New Genetic Variations in RNA-binding Protein Gene and Breast Cancer Risk: A Case-Control Study

Abstract

Background: LIN28, a highly conserved RNA-binding protein, regulate a wide variety of post-transcriptional cellular processes. The current study aimed to identify genetic variants of five single nucleotide polymorphisms (SNPs) in the LIN28B gene (rs221634, rs22163, rs314276, rs9404590, and rs12194974) and their association with Breast cancer.

Method: 220 patients and 230 controls were genotyped by the RFLP assay for Lin28B gene variants. Odds ratio analysis was used to determine the association between Lin28B variants and breast cancer. Haplotype analysis was performed to determine the combined impact of the investigated variants on BC. Novel in-silico analysis were performed to predict the potential functions of these polymorphisms, as well.

Results: Patients carrying all variant genotypes for lin28B rs221634 (codominant, dominant, recessive, and allelic inheritance models), rs221635 (codominant and dominant genotypes), and rs9404590 (codominant, dominant, and inheritance model). Significant associations between reduced cancer risk and rs12194974 and rs314276 were found in codominant, dominant, recessive, and allele inheritance models. According to haplotype analysis of rs9404590, rs12194974, rs314276, rs221634, and rs221635 SNPs ,the GGCTT, GGCAT, TGCAC, TGCTC, GGCAC, GGCTC, and GGAAC haplotypes are associated with an increased risk of BC, whereas the TACAT and TAAAT haplotypes were associated with a decreased risk of BC. The splicing enhancers (ESE) binding site was found to be altered by the SNPs rs9404590, rs12194974, and rs314276, according to in-silico analysis.

Conclusion: Breast cancer susceptibility appears to be linked to genetic variations in the Lin28B gene, and haplotypes in this region have been linked to increased risk.

Keywords: Gene variation; LIN28B; Polymorphism; RNA-binding protein; breast cancer.

Figure 1

The Effects of SNPs on Local mRNA-Secondary Structure: The effects of rs221634 (A), rs221635 (B), rs314276 (C), rs9404590 (D), and rs12194974 (E) variations on Lin28B-mRNA secondary structure. P-value color direction and graphic summary of the analysis (A, B, C, D and E). The SNP-affected region is not colored in black since of the p-value less than 0.2, which is significant structural change in mRNA structure. The optimal secondary structure of global wild-type sequence depicted in green (A', B', C', D' and E'). The optimal secondary structure of global mutant sequence showed in red (A'', B'', C'', D'' and E'').

Figure 2

The SNPs Effects on Enhancers and Silencers Motifs, Analyzed by SpliceAid 2 tool: Predicted data of changes in number and type enhancers and silencers motifs for Lin28B rs314276 (A), rs9404590 (B), and rs12194974 (C) gene polymorphisms.

Figure 3

The Conservation of the DNA Sequences around Lin28B rs221634 (A), rs221635 (B), rs314276 (C), rs9404590 (D), and rs12194974 (E) SNPs locus; human DNA sequences around these locus is presented at the top. Blue vertical line indicates the positions of the variant locus SNPs in human and the conservation of wild allele across multiple mammalian species.