Genetic polymorphisms of lncRNA-p53 regulatory network genes are associated with concurrent chemoradiotherapy toxicities and efficacy in nasopharyngeal carcinoma patients

Abstract

The relevance of the transcription factor p53 in cancer is inarguable, and numerous lncRNAs are involved in the p53 regulatory network as either regulators or effectors, triggering a transcriptional response that causes either cell arrest or apoptosis following DNA damage in a p53-dependent manner. Despite the fact that the therapeutic response is improved in NPC, heterogeneity among people remains with regard to the susceptibility of adverse effects and the efficacy of treatments. Therefore, we analysed eight potentially functional SNPs of five genes in the lncRNA-p53 regulatory network in a discovery cohort of 505 NPC patients. By performing multivariate logistic regression, the impact of genetic variations on the efficacy and risk of CRT-induced toxicities was investigated. The most dramatic finding was that the MEG3 rs10132552 CC genotype had a greater than three-fold increased risk of developing grade 3-4 anaemia (OR = 3.001, 95%CI = 1.355-6.646, P = 0.007). Furthermore, the rs10132552 CT genotype had a better response to treatment (OR = 0.261, 95%CI = 0.089-0.770, P = 0.015). Individuals carrying LINC-ROR rs2027701 with one or two variant alleles had significant associations with a reduced risk of neutropaenia (OR = 0.503, 95%CI = 0.303-0.835, P = 0.008). In conclusion, our results suggested that genetic polymorphisms of the lncRNA-p53 regulatory network could play a potential role in reducing treatment-related toxicities and improving outcomes for NPC patients.

Figure 1

LncRNAs serve as p53 regulators and effectors, participating in the p53 regulatory pathway. On the one hand, lncRNAs are able to regulate p53 directly or indirectly at the transcriptional or posttranscriptional levels such as MEG3. On the other hand, several lncRNAs could be induced or suppressed by p53 such as LINC-ROR, pR-lncRNA-1, LINC-PINT and TUSC7.

Figure 2

Analysis of receiver-operating characteristic curve to predict toxicities. ROC analysis showed the AUC of myelosuppression, neutropaenia and anaemia was 0.647, 0.731 and 0.750, respectively.

Figure 3

The predicting rs10132552 on MEG3 secondary structure. (a) Base pair probabilities of the local region rs10132552. (b) The optimal secondary structure of global wild-type sequence. Minimum free energy −150.60 kcal/mol. (c) The optimal secondary structure of global mutant sequence. Minimum free energy −153.30 kcal/mol.