Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma

Na Qin; Yuancheng Li; Cheng Wang; Meng Zhu; Juncheng Dai; Tongtong Hong; Demetrius Albanes; Stephen Lam; Adonina Tardon; Chu Chen; Gary Goodman; Stig E. Bojesen; Maria Teresa Landi; Mattias Johansson; Angela Risch; H. Erich Wichmann; Heike Bickeboller; Gadi Rennert; Susanne Arnold; Paul Brennan; John K. Field; Sanjay Shete; Loic Le Marchand; Olle Melander; Hans Brunnstrom; Geoffrey Liu; Rayjean J. Hung; Angeline Andrew; Lambertus A. Kiemeney; Shan Zienolddiny; Kjell Grankvist; Mikael Johansson; Neil Caporaso; Penella Woll; Philip Lazarus; Matthew B. Schabath; Melinda C. Aldrich; Victoria L. Stevens; Guangfu Jin; David C. Christiani; Zhibin Hu; Christopher I. Amos; Hongxia Ma; Hongbing Shen

doi:10.1007/s11684-020-0779-4

Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma

Na Qin, Yuancheng Li, Cheng Wang, Meng Zhu, Juncheng Dai, Tongtong Hong, Demetrius Albanes, Stephen Lam, Adonina Tardon, Chu Chen, Gary Goodman, Stig E. Bojesen, Maria Teresa Landi, Mattias Johansson, Angela Risch, H. Erich Wichmann, Heike Bickeboller, Gadi Rennert, Susanne Arnold, Paul BrennanJohn K. Field, Sanjay Shete, Loic Le Marchand, Olle Melander, Hans Brunnstrom, Geoffrey Liu, Rayjean J. Hung, Angeline Andrew, Lambertus A. Kiemeney, Shan Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil Caporaso, Penella Woll, Philip Lazarus, Matthew B. Schabath, Melinda C. Aldrich, Victoria L. Stevens, Guangfu Jin, David C. Christiani, Zhibin Hu, Christopher I. Amos, Hongxia Ma, Hongbing Shen

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

19 Scopus citations

Abstract

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.

Original language	English
Pages (from-to)	275-291
Number of pages	17
Journal	Frontiers of Medicine
Volume	15
Issue number	2
DOIs	https://doi.org/10.1007/s11684-020-0779-4
State	Published - Apr 2021

Bibliographical note

Publisher Copyright:
© 2020, Higher Education Press.

Funding

This study was supported by the Key International (Regional) Cooperative Research Project (No. 81820108028), the National Natural Science Foundation of China (Nos. 81521004, 81922061, 81973123, and 81803306), the Science Foundation for Distinguished Young Scholars of Jiangsu (No. BK20160046), and the Priority Academic Program for the Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine). CARET is funded by the National Cancer Institute, National Institutes of Health of USA through grants U01-CA063673, UM1-CA167462, and U01-CA167462.

Funders	Funder number
Key International (Regional) Cooperative Research Project	81820108028
Natural Science Foundation of Jiangsu Province for Distinguished Young Scholars	BK20160046
National Institutes of Health (NIH)	U01-CA063673
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer Institute	U01CA167462
National Childhood Cancer Registry – National Cancer Institute
National Natural Science Foundation of China (NSFC)	81973123, 81521004, 81922061, 81803306
National Natural Science Foundation of China (NSFC)
Priority Academic Program Development of Jiangsu Higher Education Institutions

Keywords

function annotation
genetic heterogeneity
genome-wide association study
homologous recombination repair deficiency
immune
lung cancer

ASJC Scopus subject areas

General Medicine

UN SDGs

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

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10.1007/s11684-020-0779-4

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Qin, N., Li, Y., Wang, C., Zhu, M., Dai, J., Hong, T., Albanes, D., Lam, S., Tardon, A., Chen, C., Goodman, G., Bojesen, S. E., Landi, M. T., Johansson, M., Risch, A., Wichmann, H. E., Bickeboller, H., Rennert, G., Arnold, S., ... Shen, H. (2021). Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma. Frontiers of Medicine, 15(2), 275-291. https://doi.org/10.1007/s11684-020-0779-4

