Forkhead box class O (FOXO) transcription factors play a pivotal role in regulating a variety of biological processes, including organismal development, cell signaling, cell metabolism, and tumorigenesis. Therefore, we hypothesize that genetic variants in FOXO pathway genes are associated with breast cancer (BC) risk. To test this hypothesis, we conducted a large meta-analysis using 14 published genome-wide association study (GWAS) data sets in the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) study. We assessed associations between 5214 (365 genotyped in DRIVE and 4849 imputed) common single-nucleotide polymorphisms (SNPs) in 55 FOXO pathway genes and BC risk. After multiple comparison corrections by the Bayesian false-discovery probability method, we found five SNPs to be significantly associated with BC risk. In stepwise multivariate logistic regression analysis with adjustment for age, principal components, and previously published SNPs in the same data set, three independent SNPs (i.e., FBXO32 rs10093411 A>G, FOXO6 rs61229336 C>T, and FBXO32 rs62521280 C>T) remained to be significantly associated with BC risk (p = 0.0008, 0.0011, and 0.0017, respectively). Additional expression quantitative trait loci analysis revealed that the FBXO32 rs62521280 T allele was associated with decreased messenger RNA (mRNA) expression levels in breast tissue, while the FOXO6 rs61229336 T allele was found to be associated with decreased mRNA expression levels in the whole blood cells. Once replicated by other investigators, these genetic variants may serve as new biomarkers for BC risk.

中文翻译：

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FOXO通路中FBXO32和FOXO6的遗传变异与乳腺癌风险的关联

叉头盒 O 类 (FOXO) 转录因子在调节多种生物过程中发挥着关键作用，包括生物体发育、细胞信号传导、细胞代谢和肿瘤发生。因此，我们假设 FOXO 通路基因中的遗传变异与乳腺癌 (BC) 风险相关。为了验证这一假设，我们在乳腺癌遗传变异的发现、生物学和风险 (DRIVE) 研究中使用 14 个已发表的全基因组关联研究 (GWAS) 数据集进行了大型荟萃分析。我们评估了 55 个 FOXO 通路基因中的 5214 个（365 个在 DRIVE 中基因分型和 4849 个估算的）常见单核苷酸多态性 (SNP) 与 BC 风险之间的关联。通过贝叶斯错误发现概率法进行多重比较校正后，我们发现五个 SNP 与 BC 风险显着相关。FBXO32 rs10093411 A>G、FOXO6 rs61229336 C>T 和FBXO32 rs62521280 C>T) 仍然与 BC 风险显着相关（分别为p  = 0.0008、0.0011 和 0.0017）。额外的表达数量性状基因座分析显示，FBXO32 rs62521280 T 等位基因与乳腺组织中信使 RNA (mRNA) 表达水平降低有关，而FOXO6 rs61229336 T 等位基因被发现与全血细胞中 mRNA 表达水平降低有关。一旦被其他研究人员复制，这些遗传变异可能会成为 BC 风险的新生物标志物。