Genomic characterization of individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced lung cancer.
Fusco JP., Pita G., Pajares MJ., Andueza MP., Patiño-García A., de-Torres JP., Gurpide A., Zulueta J., Alonso R., Alvarez N., Pio R., Melero I., Sanmamed MF., Rodriguez Ruiz M., Gil-Bazo I., Lopez-Picazo JM., Casanova C., Baz Davila R., Agudo A., Lozano MD., Gonzalez A., Sala N., Ardanaz E., Benitez J., Montuenga L., Gonzalez-Neira A., Perez-Gracia JL.
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 (pcombined = 5.66 × 10-5 ; ORcombined = 2.80), mapping to a noncoding transcript exon of PDE10A; and rs6835978 (pcombined = 1.02 × 10-4 ; ORcombined = 2.57), an intronic variant in ATP10D. We assessed the relevance of both proteins in early-stage NSCLC. PDE10A and ATP10DmRNA expressions correlated with survival in 821 stage I-II NSCLC patients (p = 0.01 and p