1. Department of Clinical Pharmacology, Xiangya Hospital, Central South University and Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, 410008, P.R. China;
2. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China;
3. Key Laboratory of Translational Radiation Oncology, Hunan Province; Department of Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, P.R. China;
4. Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610000, P.R. China.
MYC is a transcription factor acting as a pivotal regulator of genes involved in cell cycle progression, apoptosis, differentiation and metabolism. In this study, we evaluated the association of MYC polymorphisms with nasopharyngeal carcinoma (NPC) risk and chemoradiotherapy induced toxicities among Chinese population. By using bioinformatic tools, five potential functional single nucleotide polymorphisms of MYC were genotyped in a case-control study with 684 NPC patients and 823 healthy controls. We found two SNPs rs4645948 (C>T) and rs2071346 (G>T) were significantly associated with increased risk of developing NPC (TT+CT vs CC, OR=1.557, P=3.34×10-4; TT+GT vs GG, OR=1.361, P=0.007, respectively). In addition, rs4645948 (C>T) was conferred with increased risk of anemia (CT vs CC, OR=2.152, P=0.001) and severe leukopenia (CT vs CC, OR=1.893, P=0.034) for NPC patients receiving chemoradiotherapy. We also found rs2071346 (G>T) variant genotype carriers were subjected to higher risk of anemia (GT vs GG, OR=1.665, P=0.022) and thrombocytopenia (GT vs GG, OR=1.685, P=0.035). Our results demonstrated that the relative expression of MYC was dramatically higher in NPC tissues compared to rhinitis tissues. Over-expression of MYC was positively correlated with advanced T stage, N stage, and late clinical stage. Notably, the expression of MYC in rs4645948 CT and TT genotypes carriers were significantly higher than CC genotype carriers. Luciferase reporter assay indicated that the T allele of rs4645948 led to significantly higher transcription activity of MYC compared to the C allele. These findings suggested that individual carrying the rs4645948 T allele may be at greater risk for NPC due to an increase of MYC transcriptional activity and an augment of MYC expression.
Keywords: nasopharyngeal carcinoma, susceptibility, chemoradiotherapy, MYC, polymorphisms