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

Abstract

Single nucleotide polymorphisms (SNPs) 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 SNPs 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 SNPs in 133 additional subjects with extreme phenotypes selected from databases including >39,000 individuals. Two SNPs were validated: rs12660420 (p combined = 5.66 × 10−5; OR combined = 2.80), mapping to a noncoding transcript exon of PDE10A; and rs6835978 (p combined = 1.02 × 10−4; OR combined = 2.57), an intronic variant in ATP10D. We assessed the relevance of both proteins in early‐stage NSCLC. PDE10A and ATP10D mRNA expressions correlated with survival in 821 stage I–II NSCLC patients (p = 0.01 and p < 0.0001). PDE10A 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.

Phosphodiesterase 10A Is a Key Mediator of Lung Inflammation

“…Increased neutrophil numbers, as well as high MPO and cytokine levels in BAL fluid, are hallmarks of the inflammatory response in ALI. Interestingly, recent genome-wide association studies indicated that PDE10A is a candidate gene for asthma in mice and human (49,50) as well as smoking-induced lung cancer (51). Thus, our current findings together with previous reports suggest a critical role of PDE10A induction in pulmonary pathology.…”

Whole exome sequencing characterization of individuals presenting extreme phenotypes of high and low risk of developing tobacco-induced lung adenocarcinoma

“…In a previous study we applied the same methodology, studying as extreme cases individuals with non-small lung cancer, rather than exclusively adenocarcinoma; and assessing the germline DNA through Genome Wide Association Study (GWAS) (39). We identified and validated two new genetic variants in ATP10D and PDE10A which were differentially expressed in individuals presenting the extreme phenotypes assessed, and we confirmed the prognostic relevance of the associated proteins in early stage non-small cell lung cancer.…”

Biomarkers in Lung Cancer Screening: Achievements, Promises, and Challenges

“…95 Clinical applications aside, these susceptibility genes do provide an insight into the biological process and association with specific diseases, which are relevant to lung cancer etiology. 96,97 Clearly, there is a wealth of information captured within the current genome-wide association studies' data sets. Taking advantage of it will depend on state-of-the-art mathematical and statistical approaches capable of incorporating large numbers of single-nucleotide polymorphisms into risk models, artificial intelligence, and supervised machine learning approaches.…”