2026-06-14T03:43:04Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/66572024-11-30T01:12:22Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Fusco, Juan Pablo author Pita, Guillermo author Pajares, María José author Andueza, Maria Pilar author Patiño-García, Ana author de-Torres, Juan P author Gurpide, Alfonso author Zulueta, Javier author Alonso, Rosario author Alvarez, Nuria author Pio, Ruben author Melero, Ignacio author Sanmamed, Miguel F author Rodriguez Ruiz, Maria author Gil-Bazo, Ignacio author Lopez-Picazo, Jose María author Casanova, Ciro author Baz Davila, Rebeca author Agudo, Antonio author Lozano, Maria Dolores author Gonzalez, Alvaro author Sala, Nuria author Ardanaz, Eva author Benitez, Javier author Montuenga, Luis author Gonzalez Neira, Anna author Perez-Gracia, Jose Luis author 2018-05-15 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 < 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. Cancer Med. 2018; 10.1002/cam4.1500 2045-7634 20457634 Cancer medicine 29766673 http://hdl.handle.net/20.500.12105/6657 ATP10D PDE10A cancer risk extreme phenotypes genome-wide association study non-small cell lung cancer single nucleotide polymorphism tobacco Genomic characterization of individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced lung cancer