An miR-502–Binding Site Single-Nucleotide Polymorphism in the 3′-Untranslated Region of the SET8 Gene Is Associated with Early Age of Breast Cancer Onset

Abstract

Purpose: MicroRNAs regulate gene expression by binding to the 3′-untranslated region (UTR) of target genes. Single-nucleotide polymorphisms of critical genes may affect their regulation by microRNAs. We have identified a single-nucleotide polymorphism within the miR-502 seed binding region in the 3′-UTR of the SET8 gene. SET8 methylates TP53 and regulates genome stability. We investigated the role of this SET8 singlenucleotide polymorphism and in concert with the TP53 codon 72 single-nucleotide polymorphism in the propensity for onset of breast cancer. Experimental Design: We measured the SET8 single-nucleotide polymorphisms in a case-control study on 1,110 breast cancer cases and 1,097 controls. Results: The SET8 CC and TP53 GG genotypes were independently associated with an earlier age of breast cancer onset in an allele-dose-dependent manner (for SET8, 52.2 years for TT, 51.4 for TC, and 49.5 for CC; and for TP53, 53.1 years for CC, 51.5 for GC, 50.7 for GG). Individuals with combined SET8 CC and TP53 GG genotypes developed cancer at a median age of 47.7 years as compared with 54.6 years for individuals with combined SET8 TT and TP53 CC genotypes. In the 51 breast cancer tissue samples tested, the SET8 CC genotype was associated with reduced SET8, but not miR-502, transcript levels. Conclusions: These data suggest that the miR-502-binding site single-nucleotide polymorphism in the 3′-UTR of SET8 modulates SET8 expression and contributes to the early development of breast cancer, either independently or together with the TP53 codon 72 single-nucleotide polymorphism. Larger studies with multiethnic groups are warranted to validate our findings. (Clin Cancer Res 2009;15(19):6292-300)

SET8 expression is associated with overall survival in gastric cancer

“…SET8 has been shown to be correlated with a series of human tumors, such as hepatocellular cancer, breast cancer, ovarian cancer, and lung cancer (Song et al, 2009;Ding et al, 2012;Guo et al, 2012;Wang et al, 2012;Xu et al, 2013). However, no studies have demonstrated a correlation between SET8 and gastric cancer.…”

“…Additionally, gastric cancer outcomes may be modified by altering SET8 expression, partly because of its affinity to miR-502. Previous studies have suggested that the single-nucleotide polymorphism, located within the miR-502 binding site in SET8, modulates SET8 expression and contributes to cancer risk and early cancer development (Yu et al, 2007;Song et al, 2009). …”

“…In particular, targeting H4K20 for monomethylation (Fang et al, 2002;Nishioka et al, 2002) has been shown to have important functions in diverse biological processes, such as gene transcriptional control, replication origin modulation, genome integrity maintenance, cell cycle progression, and development (Abbas et al, 2010;Centore et al, 2010;Oda et al, 2010;Jørgensen et al, 2011;Li et al, 2011). Previous studies found that modulation of SET8 protein expression contributes to breast cancer and ovarian cancer susceptibility and affects the clinical outcome of hepatocellular carcinoma and non-small cell lung cancer (Song et al, 2009;Guo et al, 2012;Wang et al, 2012;Xu et al, 2013). Lower SET8 levels were found to be associated with longer survival in hepatic carcinoma and nonsmall cell lung cancer patients Xu et al, 2013).…”

Genomic and Epigenomic Cross-talks in the Regulatory Landscape of miRNAs in Breast Cancer

“…A SNP in a miRNA can have a significant effect on its hybridization to the target sites or can affect the processing of the mRNA. For example, a SNP within the 3 0 UTR of SET8, a methyltransferase that represses p53 activity, generates a new miR-502 binding site and is associated with early breast cancer onset in premenopausal women (140). In a study on the impact of 11 miRNA target site SNPs located in the 3 0 UTR of cancer associated genes, a significant association with familial breast cancer risk was observed (141).…”

Single-nucleotide polymorphisms among microRNA: big effects on cancer

“…We previously reviewed SNPs within miRNA binding sites and cancer risk[114], followed by case control studies in this field[108]. Recently, Liang et al [109] reported their findings that miRNA binding site SNPs may impact ovarian cancer predisposition and clinical outcome both individually and jointly with genetic variants in miRNA biosynthesis pathways.…”