title: Germline polymorphisms and survival of lung adenocarcinoma patients: a genome-wide study in two European patient series.
abstract: In lung cancer, the survival of patients with the same clinical stage varies widely for unknown reasons. In this two-phase study, we examined the hypothesis that germline variations influence the survival of patients with lung adenocarcinoma. First, we analyzed existing genotype and clinical data from 289 UK-resident patients with lung adenocarcinoma, identifying 86 single nucleotide polymorphisms (SNPs) that associated with survival (p < 0.01). We then genotyped these candidate SNPs in a validation series of 748 patients from Italy that resulted genetically compatible with the UK series based on principal component analysis. In a Cox proportional hazard model adjusted for age, sex and clinical stage, four SNPs were confirmed on the basis of their having a hazard ratio (HR) indicating the same direction of effect in the two series and p < 0.05. The strongest association was provided by rs2107561, an intronic SNP of PTPRG, protein tyrosine phosphatase, receptor type, G; the C allele was associated with poorer survival in both patient series (pooled analysis loge HR = 0.31; 95% CI: 0.15-0.46, p = 8.5 × 10(-5) ). PTPRG mRNA levels in 43 samples of lung adenocarcinoma were 40% of those observed in noninvolved lung tissue from the same patients. PTPRG overexpression significantly inhibited the clonogenicity of A549 lung carcinoma cells and the anchorage-independent growth of the NCI-H460 large cell lung cancer line. These four germline variants represent promising candidates that, with further study, may help predict clinical outcome. In addition, the PTPRG locus may have a role in tumor progression.
authors.affiliation: Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Galvan
authors.forename: Francesca
authors.initials: F
authors.lastname: Colombo
authors.forename: Elisa
authors.initials: E
authors.lastname: Frullanti
authors.forename: Alice
authors.initials: A
authors.lastname: Dassano
authors.forename: Sara
authors.initials: S
authors.lastname: Noci
authors.forename: Yufei
authors.initials: Y
authors.lastname: Wang
authors.forename: Timothy
authors.initials: T
authors.lastname: Eisen
authors.forename: Athena
authors.initials: A
authors.lastname: Matakidou
authors.forename: Luisa
authors.initials: L
authors.lastname: Tomasello
authors.forename: Marzia
authors.initials: M
authors.lastname: Vezzalini
authors.forename: Claudio
authors.initials: C
authors.lastname: Sorio
authors.forename: Matteo
authors.initials: M
authors.lastname: Dugo
authors.forename: Federico
authors.initials: F
authors.lastname: Ambrogi
authors.forename: Ilaria
authors.initials: I
authors.lastname: Iacobucci
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.forename: Matteo
authors.initials: M
authors.lastname: Incarbone
authors.forename: Marco
authors.initials: M
authors.lastname: Alloisio
authors.forename: Mario
authors.initials: M
authors.lastname: Nosotti
authors.forename: Davide
authors.initials: D
authors.lastname: Tosi
authors.forename: Luigi
authors.initials: L
authors.lastname: Santambrogio
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pelosi
authors.forename: Ugo
authors.initials: U
authors.lastname: Pastorino
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
authors.forename: Tommaso A
authors.initials: TA
authors.lastname: Dragani
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000235:genetics*; D015996:Survival Rate; D054928:Validation Studies as Topic; D044465:White People
chemical_list: D014408:Biomarkers, Tumor; C516850:PTPRG protein, human; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5
keywords: PTPRG; clinical stage; clonogenicity; genome-wide association; prognostic markers; tumor progression