Impact of METTL3/14/16 Gene Polymorphisms on Risk of Breast Cancer in Chinese Women

Objectives: Methyltransferase-like 3/14/16 (METTL3/14/16) presents the regulating valve in N6-methyladenosine (m(6)A) modification, involved in carcinogenesis. We addressed elucidating the relationship between single-nucleotide polymorphisms (SNPs) of the METTL3/14/16 gene and breast cancer (BC) susceptibility. Study design: A case-control study included 680 BC patients and 680 healthy controls, individually matched for age (+/- 2 years). Methods: 7 SNPs were screened by bioinformatics tools. Conditional Logistic analysis was used to explore the association between SNPs and BC susceptibility. SNPs-reproductive factors interaction was assessed. qRT-PCR was conducted to detect the METTL3/14/16 expression of different SNPs. The potential biomechanism was explored using bioinformatics tools. Results: Among the 7 analyzed SNPs, METTL3 rs1061026 T>G exhibited a significant association with reduced susceptibility to BC. The TC+CC genotype of METTL14 rs428409 elevated BC risk, while the AG+GG genotype of METTL14 rs3087958 restrained BC risk. The stratified analysis further identified the protective effect of rs1061026 T>G and rs3087958 T>G, and the detrimental effect of rs428409 T>G in specific subgroups. Haplotype analysis revealed that haplotypes G(rs1061026)C(rs1061027) and G(rs368669)Tr(s428409)G(rs3087958) were protective for BC. BC patients who carried the C allele in METTL14 rs428409 were more likely to be HER-2 positive. Individuals with age at menarche >= 14, number of pregnancies >1, and G allele in rs1061026 had a 47.7% decreased risk of BC. There were considerable multiplicative interactions between SNPs and reproductive factors. The relative expression of METTL3/14 was altered due to rs1061026 T>G, rs428409 T>C, and rs3087958 A>G. These three SNPs might interfere with the m(6)A modification and the expression level of BC-related genes. Conclusion: Our findings suggested that rs1061026 T>G, rs428409 T>C, and rs3087958 A>G might be associated with the risk of BC.