Genetic polymorphisms of long non-coding RNA GAS5 predict platinum-based concurrent chemoradiotherapy response in nasopharyngeal carcinoma patients

Abstract

LncRNA GAS5 plays a tumor suppressive role in a variety of human cancers and promises to be a novel diagnostic biomarker, therapy target, as well as prognostic biomarker. However, the role of GAS5 in nasopharyngeal carcinoma (NPC) remains elusive. The objective of the present study was to evaluate the effect of single nucleotide polymorphisms (SNPs) in GAS5 on treatment efficacy and toxicity in NPC patients receiving chemoradiotherapy. Three potentially functional SNPs of GAS5 were genotyped in 267 NPC patients and validated in another 238 NPC patients treated with chemoradiotherapy from southern China. Multivariate logistic regression analyses and stratification analyses were used to estimate the association of candidate SNPs and chemoradiotherapy efficacy and toxic reactions. Our results showed that rs2067079 kept a consistent association with severe myelosuppression and severe neutropenia in discovery set (OR=2.403, P=0.009; OR=2.454, P=0.015; respectively), validation set (OR=3.653, P=0.027; OR=4.767, P=0.016; respectively), and combined dataset (OR=1.880, P=0.007; OR=2.079, P=0.005; respectively). rs2067079 CT genotype carriers presented an even more remarkable increased risk of severe myelosuppression (OR=3.878, P=0.003) and severe neutropenia (OR=3.794, P=0.009) in subgroups taking paclitaxel+platinum as concurrent chemoradiotherapy regimen. Besides, we found a gene-does effect of rs6790, with the incidence rate of severe myelosuppression decreased from 23.56% to 17.21% to 10% and the incidence rate of severe neutropenia decreased from 30.4% to 20.9% to 17.1% for rs6790 GG vs GA vs AA genotype carriers. Our results indicate the potential role of lncRNA GAS5 polymorphisms rs2067079 and rs6790 as predictive biomarkers for chemoradiotherapy induced toxic reactions in NPC patients.

Keywords: GAS5; chemoradiotherapy; nasopharyngeal carcinoma; polymorphisms; toxicity.

Figure 1

Gene-dose effect of rs6790 on concurrent chemoradiotherapy induced severe neutropenia (A) and severe myelosupression (B) in NPC patients.

Figure 2. ROC curves showing the discriminatory power to predict chemoradiotherapy induced severe toxicities

Figure 3. The predicted effect of rs2067079 on GAS5 secondary structure

(A) Minimum free energy structures of the wild-type GAS5. (B) Minimum free energy structures of the mutant-type GAS5. (C) Dot plot of the GAS5 rs2067079 global structure. The upper and lower triangle of the matrix represents the base pair probabilities of wild-type and mutant sequences, respectively. The asymmetry of the two triangle matrix indicates the difference in their structure change.