The occurrence of breast cancer is a result of a long-term complex interaction between individual genetic background and environmental exposure factors. As the most common type of genetic mutation, SNP is of great significance for breast cancer risk, diagnosis, individualized treatment and prognosis prediction. This study is aimed to investigate the association between MEG3 polymorphisms (rs3087918, rs11160608 rs7158663) and breast cancer. Our study recruited 1134 subjects containing 434 breast cancer patients and 700 healthy controls. The results indicated that the mutant homozygous GG of rs3087918 may associated with a decreased risk of BC, especially in females age < = 49. Comparison between case groups showed genotype GG and TG/GG of rs3087918 were correlated with her-2 receptor expression. The results of haplotype analysis for MEG3 showed that compared with wild haploid TAG, TCG haplotype may increase the risk of breast cancer, while other haplotypes were not significantly correlated with breast cancer risk. Furthermore, we found rs3087918 may influence the secondary structure of MEG3 and affect the bind of MEG3 to some miRNAs.
Previous evidences showed that MEG3 was highly expressed in normal tissues such as brain, pituitary, placenta and adrenal gland, and its transcripts can be detected in several human organs including ovary, testes, spleen, pancreas, liver, and mammary gland . However, the expression of MEG3 was lower in various human tumors compared with that in normal human tissues, including breast cancer . MEG3 was recognized as a tumor suppressor deponed on recent researches. In vitro experiments showed that restoring the expression of MEG3 could inhibit cancer cells proliferation and induce their apoptosis , and a similar tumor inhibition effect was found in nude mice . MEG3 can also participant in epigenetic regulation of transcripts in the MEG3 region, such as DNA methylation [17, 18], snoRNA/microRNA regulation [19–22]. We used a database named LncRNASNP2 (http://bioinfo.life.hust.edu.cn/lncRNASNP/) to predict the potential function of rs3087918 on MEG3 gene. The results indicated that rs3087918 may influence MEG3 binding to miRNAs. In detail, rs3087918 may gain the targets of hsa-miR-1203 to MEG3, while loss the target of hsa-miR-139-3p and hsa-miR-5091 to MEG3. A study performed by Tomoyuki Okumura et al. found has-miR-1203 significantly associated with tumor recurrence . Downregulation of has-miR-139-3p could induce cancer cell migration and invasion [24–26], and a pooled analysis proved that high has-miR-139-3p expression was related to a better prognosis for hepatocellular carcinoma . Thus, has-miR-139-3p was attributed as a tumor suppressor. Hsa-miR-5091 was also reported as a biomarker with better prognosis for pancreatic ductal adenocarcinoma . These were coincident with our results that rs3087918 was related to a decreased risk of breast cancer.
To be best of our knowledge, this is the first study to explore the association between MEG3 SNPs (rs3087918, rs11160608 rs7158663) and breast cancer risk. We used scientific methods and designs and finally obtained credible results. However, there are still some potential limitation should to be clarify. First, we failed to consider the potential influence of environmental, lifestyle and other unknow risk factors on our study. Secondly, this is a one center case-control study with a small samples scale, we should not ignore the selective bias. In the future, more complete and larger sample scale study need to accomplish.