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Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer
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July 04 2018
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Source: J Thorac Oncol. 13(10):1483-1495
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Alternative Title:J Thorac Oncol
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Description:Background:
Genome-wide association studies (GWAS) 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 causal LC variants, we performed focused exome sequencing analyses on genes located in 121 GWAS loci previously implicated in the risk of LC, chronic obstructive pulmonary disease, pulmonary function level and smoking behavior.
Methods:
Germline DNA from 260 LC cases and 318 controls were sequenced utilizing VCRome 2.1 exome capture. Filtering was based upon 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 1,773 cases and 1,123 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 BRCA2 K3326X (OR 2.36, 95% CI 1.38 - 3.99) and three newly identified variations: LTB p.Leu87Phe (OR 7.52, 95% CI 1.01 - 16.56), P3H2 p.Gln185His (OR 5.39, 95% CI 0.75 - 15.43), and DAAM2 p.Asp762Gly (OR 0.25, 95% CI 0.10 - 0.79). Burden tests revealed strong associations between ZNF93, DAAM2, BRD9, and LTB genes 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.
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Pubmed ID:29981437
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Pubmed Central ID:PMC6366341
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Volume:13
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Issue:10
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