J Natl Cancer Inst. 2022 May 2:djac087. doi: 10.1093/jnci/djac087. Online ahead of print.
ABSTRACT
BACKGROUND: Germline genetic variation contributes to lung cancer (LC) susceptibility. Previous genome-wide association studies (GWAS) have implicated susceptibility loci involved in smoking propensity and DNA repair genes, but further work is required to identify susceptibility variants.
METHODS: To identify LC susceptibility loci, a family history-based genome-wide association (GWAx) study of LC (48,843 European “proxy” LC cases, 195,387 controls) was combined with previously LC GWAS (29,266 cases, 56,450 controls) by meta-analysis. Colocalisation was used to explore candidate genes and overlap with existing traits at discovered susceptibility loci. Polygenic Risk Scores (PRS) were tested within an independent validation cohort (1,666 LC cases vs 6,664 controls) using variants selected from the LC susceptibility loci and a novel selection approach using published GWAS summary statistics. Finally, the effects of the LC PRS on somatic mutational burden were explored in patients whose tumour resections have been profiled by exome (n = 685) and genome sequencing (n = 61). Statistical tests were 2-sided.
RESULTS: The GWAx-GWAS meta-analysis identified 8 novel LC loci. Colocalization implicated DNA repair genes (CHEK1), metabolic genes (CYP1A1) and smoking propensity (CHRNA4 and CHRNB2). PRS analysis demonstrated that these variants, as well as sub-genome wide significant variants related to eQTLs and/or smoking propensity, assisted in LC genetic risk prediction (OR = 1.37, 95% CI 1.29-1.45, P = 1.44 x10-25). Patients with higher genetic PRS loads of smoking-related variants tended to have higher mutation burdens in their lung tumours.
CONCLUSIONS: This study has expanded the number of LC susceptibility loci and provided insights into the molecular mechanisms by which these susceptibility variants contribute to LC development.
PMID:35511172 | DOI:10.1093/jnci/djac087
