Genetic Variants in the p53 Signaling Pathway Genes Predict Chemotherapy Efficacy for Colorectal Cancer

Background: Murine double minute-2 gene (MDM2) was originally identified predicting chemotherapy efficacy. However, little is known about the association between single nucleotide polymorphisms (SNPs) in the p53 signaling pathway and prognosis and chemotherapy sensitivity in colorectal cancer. Methods: In a cohort of 325 colorectal cancer patients, we analyzed the association between 111 SNPs in twenty-two p53 signaling pathway genes and progression-free survival (PFS) and disease control rate (DCR) using Cox regression and logistics regression analysis. The false discovery rate (FDR) method was used for correction of multiple testing. The secondary structure was predicted by RNAfold. The expression qualitative trait locus (eQTL) analysis and mRNA expression differences were performed by GTEx database and TCGA database. Findings: TP73 rs747828 C allele was significantly associated with poorer PFS (HR = 1.66, 95% CI = 1.28-2.14, P = 1.00x10-4) in additive model. In the stratified analysis, rs747828 C allele was significantly associated with poorer PFS (P = 1.40x10-3) and lower DCR (P = 1.82x10-2) in oxaliplatin-based chemotherapy. The secondary structure of TP73 was changed by different rs747828 genotype. Interpretation: Although rs747828 C allele was not associated with message RNA (mRNA) TP73 expression, it was significantly associated with increased mRNA TP73-AS1 expression levels in sigmoid tissues. TP73 rs747828 may affect secondary structure of TP73 to confer chemotherapy response in colorectal cancer. Funding: National Natural Science Foundation of China (81472782), the National Key R&D Program of China (2017YFC0908200), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine). Declaration of Interest: The author(s) indicated no potential conflicts of interest. Ethical Approval: Written informed consent was obtained from each patient, and this study was approved by the Institutional Ethics Review Board of the Nanjing Medical University.