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

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

I: Frontiers of Medicine, Bind 15, Nr. 2, 2021, s. 275-291.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

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, bind 15, nr. 2, s. 275-291. https://doi.org/10.1007/s11684-020-0779-4

APA

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

Vancouver

Qin N, Li Y, Wang C, Zhu M, Dai J, Hong T o.a. Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma. Frontiers of Medicine. 2021;15(2):275-291. https://doi.org/10.1007/s11684-020-0779-4

Author

Qin, Na ; Li, Yuancheng ; Wang, Cheng ; Zhu, Meng ; Dai, Juncheng ; Hong, Tongtong ; Albanes, Demetrius ; Lam, Stephen ; Tardon, Adonina ; Chen, Chu ; Goodman, Gary ; Bojesen, Stig E. ; Landi, Maria Teresa ; Johansson, Mattias ; Risch, Angela ; Wichmann, H. Erich ; Bickeboller, Heike ; Rennert, Gadi ; Arnold, Susanne ; Brennan, Paul ; Field, John K. ; Shete, Sanjay ; Le Marchand, Loic ; Melander, Olle ; Brunnstrom, Hans ; Liu, Geoffrey ; Hung, Rayjean J. ; Andrew, Angeline ; Kiemeney, Lambertus A. ; Zienolddiny, Shan ; Grankvist, Kjell ; Johansson, Mikael ; Caporaso, Neil ; Woll, Penella ; Lazarus, Philip ; Schabath, Matthew B. ; Aldrich, Melinda C. ; Stevens, Victoria L. ; Jin, Guangfu ; Christiani, David C. ; Hu, Zhibin ; Amos, Christopher I. ; Ma, Hongxia ; Shen, Hongbing. / Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma. I: Frontiers of Medicine. 2021 ; Bind 15, Nr. 2. s. 275-291.

Bibtex

@article{6230ff8db0e24e5d80621451243e7b00,
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",
note = "Funding Information: 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. Publisher Copyright: {\textcopyright} 2020, Higher Education Press.",
year = "2021",
doi = "10.1007/s11684-020-0779-4",
language = "English",
volume = "15",
pages = "275--291",
journal = "Frontiers of Medicine",
issn = "2095-0217",
publisher = "Springer Science+Business Media",
number = "2",

}

RIS

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

N1 - Funding Information: 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. Publisher Copyright: © 2020, Higher Education Press.

PY - 2021

Y1 - 2021

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

U2 - 10.1007/s11684-020-0779-4

DO - 10.1007/s11684-020-0779-4

M3 - Journal article

C2 - 32889700

AN - SCOPUS:85090192677

VL - 15

SP - 275

EP - 291

JO - Frontiers of Medicine

JF - Frontiers of Medicine

SN - 2095-0217

IS - 2

ER -

ID: 301346773