Abstract
Single nucleotide polymorphisms (SNPs) in tumor-related genes have been reported to play important roles in cancer development. Recent studies have shown that 3’-untranslated regions (UTR) polymorphisms are associated with the occurrence and prognosis of cancers. The aim of this study is to analyze the association between KRAS and VEGF gene 3’-UTR SNPs and genetic susceptibility to colorectal cancer (CRC). In this case-control study of 371 CRC cases and 246 healthy controls, we analyzed the association between one SNP (rs1137188G > A) in the KRAS gene and four SNPs (rs3025039C > T, rs3025040C > T, rs3025053G > A and rs10434A > G) in the VEGF gene and CRC susceptibility by the improved multiplex ligase detection reaction (iMLDR) method. We checked the selected SNPs’ minor allele frequency and its distribution in the frequency of Chinese people by Hap-map database and Hardy-Weinberg equilibrium, and used multivariate logistic regression models to estimate adjusted odds ratios (AORs) and 95% confidence intervals (95% CIs). We found that the rs3025039C variant genotype in the VEGF gene was associated with a significant protection for CRC (AOR = 0.693, 95% CI = 0.485–0.989; P = 0.043 for CC and CT+TT). Nevertheless, the difference was no longer significant after Bonferroni correction (Bonferroni-adjusted P = 0.172). In genetic polymorphisms analysis, we found that the KRAS rs1137188 variant AA genotype had higher portion of tumor size (≥ 5 cm) (P = 0.01; Bonferroni-adjusted P = 0.04), which suggested that the rs1137188 variant AA genotype may significantly be associated with increased progression of CRC. In conclusion, our study suggested that these five SNPs in the KRAS gene and the VEGF gene were not associated with CRC susceptibility in Han Chinese in Sichuan province.
Highlights
Colorectal cancer (CRC) is the third most common cancer, the fourth leading cause of cancer-related death globally, and the second most common cancer in terms of the number of individuals living with cancer for five years or more, making up about 10% of all malignant diagnoses
It is been estimated that 1.4 million people are diagnosed with CRC per year, 65% of whom are found in developed countries; approximately 700,000 die of this disease per year; and 3.5 million individuals are living with CRC [1]
Previous studies have investigated that the single nucleotide polymorphisms (SNPs) in the KRAS 3’-untranslated regions (UTR) might cause high levels of the KRAS oncogenic protein and lower levels of the let-7 miRNA, the overexpressed KRAS oncogenic protein can increase the activation of the RAF/MEK/mitogen-activated protein kinase (MAPK) pathway, which might promote the tumorigenesis of CRC [12, 13]
Summary
Colorectal cancer (CRC) is the third most common cancer, the fourth leading cause of cancer-related death globally, and the second most common cancer in terms of the number of individuals living with cancer for five years or more, making up about 10% of all malignant diagnoses. Single nucleotide polymorphisms (SNPs) play an important role in the development and progression of CRC [7,8,9]. The KRAS mutation is an essential step which is thought to contribute to cancer development by driving proliferation of cells and resisting to apoptosis with initiated mutations. The SNPs of KRAS 3’-UTR may prevent the let-7 miRNA from binding to KRAS and regulate the activity of KRAS so as to adjust the expression of its protein. Previous studies have investigated that the SNPs in the KRAS 3’-UTR might cause high levels of the KRAS oncogenic protein and lower levels of the let-7 miRNA, the overexpressed KRAS oncogenic protein can increase the activation of the RAF/MEK/MAPK pathway, which might promote the tumorigenesis of CRC [12, 13]
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