Functional Evaluation of ZNF350 Missense Genetic Variants Associated with Breast Cancer Susceptibility

摘要

ZNF350, a BRCA1-interacting protein, could mediate BRCA1-induced sequence-specific transcriptional repression of several genes, including GADD45. As a potential breast cancer susceptibility gene, single nucleotide polymorphisms (SNPs), especially missense SNPs, may influence the transcriptional repression of its target tumor suppressor genes and individuals' breast cancer risk. Using the gene-based haplotype-tagging SNPs strategy, we evaluated the association between six ZNF350 polymorphisms and breast cancer risk in a case-control set from a northern Chinese population. The impact of ZNF350 variations on transcriptional repression of GADD45 was also examined. It was found that ZNF350 rs2278420 (L66P) and rs2278415 (S501R) missense genetic variants are in complete linkage disequilibrium and have a significant impact on inter-individual susceptibility to breast cancer. Additionally, ZNF350 GGCGT or GGCGC haplotype is also associated with a significantly increased breast cancer risk compared with the GGCAC haplotype. ZNF350 L66P variant modifies the risk of breast cancer not only by itself but also in a gene-environment interaction manner with age, age at menarche, menopause status, or estrogen receptor status. Interestingly, we observed that ZNF350 L66P and S501R SNPs could weaken the capability of ZNF350-mediated GADD45 transcription repression and it may be an underlying mechanism of the observed epidemiological associations. Our results highlight ZNF350 as an important gene in human mammary oncogenesis and ZNF350 missense genetic polymorphisms confer susceptibility to breast cancer.