Genetic Variations in the Regulator of G-Protein Signaling Genes Are Associated with Survival in Late-Stage Non-Small Cell Lung Cancer

Jingyao Dai,Charles Lu,Jie Lin,Xifeng Wu,Jack A Roth,Jian Gu,David Chang,David Stewart,Lin Zhang

doi:10.1371/journal.pone.0021120

Abstract

The regulator of G-protein signaling (RGS) pathway plays an important role in signaling transduction, cellular activities, and carcinogenesis. We hypothesized that genetic variations in RGS gene family may be associated with the response of late-stage non-small cell lung cancer (NSCLC) patients to chemotherapy or chemoradiotherapy. We selected 95 tagging single nucleotide polymorphisms (SNPs) in 17 RGS genes and genotyped them in 598 late-stage NSCLC patients. Thirteen SNPs were significantly associated with overall survival. Among them, rs2749786 of RGS12 was most significant. Stratified analysis by chemotherapy or chemoradiation further identified SNPs that were associated with overall survival in subgroups. Rs2816312 of RGS1 and rs6689169 of RGS7 were most significant in chemotherapy group and chemoradiotherapy group, respectively. A significant cumulative effect was observed when these SNPs were combined. Survival tree analyses identified potential interactions between rs944343, rs2816312, and rs1122794 in affecting survival time in patients treated with chemotherapy, while the genotype of rs6429264 affected survival in chemoradiation-treated patients. To our knowledge, this is the first study to reveal the importance of RGS gene family in the survival of late-stage NSCLC patients.

Highlights

Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide [1]
The variant alleles of four single nucleotide polymorphisms (SNPs), rs7549021 and rs1056515 of RGS5, rs944343 of RGS3, and rs2749786 of RGS12, were associated with decreased risks of death, with adjusted hazard ratio (HR) of 0.42, 0.72, 0.80, and 0.58, respectively
We found that only 5 SNPs, rs944343 (RGS3), rs6678136 (RGS4), rs7549021 (RGS5), rs3820487 (RGS5), and rs2749786 (RGS12), had bootstrap P values,0.05 at least 70 times out of 100 times (Table 2)

Summary

Introduction

Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide [1]. Over 45% of NSCLC patients present with unresectable late-stage (stage IIIA/B or stage IV) disease in the United States [2]. A combined modality therapy is the current standard of care for patients with stage III NSCLC with good performance status (performance score 0 or 1). Numerous clinical trials have shown that concurrent chemoradiation offers a significant survival advantage over sequential chemoradiation [3]. The stage IV patients are usually offered palliative chemotherapy and supportive care [5]. The application of pharmacogenomics may improve the prediction of response and help clinicians determine cancer treatments for individual NSCLC patient according to his unique genetic background. In this study, we aimed to identify genetic predictors for clinical outcomes of late stage NSCLC patients

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Methods

Conclusion