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

Ruyang Zhang; Sipeng Shen; Yongyue Wei; Ying Zhu; Yi Li; Jiajin Chen; Jinxing Guan; Zoucheng Pan; Yuzhuo Wang; Meng Zhu; Junxing Xie; Xiangjun Xiao; Dakai Zhu; Yafang Li; Demetrios Albanes; Maria Teresa Landi; Neil E. Caporaso; Stephen Lam; Adonina Tardon; Chu Chen; Stig E. Bojesen; Mattias Johansson; Angela Risch; Heike Bickeböller; H. Erich Wichmann; Gadi Rennert; Susanne Arnold; Paul Brennan; James D. McKay; John K. Field; Sanjay S. Shete; Loic Le Marchand; Geoffrey Liu; Angeline S. Andrew; Lambertus A. Kiemeney; Shan Zienolddiny-Narui; Annelie Behndig; Mikael Johansson; Angela Cox; Philip Lazarus; Matthew B. Schabath; Melinda C. Aldrich; Juncheng Dai; Hongxia Ma; Yang Zhao; Zhibin Hu; Rayjean J. Hung; Christopher I. Amos; Hongbing Shen; Feng Chen; David C. Christiani

doi:10.1016/j.jtho.2022.04.011

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

Ruyang Zhang, Sipeng Shen, Yongyue Wei, Ying Zhu, Yi Li, Jiajin Chen, Jinxing Guan, Zoucheng Pan, Yuzhuo Wang, Meng Zhu, Junxing Xie, Xiangjun Xiao, Dakai Zhu, Yafang Li, Demetrios Albanes, Maria Teresa Landi, Neil E. Caporaso, Stephen Lam, Adonina Tardon, Chu ChenStig E. Bojesen, Mattias Johansson, Angela Risch, Heike Bickeböller, H. Erich Wichmann, Gadi Rennert, Susanne Arnold, Paul Brennan, James D. McKay, John K. Field, Sanjay S. Shete, Loic Le Marchand, Geoffrey Liu, Angeline S. Andrew, Lambertus A. Kiemeney, Shan Zienolddiny-Narui, Annelie Behndig, Mikael Johansson, Angela Cox, Philip Lazarus, Matthew B. Schabath, Melinda C. Aldrich, Juncheng Dai, Hongxia Ma, Yang Zhao, Zhibin Hu, Rayjean J. Hung, Christopher I. Amos, Hongbing Shen, Feng Chen, David C. Christiani

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

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 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., rs521828_C6orf10 and rs204999_PRRT1, OR_interaction = 1.17, p = 6.57 × 10⁻¹³; rs3135369_BTNL2 and rs2858859_HLA-DQA1, OR_interaction = 1.17, p = 2.43 × 10⁻¹³; rs2858859_HLA-DQA1 and rs9275572_HLA-DQA2, OR_interaction = 1.15, p = 2.84 × 10⁻¹³; rs2853668_TERT and rs62329694_CLPTM1L, OR_interaction = 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 (rs521828_C6orf10 and rs204999_PRRT1, OR_interaction = 1.13, p = 0.008; rs3135369_BTNL2 and rs2858859_HLA-DQA1, OR_interaction = 1.11, p = 5.23 × 10⁻⁴; rs3135369_BTNL2 and rs9271300_HLA-DQA1, OR_interaction = 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.

Original language	English
Pages (from-to)	974-990
Number of pages	17
Journal	Journal of Thoracic Oncology
Volume	17
Issue number	8
DOIs	https://doi.org/10.1016/j.jtho.2022.04.011
State	Published - Aug 2022

Bibliographical note

Publisher Copyright:
© 2022 International Association for the Study of Lung Cancer

Funding

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.

Funders	Funder number
Outstanding Young Level Academic Leadership Training Program of Nanjing Medical University
Qing Lan Project of the Higher Education Institutions of Jiangsu Province
Centre International de Recherche sur le Cancer
National Institutes of Health (NIH)
Priority Academic Program Development of Jiangsu Higher Education Institutions
World Health Organization
National Childhood Cancer Registry – National Cancer Institute	R35CA197449, P30CA016672, U01CA209414, R01CA092824, R01CA249096, P30CA076292
National Natural Science Foundation of China (NSFC)	81973123, 82103946, 81922061, 81973142, 81820108028
National Institutes of Health/National Institute of Environmental Health Sciences	P30ES000002
National Institute on Aging	R01AG056764
China Postdoctoral Science Foundation	2020M681671
National Key Basic Research and Development Program of China	2016YFE0204900
Natural Science Foundation of Jiangsu Province	BK20191354
Jiangsu Planned Projects for Postdoctoral Research Funds	2020Z019

