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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11130%2F18%3A10381211" target="_blank" >RIV/00216208:11130/18:10381211 - isvavai.cz</a>

Alternative codes found

RIV/61989592:15120/18:73589923

Result on the web

<a href="https://doi.org/10.1016/j.jtho.2018.06.016" target="_blank" >https://doi.org/10.1016/j.jtho.2018.06.016</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.jtho.2018.06.016" target="_blank" >10.1016/j.jtho.2018.06.016</a>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30304 - Public and environmental health

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2018

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Journal of Thoracic Oncology

ISSN

1556-0864

e-ISSN

—

Volume of the periodical

13

Issue of the periodical within the volume

10

Country of publishing house

US - UNITED STATES

Number of pages

13

Pages from-to

1483-1495

UT code for WoS article

000445154800018

EID of the result in the Scopus database

2-s2.0-85051695595