BAX -248 G>A and BCL2 -938 C>A Variant Lowers the Survival in Patients with Nasopharyngeal Carcinoma and Could be Associated with Tissue-Specific Malignancies: A Multi-Method Approach.

Abstract

Background:The association of BAX -248 G>A and BCL2 -938 C>A with different cancers created conflicts. We studied the correlation and the effect of these polymorphisms in patients with Nasopharyngeal Carcinoma (NPC). Methods:PCR-RFLP and Sanger sequencing were used to detect polymorphisms. Statistical analysis including forest plot and Kaplan-Meier Log-rank test was conducted to investigate the association and effect of these SNPs on the NPC patients’ survival. The computational study was performed to investigate the possible regulatory role between these polymorphisms and the poor survival of NPC patients. Meta-analysis was executed to check the tissue-specific association of these polymorphisms in the context of global cancer prognosis. Results:We observed an increased and significant association of BAX -248 G>A [GA:OR=5.29, 95%CI=1.67,16.67, P=0.004; GA+AA:OR=5.71, 95%CI=1.82,17.90, P =0.002; A:OR=5.33, 95%CI=1.76,16.13, P=0.003], and BCL2 -938 C>A [CA:OR=2.26, 95%CI=1.03,4.96, P=0.04; AA:OR=3.56, 95%CI=0.97,13.05, P=0.05; CA+AA:OR=3.10, 95%CI=1.51,6.35, P=0.002; A:OR=2.90, 95% CI=1.59,5.29, P=0.0005] with the risk of NPC. Also, these SNPs were strongly correlated with poor survival in NPC patients (lower estimated survival mean, lower estimated proportion surviving at 5 years with p<0.05). The computational study showed that these SNPs altered the binding affinity of transcription factors HIF1, SP1, PAX3, PAX9 and CREB towards promoter (Lower p indicates strong affinity). The meta-analysis revealed the tissue-specific association of these polymorphisms. BAX -248 G>A showed a significant correlation with carcinomas [A vs G:OR=1.60, 95%CI=1.09,2.34, P=0.01; AA vs GG:OR=2.61, 95%CI=1.68,4.06, P<0.001; AA+GA vs GG:OR=1.53,95%CI=1.04,2.25, P=0.02); AA vs GG+GA:OR=2.53, 95%CI=1.65,3.87, P<0.001], and BCL2 -938 C>A with other malignancies [A vs C:OR=1.45, 95%CI=1.26,1.66, P<0.001; AA vs CC:OR=2.07, 95%CI: 1.15,3.72, P=0.01; AA+CA vs CC:OR=1.42, 95%CI=1.18,1.72, P<0.001; AA vs CC+CA:OR=1.89, 95%CI=1.02,3.50, P=0.04]. Conclusions:BAX -248 G>A and BCL2 -938 C>A was associated with poor survival in NPC patients. It may increase cancer susceptibility through transcriptional regulation. Moreover, these SNPs’ effects could be tissue-specific.