. Li), and Priority Academic Program Development of Jiangsu Higher Education Institutions. Dr. R. Zhang was partially supported by the Qing Lan Project of the Higher Education Institutions of Jiangsu Province and the Outstanding Young Level Academic Leadership Training Program of Nanjing Medical University. Where authors are identified as personnel of the International Agency for Research on Cancer, WHO, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer, WHO.
Funding Information:
This study was funded by the National Natural Science Foundation of China ( 81820108028 to Dr. H. Shen, 81973142 to Dr. Y. Wei, 82103946 to Dr. S. Shen, 81922061 and 81973123 to Dr. H. Ma), National Key Research and Development Program of China ( 2016YFE0204900 to Dr. F. Chen), Natural Science Foundation of Jiangsu Province ( BK20191354 to Dr. R. Zhang), China Postdoctoral Science Foundation ( 2020M681671 to Dr. S. Shen), Jiangsu Planned Projects for Postdoctoral Research Funds (2020Z019 to Dr. S. Shen), the U.S. National Institutes of Health (CA209414, CA092824, and ES000002 to Dr. D.C. Christiani, AG056764 to Dr. Y. Li), and Priority Academic Program Development of Jiangsu Higher Education Institutions. Dr. R. Zhang was partially supported by the Qing Lan Project of the Higher Education Institutions of Jiangsu Province and the Outstanding Young Level Academic Leadership Training Program of Nanjing Medical University . Where authors are identified as personnel of the International Agency for Research on Cancer, WHO, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer, WHO.
Publisher Copyright:
© 2022 International Association for the Study of Lung Cancer
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