Several mutations act as driver mutations in breast cancer, including GATA3 mutations. Reports of the relation between GATA3 mutations and breast cancer prognosis remain conflicting. Also, the role of GATA3 germline mutations is not well studied. We hypothesize that different mutation types could have different effects. Also, this study aims to assess effect of GATA3 mutations on GATA3 protein function as a transcription factor, and target pathways affected. DNA from de novo breast cancer female patients was sequenced to detect exon 6 GATA3 mutation. Sequence analysis was performed along with clinical and prognostic parameters and disease-free survival. Public datasets were analyzed for differentially expressed genes and pathways with mutant GATA3 patients. Mutations in GATA3 exon 6 were detected in 56.1% of patients (including 2 novel, Lys368fs, Pro354Lys). Intronic mutations were significantly higher in long disease-free survival group, while frameshift mutations were significantly higher in short DFS group. Patients with tumor size ≥20 had significantly higher protein coding and lower intronic mutations compared to patients with tumor size <20 mm. Differential expression and pathway analysis showed that mutant GATA3 had lost its negative regulatory effect on several pathways such as: signaling by interleukins, regulation of TP53 expression, and RUNX3 regulated CDKN1A transcription pathway. PIK3CA, SKP1, FBP1, SMAD3, ANXA9 and CLSTN2 were positively correlated to wild-type GATA3 expression, but not mutant GATA3. Intronic germline mutations of GATA3 could be related to better prognosis, while protein coding GATA3 germline mutations could be related to unfavorable prognosis. GATA3 mutations lead to dysregulation of pathways related to immunity, breast cancer development, and metabolism.

Impact statement

GATA3 mutations are known to play an important role in breast cancer progression. The exact role and mechanisms of these mutations remain controversial as some studies suggest a relation to breast tumor growth, while others suggest a relation to longer survival. GATA3 germline mutations are not well studied in breast cancer. In this study, it was hypothesized that different types of GATA3 mutations could contribute to the breast cancer progression in different ways. GATA3 exon 6, which is important for GATA3 protein functions, was reported to have hotspots, and hence it was selected for study. Intronic GATA3 germline mutations were found to be related to favorable prognosis, while protein coding mutations were found to be related to unfavorable prognosis. Bioinformatics study of large publically available datasets showed that GATA3 mutations lead to dysregulation of pathways related to T-cells activation, inflammation, and breast cancer development.

中文翻译：

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GATA3 外显子 6 种系突变在埃及女性患者乳腺癌进展中的作用。

几种突变作为乳腺癌的驱动突变，包括 GATA3 突变。关于 GATA3 突变与乳腺癌预后之间关系的报道仍然相互矛盾。此外，GATA3 胚系突变的作用尚未得到充分研究。我们假设不同的突变类型可能有不同的影响。此外，本研究旨在评估 GATA3 突变对作为转录因子的 GATA3 蛋白功能的影响，以及受影响的靶通路。来自de novo的 DNA对乳腺癌女性患者进行测序，检测外显子 6 GATA3 突变。序列分析与临床和预后参数以及无病生存率一起进行。对公共数据集进行了分析，以了解突变 GATA3 患者的差异表达基因和通路。在 56.1% 的患者中检测到 GATA3 外显子 6 的突变（包括 2 个新的，Lys368fs，Pro354Lys）。内含子突变在长无病生存组中显着更高，而移码突变在短DFS组中显着更高。与肿瘤大小 <20 mm 的患者相比，肿瘤大小 ≥ 20 的患者具有显着更高的蛋白质编码和更低的内含子突变。差异表达和通路分析表明，突变体 GATA3 已失去其对多种通路的负调节作用，例如：白细胞介素信号传导，TP53表达的调控，RUNX3调控CDKN1A转录通路。PIK3CA、SKP1、FBP1、SMAD3、ANXA9 和 CLSTN2 与野生型 GATA3 表达呈正相关，但与突变体 GATA3 无关。GATA3 的内含子种系突变可能与更好的预后相关，而编码 GATA3 种系突变的蛋白质可能与不良预后相关。GATA3 突变导致与免疫、乳腺癌发展和新陈代谢相关的通路失调。

影响声明

已知 GATA3 突变在乳腺癌进展中起重要作用。这些突变的确切作用和机制仍然存在争议，因为一些研究表明与乳腺肿瘤生长有关，而另一些研究表明与更长的生存期有关。GATA3 胚系突变在乳腺癌中的研究还不够充分。在这项研究中，假设不同类型的 GATA3 突变可能以不同的方式促进乳腺癌的进展。据报道，对 GATA3 蛋白功能很重要的 GATA3 外显子 6 具有热点，因此选择它进行研究。内含子 GATA3 种系突变被发现与良好的预后相关，而蛋白质编码突变被发现与不良预后相关。