Journal of Thoracic Oncology | VOL. 17

A Large-Scale Genome-Wide Gene-Gene Interaction Study of Lung Cancer Susceptibility in Europeans With a Trans-Ethnic Validation in Asians

Publication Date Aug 1, 2022


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). 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. 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 am...


Lung Cancer Risk Stratification Polygenetic Risk Score Pairs Of Single-nucleotide Polymorphisms Non-small Cell Lung Cancer Lung Cancer European-descent Participants Transdisciplinary Research Genome-wide Association Studies UK Biobank Gene-Gene Interaction

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