Genetic variations in miRNA binding site of TPST1 and ZG16B associated with prognosis for patients with colorectal cancer.

Abstract

3553 Background: MicroRNAs (miRNA) may play important roles in tumorigenesis by regulating the expressions of proto-oncogenes or tumor suppressor genes. Single nucleotide polymorphisms (SNP) located in the 3’-UTR of miRNA target genes might affect miRNA-mediated gene regulation, thereby contributing to the susceptibility or prognosis of cancer. Accordingly, the present study analyzed SNPs located in the putative miRNA-binding sites of the 3’-UTR of various genes and their impact on the prognosis for patients with colorectal cancer by altering miRNA binding efficiency. Methods: Eight hundred and thirty-one consecutive patients (discovery cohort, n=309; validation cohort, n=522) with curatively resected colorectal adenocarcinoma were enrolled in the present study. The genomic DNA was extracted from fresh colorectal tissue. One hundred fifty-seven SNPs were selected in Silico analysis for the current study, which was based on several miRNA database and HapMap database. The SNP genotyping was performed using the Sequenom MassARRAY. Results: The median age of all patients was 65 years, and 468 (56.3%) patients had colon cancer, while 363 (45.1%) patients had rectal cancer. The pathologic stages after the surgical resection were as follows: stage I (n=150, 18.1%), stage II (n=332, 40.0%), stage III (n=333, 40.1%), and stage IV (n=16, 1.9%). In the discovery cohort, 19 SNPs were identified as possible prognostic biomarkers in a multivariate survival analysis [disease-free survival (DFS) and/or overall survival (OS)] adjusted for age, preoperative CEA level, and pathologic stage. In the validation cohort, the TPST1 rs3757417T>G and ZG16B rs12373A>C were significantly associated with prognosis as same direction in the discovery cohort (discovery + validation cohort; TPST1 rs3757417T>G, DFS, p value=0.0007, OS, p value=0.0091 in recessive model; ZG16B rs12373A>C, DFS, p value=<0.0001, OS, p value=0.0009 in dominant model). Conclusions: The current study provides evidence that the rs3757417T>G and rs12373A>C polymorphism in the 3’-UTR of TPST1 and ZG16B, respectively, are possible prognostic biomarker for patients with colorectal cancer.