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 log e HR 5 0.31; 95% CI: 0.15-0.46, p 5 8.5 3 10 25). 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.

A Decade of GWAS Results in Lung Cancer

“…So far, GWAS on lung cancer survival were performed in patients with early-stage NSCLC (58, 59), advanced-stage NSCLC (60–63), and SCLC (64). GWAS were also performed in more specific subgroups of lung cancer patients including never smokers with NSCLC (65) and patients with lung adenocarcinoma (66). Together, these studies have identified 23 loci associated with lung cancer survival (Supplementary Table S1).…”

Regulative Loop between β-catenin and Protein Tyrosine Receptor Type γ in Chronic Myeloid Leukemia

“…PTPRG is widely expressed in human tissues [6] and is involved in the regulation of cell growth, differentiation, mitotic cycle, and oncogenic transformation [7,8]. The gene encoding for this phosphatase is located in a chromosomal region (3p21-p14), frequently deleted in renal cell and lung carcinoma, where PTPRG acts as a tumor suppressor [9][10][11]. Epigenetic events, such as hyper-methylation of its promoter region, negatively regulates the transcription of PTPRG, as demonstrated in CML and childhood acute lymphoblastic leukemia [12,13] Re-expression of this protein occurs in the leukocytes of CML patients following targeted therapy [12].…”

Genetic susceptibility variants for lung cancer: replication study and assessment as expression quantitative trait loci

“…These materials were stored in the biobank of Fondazione IRCCS Istituto Nazionale dei Tumori. Methods for the collection of samples and associated clinical data have already been reported 15 20 57 . The Committees for Ethics of the institutes involved in recruitment (Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, Ospedale San Giuseppe, Milan, Italy, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy) approved the protocol for collecting samples and clinical data.…”

“…Moreover, rs667282 in CHRNA5 has recently been proposed as a modifier of prognosis in advanced NSCLC 19 . Several other SNPs, found using a GWAS approach, were proposed to be associated with prognosis or survival of lung cancer patients in different populations 20 21 22 23 . However, these studies did not identify the same candidate polymorphisms, which may be due (at least in part) to the wide genetic heterogeneity of the human population.…”