Zhang, R, Shen, S, Wei, Y et al. (48 more authors) (2022) A large-scale genome-wide gene-gene interaction study of lung cancer susceptibility in Europeans with a trans-ethnic validation in Asians. Journal of Thoracic Oncology, 17 (8). pp. 974-990.
Abstract
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 via a series of analyses. First, we used BiForce to evaluate and rank over 58 billion G×G interactions from 340,958 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 (iPRS) that integrated classical polygenetic risk score and G×G information score was remarkable in lung cancer risk stratification.
Conclusions
Significant G×G interactions were identified and enriched in the 5p15.33 and 6p21.32 regions, which may enhance lung cancer screening models.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. Article available under the terms of the CC-BY-NC-ND licence (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
Keywords: | cancer risk; gene-gene interaction; genetic epidemiology; genetic screening model; GWAS; lung cancer; single nucleotide polymorphism |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) |
Funding Information: | Funder Grant number Weston Park Hospital Cancer Charity n/a Cancer Research UK C9267/A25152 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 05 May 2022 13:22 |
Last Modified: | 04 Nov 2022 12:40 |
Status: | Published |
Publisher: | Elsevier |
Refereed: | Yes |
Identification Number: | 10.1016/j.jtho.2022.04.011 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:186489 |