Genomic characterization of individuals presenting extreme phenotypes of high and low risk to develop tobacco‐induced lung cancer

Abstract

Abstract Single nucleotide polymorphisms ( SNP s) may modulate individual susceptibility to carcinogens. We designed a genome‐wide association study to characterize individuals presenting extreme phenotypes of high and low risk to develop tobacco‐induced non‐small cell lung cancer ( NSCLC ), and we validated our results. We hypothesized that this strategy would enrich the frequencies of the alleles that contribute to the observed traits. We genotyped 2.37 million SNP s in 95 extreme phenotype individuals, that is: heavy smokers that either developed NSCLC at an early age (extreme cases); or did not present NSCLC at an advanced age (extreme controls), selected from a discovery set ( n = 3631). We validated significant SNP s in 133 additional subjects with extreme phenotypes selected from databases including >39,000 individuals. Two SNP s were validated: rs12660420 ( p combined = 5.66 × 10 −5 ; OR combined = 2.80), mapping to a noncoding transcript exon of PDE 10A ; and rs6835978 ( p combined = 1.02 × 10 −4 ; OR combined = 2.57), an intronic variant in ATP 10D . We assessed the relevance of both proteins in early‐stage NSCLC . PDE 10A and ATP 10D mRNA expressions correlated with survival in 821 stage I– II NSCLC patients ( p = 0.01 and p < 0.0001). PDE 10A protein expression correlated with survival in 149 patients with stage I– II NSCLC ( p = 0.002). In conclusion, we validated two variants associated with extreme phenotypes of high and low risk of developing tobacco‐induced NSCLC . Our findings may allow to identify individuals presenting high and low risk to develop tobacco‐induced NSCLC and to characterize molecular mechanisms of carcinogenesis and resistance to develop NSCLC .