1 Cheeloo College of Medicine, Shandong University , Jinan, China .
2 Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital Affiliated to Shandong University , Shandong Academy of Medical Sciences, Jinan, China .
DNA Cell Biol. 2018 Jun;37(6):543-550. doi: 10.1089/dna.2018.4160. Epub 2018 Apr 13.
ZNF350, a BRCA1-interacting protein, could mediate BRCA1-induced sequence-specific transcriptional repression of several genes, including GADD45α. 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 GADD45α 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 GADD45α 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.
锌指蛋白 350（ZNF350）是 BRCA1 相互作用蛋白，可介导 BRCA1 诱导的几个基因的序列特异性转录抑制，包括 GADD45α。作为一种潜在的乳腺癌易感基因，单核苷酸多态性（SNP），特别是错义 SNP，可能影响其靶肿瘤抑制基因的转录抑制和个体的乳腺癌风险。使用基于基因的单体型标签 SNP 策略，我们在来自中国北方人群的病例对照集中评估了六个 ZNF350 多态性与乳腺癌风险的关联。还研究了 ZNF350 变异对 GADD45α 转录抑制的影响。结果发现，ZNF350 rs2278420（L66P）和 rs2278415（S501R）错义遗传变异完全连锁不平衡，对个体乳腺癌易感性有显著影响。此外，与 GGCAC 单体型相比，ZNF350 GGCGT 或 GGCGC 单体型也与乳腺癌风险显著增加相关。ZNF350 L66P 变体不仅自身而且还与年龄、初潮年龄、绝经状态或雌激素受体状态的基因-环境相互作用方式改变乳腺癌的风险。有趣的是，我们观察到 ZNF350 L66P 和 S501R SNP 可以削弱 ZNF350 介导的 GADD45α 转录抑制能力，这可能是观察到的流行病学关联的潜在机制。我们的结果强调 ZNF350 是人类乳腺肿瘤发生中的一个重要基因，ZNF350 错义遗传多态性赋予乳腺癌易感性。
