Expression status of GATA3 and mismatch repair proteins in upper tract urothelial carcinoma

Abstract

GATA binding protein 3 (GATA3) and mismatch repair (MMR) deficiency contribute to the development of urothelial carcinoma. However, the combined expression of GATA3 and microsatellite instability (MSI) in upper tract urothelial carcinoma (UTUC) and its prognostic value have not been investigated. Here, we immunohistochemically stained GATA3 and MMR proteins in 108 UTUC samples. GATA3 was positive in 74 cases, and its expression was significantly lower than in adjacent benign urothelium (P<0.001). Loss of GATA3 expression was statistically associated with adverse clinicopathologic parameters, such as advanced stage, lymphovascular invasion, neural invasion, lymph node metastasis, and extensive necrosis. Cancer-specific survival (CSS, P=0.028) and disease-free survival (DFS, P=0.024) were significantly shorter in patients with GATA3 negative tumors than in patients with GATA3 positive tumors. The absence of MMR proteins was observed in 8.3% of the cases, and focal staining was identified in 13.0%. When using “lax criteria” which resulted in counting cases as negative where MMR staining was in fact focally positive (<5%), we found that GATA3 was inversely associated with MSI (P=0.005). Moreover, GATA3⁻/microsatellite stability (MS) tumors were correlated with advanced pT stage (P<0.001) and poor outcome (P=0.019 for CSS, P=0.016 for DFS) compared with GATA3⁺/MSI ones. The GATA3⁻/MSI cases had unfavorable clinical outcomes compared with GATA3⁺/MSI cases (P=0.008 for CSS, P=0.023 for DFS). This finding raises a question as to whether GATA3 interacts with MSI through the TGF-β signaling pathway and regulates UTUC progression.

Keywords

upper tract urothelial carcinoma / GATA binding protein 3 / mismatch repair / microsatellite instability / prognosis

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Acknowledgements

This work was supported by the grants provided by the Leading Academic Discipline Project of Beijing Education Bureau (No. BMU20110254) and Peking University Shougang Hospital Youth Foundation (No. SGYYQ201701).

Compliance with ethics guidelines

Yue Wang, Jinxia Zhang, Yunfan Wang, Shufang Wang, Yu Zhang, Fei Gao, and Huiying He declare no conflicts of interest. All the procedures were in accordance with the ethical standards of the responsible committee on human experimentation (Peking University Shougang Hospital Institutional Review Board) and the Helsinki Declaration of 1975, as revised in 2000.

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