Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer

被引：26

作者：

Liu, Yanhong ^{[1
]}

Lusk, Christine M. ^{[2
]}

Cho, Michael H. ^{[3
,4
]}

Silverman, Edwin K. ^{[3
,4
]}

Qiao, Dandi ^{[3
,4
]}

Zhang, Ruyang ^{[5
]}

Scheurer, Michael E. ^{[6
]}

Kheradmand, Farrah ^{[1
,7
]}

Wheeler, David A. ^{[8
]}

Tsavachidis, Spiridon ^{[1
]}

Armstrong, Georgina ^{[1
]}

Zhu, Dakai ^{[1
,9
]}

Wistuba, Ignacio I. ^{[10
]}

Chow, Chi-Wan B. ^{[10
]}

Behrens, Carmen ^{[11
]}

Pikielny, Claudio W. ^{[12
]}

Neslund-Dudas, Christine ^{[13
]}

Pinney, Susan M. ^{[14
]}

Anderson, Marshall ^{[14
]}

Kupert, Elena ^{[14
]}

Bailey-Wilson, Joan ^{[15
]}

Gaba, Colette ^{[16
]}

Mandal, Diptasri ^{[17
]}

You, Ming ^{[18
]}

de Andrade, Mariza ^{[19
]}

Yang, Ping ^{[19
]}

Field, John K. ^{[20
]}

Liloglou, Triantafillos ^{[20
]}

Davies, Michael ^{[20
]}

Lissowska, Jolanta ^{[21
]}

Swiatkowska, Beata ^{[22
]}

Zaridze, David ^{[23
]}

Mukeriya, Anush ^{[23
]}

Janout, Vladimir ^{[24
]}

Holcatova, Ivana ^{[25
]}

Mates, Dana ^{[26
]}

Milosavljevic, Sasa ^{[27
]}

Scelo, Ghislaine ^{[28
]}

Brennan, Paul ^{[28
]}

McKay, James ^{[28
]}

Liu, Geoffrey ^{[29
]}

Hung, Rayjean J. ^{[30
]}

Christiani, David C. ^{[5
]}

Schwartz, Ann G. ^{[2
]}

Amos, Christopher I. ^{[1
,9
]}

Spitz, Margaret R. ^{[1
]}

机构：

[1] Baylor Coll Med, Dept Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX 77030 USA

[2] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA

[3] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA

[4] Harvard Med Sch, Boston, MA USA

[5] Harvard Univ, Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA

[6] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA

[7] Michael E DeBakey VA Med Ctr, Houston, TX USA

[8] Baylor Coll Med, Dept Mol & Human Genet, Human Genome Sequence Ctr, Houston, TX 77030 USA

[9] Baylor Coll Med, Inst Clin & Translat Res, Houston, TX 77030 USA

[10] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA

[11] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA

[12] Dartmouth Coll, Geisel Sch Med, Dept Biomed Data Sci, 1 Med Ctr Dr, Lebanon, NH 03756 USA

[13] Henry Ford Hlth Syst, Dept Publ Hlth Sci, Detroit, MI USA

[14] Univ Cincinnati, Coll Med, Cincinnati, OH USA

[15] Natl Human Genome Res Inst, Bethesda, MD USA

[16] Univ Toledo, Coll Med, 2801 W Bancroft St, Toledo, OH 43606 USA

[17] Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA

[18] Med Coll Wisconsin, Milwaukee, WI 53226 USA

[19] Mayo Clin, Coll Med, Rochester, MN USA

[20] Univ Liverpool, Dept Mol & Clin Canc Med, Roy Castle Lung Canc Res Programme, Liverpool, Merseyside, England

[21] Maria Sklodowska Curie Inst Oncol Ctr, Warsaw, Poland

[22] Nofer Inst Occupat Med, Dept Environm Epidemiol, Lodz, Poland

[23] Russian NN Blokhin Canc Res Ctr, Moscow, Russia

[24] Palacky Univ, Fac Hlth Sci, Olomouc, Czech Republic

[25] Charles Univ Prague, Fac Med 2, Inst Publ Hlth & Prevent Med, Prague, Czech Republic

[26] Natl Inst Publ Hlth, Bucharest, Romania

[27] Int Org Canc Prevent & Res, Belgrade, Serbia

[28] Int Agcy Res Canc, Lyon, France

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

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

来源：

JOURNAL OF THORACIC ONCOLOGY | 2018年 / 13卷 / 10期

基金：

美国国家卫生研究院;

关键词：

Exome sequencing; Rare variants; Lung cancer; Susceptibility loci; GENOME-WIDE ASSOCIATION; BRCA2; MUTATION; REVEALS; IMPACT;

D O I：

10.1016/j.jtho.2018.06.016

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: Genome-wide association studies are widely used to map genomic regions contributing to lung cancer (LC) susceptibility, but they typically do not identify the precise disease-causing genes/variants. To unveil the inherited genetic variants that cause LC, we performed focused exome-sequencing analyses on genes located in 121 genome-wide association study-identified loci previously implicated in the risk of LC, chronic obstructive pulmonary disease, pulmonary function level, and smoking behavior. Methods: Germline DNA from 260 case patients with LC and 318 controls were sequenced by utilizing VCRome 2.1 exome capture. Filtering was based on enrichment of rare and potential deleterious variants in cases (risk alleles) or controls (protective alleles). Allelic association analyses of single-variant and gene-based burden tests of multiple variants were performed. Promising candidates were tested in two independent validation studies with a total of 1773 case patients and 1123 controls. Results: We identified 48 rare variants with deleterious effects in the discovery analysis and validated 12 of the 43 candidates that were covered in the validation platforms. The top validated candidates included one well-established truncating variant, namely, BRCA2, DNA repair associated gene (BRCA2) K3326X (OR = 2.36, 95% confidence interval [CI]: 1.38-3.99), and three newly identified variations, namely, lymphotoxin beta gene (LTB) p.Leu87Phe (OR = 7.52, 95% CI: 1.01-16.56), prolyl 3-hydroxylase 2 gene (P3H2) p.Gln185His (OR = 5.39, 95% CI: 0.75-15.43), and dishevelled associated activator of morphogenesis 2 gene (DAAM2) p.Asp762Gly (OR = 0.25, 95% CI: 0.10-0.79). Burden tests revealed strong associations between zinc finger protein 93 gene (ZNF93), DAAM2, bromodomain containing 9 gene (BRD9), and the gene LTB and LC susceptibility. Conclusion: Our results extend the catalogue of regions associated with LC and highlight the importance of germline rare coding variants in LC susceptibility. (C) 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

引用

页码：1483 / 1495

页数：13

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