TY - JOUR
T1 - A Large-Scale Genome-Wide Gene-Gene Interaction Study of Lung Cancer Susceptibility in Europeans With a Trans-Ethnic Validation in Asians
AU - Zhang, Ruyang
AU - Shen, Sipeng
AU - Wei, Yongyue
AU - Zhu, Ying
AU - Li, Yi
AU - Chen, Jiajin
AU - Guan, Jinxing
AU - Pan, Zoucheng
AU - Wang, Yuzhuo
AU - Zhu, Meng
AU - Xie, Junxing
AU - Xiao, Xiangjun
AU - Zhu, Dakai
AU - Li, Yafang
AU - Albanes, Demetrios
AU - Landi, Maria Teresa
AU - Caporaso, Neil E
AU - Lam, Stephen
AU - Tardon, Adonina
AU - Chen, Chu
AU - Bojesen, Stig E
AU - Johansson, Mattias
AU - Risch, Angela
AU - Bickeböller, Heike
AU - Wichmann, H-Erich
AU - Rennert, Gadi
AU - Arnold, Susanne
AU - Brennan, Paul
AU - McKay, James D
AU - Field, John K
AU - Shete, Sanjay S
AU - Le Marchand, Loic
AU - Liu, Geoffrey
AU - Andrew, Angeline S
AU - Kiemeney, Lambertus A
AU - Zienolddiny-Narui, Shan
AU - Behndig, Annelie
AU - Johansson, Mikael
AU - Cox, Angela
AU - Lazarus, Philip
AU - Schabath, Matthew B
AU - Aldrich, Melinda C
AU - Dai, Juncheng
AU - Ma, Hongxia
AU - Zhao, Yang
AU - Hu, Zhibin
AU - Hung, Rayjean J
AU - Amos, Christopher I
AU - Shen, Hongbing
AU - Chen, Feng
AU - Christiani, David C
N1 - Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
PY - 2022/8
Y1 - 2022/8
N2 - 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.
AB - 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.
KW - Carcinoma, Non-Small-Cell Lung/genetics
KW - Case-Control Studies
KW - Early Detection of Cancer
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Humans
KW - Lung Neoplasms/genetics
KW - Polymorphism, Single Nucleotide
KW - GWAS
KW - Lung cancer
KW - Genetic screening model
KW - Cancer risk
KW - Gene-gene interaction
KW - Single nucleotide polymorphism
UR - http://www.scopus.com/inward/record.url?scp=85130893494&partnerID=8YFLogxK
U2 - 10.1016/j.jtho.2022.04.011
DO - 10.1016/j.jtho.2022.04.011
M3 - Journal article
C2 - 35500836
SN - 1556-0864
VL - 17
SP - 974
EP - 990
JO - Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
JF - Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
IS - 8
ER -