Systematic analyses of regulatory variants in DNase I hypersensitive sites identified two novel lung cancer susceptibility loci

被引：9

作者：

Dai, Juncheng ^{[1
,2
]}

Li, Zhihua ^{[1
,3
]}

Amos, Christopher I. ^{[4
]}

Hung, Rayjean J. ^{[5
,6
]}

Tardon, Adonina ^{[7
,8
]}

Andrew, Angeline S. ^{[9
]}

Chen, Chu ^{[10
]}

Christiani, David C. ^{[11
,12
]}

Albanes, Demetrios ^{[13
]}

van der Heijden, Erik H. F. M. ^{[14
]}

Duell, Eric J. ^{[15
]}

Rennert, Gad ^{[16
]}

Mckay, James D. ^{[17
]}

Yuan, Jian-Min ^{[18
]}

Field, John K. ^{[19
]}

Manjer, Jonas ^{[20
,21
]}

Grankvist, Kjell ^{[22
]}

Le Marchand, Loic ^{[23
]}

Teare, M. Dawn ^{[24
]}

Schabath, Matthew B. ^{[25
]}

Aldrich, Melinda C. ^{[26
]}

Tsao, Ming-Sound ^{[27
]}

Lazarus, Philip ^{[28
]}

Lam, Stephen ^{[29
]}

Bojesen, Stig E. ^{[30
,31
,32
]}

Arnold, Susanne ^{[33
]}

Wu, Xifeng ^{[34
]}

Haugen, Aage ^{[35
]}

Janout, Vladimir ^{[36
]}

Johansson, Mikael ^{[37
]}

Brhane, Yonathan ^{[5
,6
]}

Fernandez-Somoano, Ana ^{[7
,8
]}

Kiemeney, Lambertus A. ^{[14
]}

Davies, Michael P. A. ^{[19
]}

Zienolddiny, Shanbeh ^{[35
]}

Hu, Zhibin ^{[1
,2
]}

Shen, Hongbing ^{[1
,2
]}

机构：

[1] Nanjing Med Univ, Dept Epidemiol, Ctr Global Hlth, Int Joint Res Ctr,Sch Publ Hlth, Nanjing 211166, Jiangsu, Peoples R China

[2] Nanjing Med Univ, Jiangsu Key Lab Canc Biomarkers Prevent & Treatme, Jiangsu Collaborat Innovat Ctr Canc Personalized, Nanjing 211166, Jiangsu, Peoples R China

[3] Nanjing Med Univ, Dept Thorac Surg, Affiliated Hosp 1, Nanjing, Jiangsu, Peoples R China

[4] Dartmouth Coll, Biomed Data Sci, Geisel Sch Med, Hanover, NH 03755 USA

[5] Univ Toronto, Lunenfeld Tanenbaum Res Inst, Sinai Hlth Syst, Toronto, ON, Canada

[6] Univ Toronto, Div Epidemiol, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada

[7] Univ Oviedo, Fac Med, IUOPA, Oviedo, Spain

[8] CIBERESP, Oviedo, Spain

[9] Geisel Sch Med, Norris Cotton Canc Ctr, Hanover, NH USA

[10] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA

[11] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA

[12] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA

[13] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA

[14] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Nijmegen, Netherlands

[15] ICO, Unit Nutr & Canc, Barcelona, Spain

[16] Carmel Hosp, Clalit Natl Canc Control Ctr, Haifa, Israel

[17] WHO, IARC, Lyon, France

[18] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA

[19] Univ Liverpool, Roy Castle Lung Canc Res Programme, Dept Mol & Clin Canc Med, William Duncan Bldg, Liverpool L7 8TX, Merseyside, England

[20] Lund Univ, Unit Breast Surg, Dept Surg, Malmo, Sweden

[21] Skane Univ Hosp, Dept Surg, Malmo, Sweden

[22] Umea Univ, Dept Med Biosci, Umea, Sweden

[23] Univ Hawaii, Ctr Canc, Epidemiol Program, Honolulu, HI 96822 USA

[24] Univ Sheffield, Sch Hlth & Related Res, Sheffield, S Yorkshire, England

[25] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA

[26] Vanderbilt Univ, Med Ctr, Dept Thorac Surg, Div Epidemiol, Nashville, TN USA

[27] Princess Margaret Canc Ctr, Toronto, ON, Canada

[28] Washington State Univ, Dept Pharmaceut Sci, Coll Pharm, Spokane, WA USA

[29] British Columbia Canc Agcy, Vancouver, BC, Canada

[30] Copenhagen Univ Hosp, Copenhagen Gen Populat Study, Herlev & Gentofte Hosp, Copenhagen, Denmark

[31] Copenhagen Univ Hosp, Dept Clin Biochem, Herlev & Gentofte Hosp, Copenhagen, Denmark

[32] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark

[33] Markey Canc Ctr, Div Med Oncol, Lexington, KY USA

[34] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA

[35] Natl Inst Occupat Hlth STAMI, Dept Chem & Biol Work Environm, Oslo, Norway

[36] Palacky Univ, Dept Epidemiol & Publ Hlth, Fac Hlth Sci, Olomouc, Czech Republic

[37] Umea Univ, Dept Radiat Sci, Umea, Sweden

来源：

CARCINOGENESIS | 2019年 / 40卷 / 03期

关键词：

POTENTIAL THERAPEUTIC TARGET; ASSOCIATION; RISK; GENE; EXPRESSION; HETEROGENEITY; C20ORF20; PROTEIN; RARE; 20Q;

D O I：

10.1093/carcin/bgy187

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

DNase I hypersensitive sites (DHS) are abundant in regulatory elements, such as promoter, enhancer and transcription factor binding sites. Many studies have revealed that disease-associated variants were concentrated in DHS-related regions. However, limited studies are available on the roles of DHS-related variants in lung cancer. In this study, we performed a large-scale case-control study with 20 871 lung cancer cases and 15 971 controls to evaluate the associations between regulatory genetic variants in DHS and lung cancer susceptibility. The expression quantitative trait loci (eQTL) analysis and pathway-enrichment analysis were performed to identify the possible target genes and pathways. In addition, we performed motif-based analysis to explore the lung-cancer-related motifs using sequence kernel association test. Two novel variants, rs186332 in 20q13.3 (C>T, odds ratio [OR] = 1.17, 95% confidence interval [95% CI]: 1.10-1.24, P = 8.45 x 10(-7)) and rs4839323 in 1p13.2 (T>C, OR = 0.92, 95% CI: 0.89-0.95, P = 1.02 x 10(-6)) showed significant association with lung cancer risk. The eQTL analysis suggested that these two SNPs might regulate the expression of MRGBP and SLC16A1, respectively. What's more, the expression of both MRGBP and SLC16A1 was aberrantly elevated in lung tumor tissues. The motif-based analysis identified 10 motifs related to the risk of lung cancer (P < 1.71 x 10(-4)). Our findings suggested that variants in DHS might modify lung cancer susceptibility through regulating the expression of surrounding genes. This study provided us a deeper insight into the roles of DHS-related genetic variants for lung cancer.

引用

页码：432 / 440

页数：9

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