Keywords

Cancer risk
GWAS
Gene-gene interaction
Genetic screening model
Lung cancer
Single nucleotide polymorphism

ASJC Scopus subject areas

Oncology
Pulmonary and Respiratory Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.jtho.2022.04.011

Cite this

Zhang, R., Shen, S., Wei, Y., Zhu, Y., Li, Y., Chen, J., Guan, J., Pan, Z., Wang, Y., Zhu, M., Xie, J., Xiao, X., Zhu, D., Li, Y., Albanes, D., Landi, M. T., Caporaso, N. E., Lam, S., Tardon, A., ... Christiani, D. C. (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), 974-990. https://doi.org/10.1016/j.jtho.2022.04.011

@article{0ab1e37d58544c27af69222abad16c1e,

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

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 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.",

keywords = "Cancer risk, GWAS, Gene-gene interaction, Genetic screening model, Lung cancer, Single nucleotide polymorphism",

author = "Ruyang Zhang and Sipeng Shen and Yongyue Wei and Ying Zhu and Yi Li and Jiajin Chen and Jinxing Guan and Zoucheng Pan and Yuzhuo Wang and Meng Zhu and Junxing Xie and Xiangjun Xiao and Dakai Zhu and Yafang Li and Demetrios Albanes and Landi, \{Maria Teresa\} and Caporaso, \{Neil E.\} and Stephen Lam and Adonina Tardon and Chu Chen and Bojesen, \{Stig E.\} and Mattias Johansson and Angela Risch and Heike Bickeb{\"o}ller and Wichmann, \{H. Erich\} and Gadi Rennert and Susanne Arnold and Paul Brennan and McKay, \{James D.\} and Field, \{John K.\} and Shete, \{Sanjay S.\} and \{Le Marchand\}, Loic and Geoffrey Liu and Andrew, \{Angeline S.\} and Kiemeney, \{Lambertus A.\} and Shan Zienolddiny-Narui and Annelie Behndig and Mikael Johansson and Angela Cox and Philip Lazarus and Schabath, \{Matthew B.\} and Aldrich, \{Melinda C.\} and Juncheng Dai and Hongxia Ma and Yang Zhao and Zhibin Hu and Hung, \{Rayjean J.\} and Amos, \{Christopher I.\} and Hongbing Shen and Feng Chen and Christiani, \{David C.\}",

note = "Publisher Copyright: {\textcopyright} 2022 International Association for the Study of Lung Cancer",

year = "2022",

month = aug,

doi = "10.1016/j.jtho.2022.04.011",

language = "English",

volume = "17",

pages = "974--990",

number = "8",

}

Zhang, R, Shen, S, Wei, Y, Zhu, Y, Li, Y, Chen, J, Guan, J, Pan, Z, Wang, Y, Zhu, M, Xie, J, Xiao, X, Zhu, D, Li, Y, Albanes, D, Landi, MT, Caporaso, NE, Lam, S, Tardon, A, Chen, C, Bojesen, SE, Johansson, M, Risch, A, Bickeböller, H, Wichmann, HE, Rennert, G, Arnold, S, Brennan, P, McKay, JD, Field, JK, Shete, SS, Le Marchand, L, Liu, G, Andrew, AS, Kiemeney, LA, Zienolddiny-Narui, S, Behndig, A, Johansson, M, Cox, A, Lazarus, P, Schabath, MB, Aldrich, MC, Dai, J, Ma, H, Zhao, Y, Hu, Z, Hung, RJ, Amos, CI, Shen, H, Chen, F & Christiani, DC 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, vol. 17, no. 8, pp. 974-990. https://doi.org/10.1016/j.jtho.2022.04.011

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.

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 - Cancer risk

KW - GWAS

KW - Gene-gene interaction

KW - Genetic screening model

KW - Lung cancer

KW - Single nucleotide polymorphism

UR - http://www.scopus.com/inward/record.url?scp=85130893494&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85130893494&partnerID=8YFLogxK

U2 - 10.1016/j.jtho.2022.04.011

DO - 10.1016/j.jtho.2022.04.011

M3 - Article

C2 - 35500836

AN - SCOPUS:85130893494

SN - 1556-0864

VL - 17

SP - 974

EP - 990

JO - Journal of Thoracic Oncology

JF - Journal of Thoracic Oncology

IS - 8

ER -

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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