Association of functional genetic variants in the N6-methyladenosine reader protein YTHDC1/2 with breast cancer susceptibility

Objective N6-methyladenosine (m ⁶ A), the most abundant mRNA modification in eukaryotes, is critical in cancer development. As key m ⁶ A reader, YTHDC1 and YTHDC2 may affect breast cancer risk. This study investigates the association of single nucleotide polymorphisms (SNPs) of YTHDC1/2 with breast cancer susceptibility and their interactions with environmental factors. Methods Functional SNPs of YTHDC1/2 were screened through literature and public databases, yielding nine candidates. In a frequency-matched case-control study (n = 746; age ± 2 years), their association with breast cancer susceptibility was evaluated using conditional logistic regression, followed by gene-environment interactions analysis. qRT-PCR measured expression of YTHDC2 in blood across rs9552 and rs2416282 genotypes. Public databases were further used to explore the potential target genes and functional mechanisms of YTHDC2 . Results YTHDC2 rs9552G > A was associated with an increased risk of breast cancer. YTHDC2 rs2416282 C > A was associated with a reduced risk of breast cancer. YTHDC1 haplotype C _rs1715080 A _rs17592288 T _rs2293596 T _rs3813832 was associated with an increased risk of breast cancer. YTHDC2 haplotype G _rs9552 G _rs17135754 A _rs2416282 C _rs654732 G _rs2303718 decreased the risk of breast cancer. rs1715080 and rs3813832 were associated with PR receptor status, Luminal type and HER-2 positive breast cancer, and rs17135754 was associated with HER-2 positive breast cancer. Negative multiplication interactions were observed between rs2293596 and family history of cancer, rs2416282 and menarche age and menopausal status. There were positive multiplication interactions between rs9552 and age at menarche, rs2416282 and family history of cancer. qRT-PCR results showed that the relative expression of YTHDC2 was changed by rs9552 G > A and rs2416282 C > A. YTHDC2 SNPs may identify and bind to the m6A modification sites of potential target genes to regulate the target genes, and then affect the susceptibility of breast cancer. Conclusion Our findings suggested that rs9552 G > A and rs2416282 C > A might be associated with the risk of BC.