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

• Main Authors: Juan Pablo Fusco, Guillermo Pita, María José Pajares, Maria Pilar Andueza, Ana Patiño‐García, Juan P. de‐Torres, Alfonso Gurpide, Javier Zulueta, Rosario Alonso, Nuria Alvarez, Ruben Pio, Ignacio Melero, Miguel F. Sanmamed, Maria Rodriguez Ruiz, Ignacio Gil‐Bazo, Jose María Lopez‐Picazo, Ciro Casanova, Rebeca Baz Davila, Antonio Agudo, Maria Dolores Lozano, Alvaro Gonzalez, Nuria Sala, Eva Ardanaz, Javier Benitez, Luis Montuenga, Anna Gonzalez‐Neira, Jose Luis Perez‐Gracia
• Format: Article
• Language: English
• Published: Wiley 2018-07-01
• Series: Cancer Medicine
• Subjects: ATP10D; cancer risk; extreme phenotypes; genome‐wide association study; non‐small cell lung cancer; PDE10A
• Online Access: https://doi.org/10.1002/cam4.1500

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 (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.