A miR-146 a Polymorphism ( rs 2910164 ) Predicts Risk of and Survival from Colorectal Cancer

Background: Recent evidence suggests that the rs2910164 variant of miR-146a is associated with the development of certain types of cancer. Therefore, the aim of this study was to investigate the association of this genetic variant with susceptibility and prognosis in patients with colorectal cancer (CRC). Materials and Methods: Genotyping analyses of miR-146a rs2690164 for risk and survival in CRC were performed in a case−control study (n=967) using a polymerase chain reaction (PCR)-restriction fragment length polymorphism assay. Results: The C allelic frequency of miR-146 rs2690164 in the 399 patients and 568 controls was 61.9% and 53.9%, respectively. In the case−control study, those who possessed the CC genotype had a higher risk of CRC compared to those with the CG or GG genotype (odds ratio=1.569; 95% confidence interval=1.196-2.059; p=0.001), regardless of the tumor site. In the survival analysis of 343 patients with CRC who underwent curative surgery, those with CC genotype had a worse survival outcome compared with those with CG or GG genotype in a Kaplan−Meier survival analysis. Moreover, a multivariate analysis showed that the CC genotype of miR146a rs2910164 was associated with worse relapse-free and disease-specific survival compared to the CG or GG genotype in a recessive model of the C allele, adjusted for patient and tumor characteristics (hazard ratio=2.120 and 2.349, p=0.005 and 0.007, respectively). Conclusion: The current study provides evidence that the miR-146a rs2690164 polymorphism, as the dominant model of the G allele, is associated with the susceptibility and prognosis of CRC. Colorectal cancer (CRC) is a leading cause of death and annually responsible for more than 500,000 deaths worldwide. To date, although the main prognostic factor used in clinical practice is the tumor stage, several molecules and genetic alterations have also been introduced as potential markers. In particular, constitutional host-related biological features have long been suspected on explaining why some patients treated for CRC will experience relapse while others will not, despite similar baseline characteristics and polymorphisms in the genes involved in tumor progression. Thus, apoptosis and angiogenesis have been widely studied for their association with CRC susceptibility and prognosis (1-8). MicroRNAs (miRNAs), a class of small, endogenous, non-coding RNAs, can regulate gene expression by translational repression or mRNA degradation of the target, affecting critical functions in various physiological processes, including cell proliferation and apoptosis, and tumor development (9, 10). Previous studies have already demonstrated the relationship of the expression of miRNAs with prognosis or responsiveness to treatment in CRC (1113). Moreover, some variants of miRNAs have recently been introduced as potential biomarkers of CRC. The miRNA-146a polymorphism rs2910164 causes a change from a G:U pair to a C:U mismatch in the stem structure of the miR-146a precursor, leading to process variation and lower expression of the mature sequence. Recent evidence also suggests that the rs2910164 singlenucleotide polymorphism (SNP) in miR-146a is associated with the development and prognosis of various types of cancer (14-21). However, its effect on cancer is still 3233 *These Authors contributed equally to this study. Correspondence to: Professor Jong Gwang Kim, Department of Oncology/Hematology, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, 807 Hogukno, Buk-Gu, Daegu 702-210, Korea. Tel: +82 532003521, Fax: +82 532002029, e-mail: jkk21c@knu.ac. kr and Professor Jae Yong Park, Department of Internal Medicine, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, 807 Hogukno, Buk-Gu, Daegu 702-210, Korea. Tel: +82 532005506, Fax: +82 534262046, e-mail: jaeyong@knu.ac. kr