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title = "Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma",

abstract = "Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.",

keywords = "function annotation, genetic heterogeneity, genome-wide association study, homologous recombination repair deficiency, immune, lung cancer",

author = "Na Qin and Yuancheng Li and Cheng Wang and Meng Zhu and Juncheng Dai and Tongtong Hong and Demetrius Albanes and Stephen Lam and Adonina Tardon and Chu Chen and Gary Goodman and Bojesen, {Stig E.} and Landi, {Maria Teresa} and Mattias Johansson and Angela Risch and Wichmann, {H. Erich} and Heike Bickeboller and Gadi Rennert and Susanne Arnold and Paul Brennan and Field, {John K.} and Sanjay Shete and {Le Marchand}, Loic and Olle Melander and Hans Brunnstrom and Geoffrey Liu and Hung, {Rayjean J.} and Angeline Andrew and Kiemeney, {Lambertus A.} and Shan Zienolddiny and Kjell Grankvist and Mikael Johansson and Neil Caporaso and Penella Woll and Philip Lazarus and Schabath, {Matthew B.} and Aldrich, {Melinda C.} and Stevens, {Victoria L.} and Guangfu Jin and Christiani, {David C.} and Zhibin Hu and Amos, {Christopher I.} and Hongxia Ma and Hongbing Shen",

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year = "2021",

month = apr,

doi = "10.1007/s11684-020-0779-4",

language = "English",

volume = "15",

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Qin, N, Li, Y, Wang, C, Zhu, M, Dai, J, Hong, T, Albanes, D, Lam, S, Tardon, A, Chen, C, Goodman, G, Bojesen, SE, Landi, MT, Johansson, M, Risch, A, Wichmann, HE, Bickeboller, H, Rennert, G, Arnold, S, Brennan, P, Field, JK, Shete, S, Le Marchand, L, Melander, O, Brunnstrom, H, Liu, G, Hung, RJ, Andrew, A, Kiemeney, LA, Zienolddiny, S, Grankvist, K, Johansson, M, Caporaso, N, Woll, P, Lazarus, P, Schabath, MB, Aldrich, MC, Stevens, VL, Jin, G, Christiani, DC, Hu, Z, Amos, CI, Ma, H & Shen, H 2021, 'Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma', Frontiers of Medicine, vol. 15, no. 2, pp. 275-291. https://doi.org/10.1007/s11684-020-0779-4

TY - JOUR

T1 - Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma

AU - Qin, Na

AU - Li, Yuancheng

AU - Wang, Cheng

AU - Zhu, Meng

AU - Dai, Juncheng

AU - Hong, Tongtong

AU - Albanes, Demetrius

AU - Lam, Stephen

AU - Tardon, Adonina

AU - Chen, Chu

AU - Goodman, Gary

AU - Bojesen, Stig E.

AU - Landi, Maria Teresa

AU - Johansson, Mattias

AU - Risch, Angela

AU - Wichmann, H. Erich

AU - Bickeboller, Heike

AU - Rennert, Gadi

AU - Arnold, Susanne

AU - Brennan, Paul

AU - Field, John K.

AU - Shete, Sanjay

AU - Le Marchand, Loic

AU - Melander, Olle

AU - Brunnstrom, Hans

AU - Liu, Geoffrey

AU - Hung, Rayjean J.

AU - Andrew, Angeline

AU - Kiemeney, Lambertus A.

AU - Zienolddiny, Shan

AU - Grankvist, Kjell

AU - Johansson, Mikael

AU - Caporaso, Neil

AU - Woll, Penella

AU - Lazarus, Philip

AU - Schabath, Matthew B.

AU - Aldrich, Melinda C.

AU - Stevens, Victoria L.

AU - Jin, Guangfu

AU - Christiani, David C.

AU - Hu, Zhibin

AU - Amos, Christopher I.

AU - Ma, Hongxia

AU - Shen, Hongbing

PY - 2021/4

Y1 - 2021/4

N2 - Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.

AB - Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.

KW - function annotation

KW - genetic heterogeneity

KW - genome-wide association study

KW - homologous recombination repair deficiency

KW - immune

KW - lung cancer

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UR - http://www.scopus.com/inward/citedby.url?scp=85090192677&partnerID=8YFLogxK

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SN - 2095-0217

VL - 15

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EP - 291

JO - Frontiers of Medicine

JF - Frontiers of Medicine

IS - 2

ER -

Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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