Germline polymorphisms and survival of lung adenocarcinoma patients: a genome-wide study in two European patient series

Int J Cancer. 2015 Mar 1;136(5):E262-71. doi: 10.1002/ijc.29195. Epub 2014 Sep 19.

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.

Keywords: PTPRG; clinical stage; clonogenicity; genome-wide association; prognostic markers; tumor progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / mortality*
  • Adenocarcinoma / pathology
  • Biomarkers, Tumor / genetics
  • European Continental Ancestry Group
  • Follow-Up Studies
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study*
  • Germ-Line Mutation / genetics*
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / mortality*
  • Lung Neoplasms / pathology
  • Neoplasm Staging
  • Polymorphism, Single Nucleotide / genetics*
  • Prognosis
  • Receptor-Like Protein Tyrosine Phosphatases, Class 5 / genetics*
  • Survival Rate
  • Validation Studies as Topic

Substances

  • Biomarkers, Tumor
  • PTPRG protein, human
  • Receptor-Like Protein Tyrosine Phosphatases, Class 5