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

Introduction

Upper tract urothelial carcinoma (UTUC), derived from the urothelium of renal pelvis and ureter, is relatively uncommon and constitute only 5%–10% of all cases of urothelial carcinomas in western countries [¹]. By contrast, the prevalence of UTUC is as high as 20%–30% in some regions of China [²]. Compared with patients in western countries, patients in China show earlier age of onset, higher tumor grade, more advanced stage, higher rate of lymph node metastasis, and poorer survival [³,⁴]. UTUC is clinically much more aggressive than bladder cancer and has a worse prognosis. Thus, the identification of novel therapeutic targets for the management of UTUC is warranted.

GATA3 is a member of the GATA family of zinc finger transcription factors and was originally identified as a T-cell lineage-specific factor [⁵]. Subsequently, GATA3 has been implicated in the development and progression of breast cancer [⁶,⁷]. Since first reported in 2007 [⁸], GATA3 has been used as one of the most useful urothelial markers in diagnostic practice, and loss of GATA3 was found to promote bladder cancer cell migration and invasion [⁹]. A recent study demonstrated that GATA3 inhibits the metastasis of breast cancer by terminating the TGF-b signaling pathway [¹⁰]. However, the prognostic values of GATA3 expression in Chinese patients with UTUC and the regulatory mechanisms involving GATA3-interacting proteins remain unclear.

Microsatellite instability (MSI) is widely recognized as an important molecular event in the pathogenesis of colorectal cancer and useful in identifying the subgroups of colorectal cancer patients with differing survival rate. One study found that TGF-b signaling was ablated secondary to the high frequency of an inactivating mutation of the TGF-b receptor in MSI-H colorectal cancer [¹¹]. Although previous studies [¹²–¹⁴] have shown that MMR deficiency contributes to the development of urothelial carcinomas, MSI status in Chinese patients with UTUC remains controversial. Therefore, the aim of this study is to investigate GATA3 expression and MSI status, as well as the prognostic value of the expression of GATA3 and MMR proteins in combination in Chinese patients with UTUC.

Study subjects

The medical records of 108 UTUC patients who underwent radical nephroureterectomy between January 2007 and March 2017 at Peking University Shougang Hospital and Peking University Third Hospital were retrieved. The cases were reviewed, and pathologic diagnoses were confirmed independently by two GU pathologists (Y Wang and HY He). Data were collected during follow-ups until June 2017. A total of 14 patients were lost to follow-up after surgery, leaving 94 cases for final survival analysis.

Research design and methods

Tissue microarrays (TMA) were constructed from 108 urothelial tumor samples and 24 adjacent benign urothelium samples. A previous study suggested that≥3 cores from each sample gave an acceptable statistical analysis in TMAs in diverse tumor types [¹⁵]. Thus, three cores were punched from the marked area on the donor block and transferred to premade recipient paraffin block. Each core was 1 mm in diameter, and the cores were spaced 0.8 mm apart on a single glass slide.

Immunohistochemical staining (IHC) was performed on the TMA sections. The primary antibodies were mouse monoclonal antibody GATA3 (clone L50-823; 1:200), rabbit monoclonal antibody MSH2 (clone RED2; 1:200), rabbit monoclonal antibody MSH6 (clone EP49; 1:200), mouse monoclonal antibody MLH1 (clone ES05; 1:100), and rabbit monoclonal antibody PMS2 (clone EP51; 1:40). The antibodies were all obtained from Origene, Rockville, USA. Human colorectal cancer served as the positive control for MMR proteins, and tris-buffered saline omitting primary antibodies was used as the negative control.

Immunostaining results were evaluated independently by two pathologists (YW and HH). Discrepancies in analysis were reconciled by a third reviewer (JZ). German Immunoreactive Score criteria (range 0–12) were used for the evaluation of GATA3. The percentage of immunoreactive cells (0%, 0; 1%−10%, 1; 11%−50%, 2; 51%−80%, 3; 81%−100%, 4) was multiplied by staining intensity (0, negative; 1, weak; 2, moderate; 3, strong) [¹⁶]. Cases with weighted scores of 2–12 were defined as positive. The immunohistochemical expression of four MMR proteins were scored as negative if the tumor showed complete absence of nuclear staining within tumor cells (stringent criteria). Mangold et al. [¹⁷] and Joost et al. [¹⁸] suggested that focal staining defined as nuclear staining in less than 5% of tumor cells indicates the presence of MSI-H (lax criteria). Thus, both of these cutoffs were independently used in this study.

SPSS software version 16.0 (SPSS, Chicago, IL) was used for data processing and statistical analysis. The relationships between IHC staining results and clinicopathologic parameters were analyzed with Pearson’s chi-square test and Fisher’s exact test. Cancer-specific survival (CSS) and disease-free survival (DFS) analysis were performed using the Kaplan–Meier method and Log-rank test. Multivariate Cox regression analysis was performed for multivariate predictive modeling. Qualifying criteria for inclusion in the Cox regression analysis were P value of≤0.1 or risk ratio≤0.5 or>2 in univariate Cox analysis. Tumor necrosis was defined as necrosis greater than 10% of tumor area based on microscopic evaluation in UTUC [¹⁹]. CSS was defined as the interval between surgery and death from UTUC. Death was scored as an event, and patients who died from other causes or were still alive were censored at the time of the last follow-up. DFS was calculated from the date of surgery to the date of the first documented evidence of recurrent disease or last follow-up visit alive. For all statistical tests, a P value of<0.05 represented a significant difference.

Clinical data

The clinicopathologic characteristics of the patients are summarized in Table 1. The median age at diagnosis was 70 years (range of 41–86 years). Of the 108 UTUC cases, 14 were low-grade and 94 were high-grade tumors, and the stage distribution was as follows: pTa, 14 cases (13.0%); pT1, 29 cases (26.8%); pT2, 27 cases (25.0%); pT3, 29 cases (26.9%); and pT4, 9 cases (8.3%). Median follow-up time was 28 months (range of 1–101 months). During the observation period, complete follow-up information was obtained from 94 patients, and 28 (29.8%) patients died of tumor progression.

Clinicopathologic significance of GATA3 expression and MSI in UTUC

Immunohistochemical staining for GATA3 and four MMR proteins was carried out in 108 UTUC samples and 24 corresponding normal urothelial tissues. Nuclear staining was considered a positive signal (Fig. 1). GATA3 expression was observed in 74 (68.5%) of 108 UTUC and all 24 (100%) normal tissues. The levels of GATA3 expression were significantly lower in tumor specimens than in normal urothelium (P<0.001). After the evaluation of MMR protein expression, 1 of 108 (0.9%) UTUC cases demonstrated the absence of MSH2 staining, 1 (0.9%) showed the absence of MSH6, 6 (5.6%) showed the absence of MLH1, and 7 (6.5%) showed the absence of PMS2. The total loss of MMR protein was observed in 9 (8.3%) cases, and focal staining was observed in 14 (13.0%) cases. An inverse relationship between GATA3 expression and MSI (strict criteria) was observed but was not statistically significant (P = 0.136). However, the relationship became significant when lax criteria were used and focal staining cases were included (P = 0.005, Table 2).

In all the patients with UTUC, loss of GATA3 expression was associated with tumor site (P = 0.048), pathological stage (P = 0.001), lymphovascular involvement (P = 0.035), neural invasion (P = 0.004), lymph node metastasis (P = 0.010), and extensive necrosis (P<0.001). In cases with muscle invasion, loss of GATA3 expression was more frequently observed in cases that also showed neural invasion (P = 0.032) or extensive necrosis (P = 0.011). However, neither absence nor focal staining of MMR protein showed an association with clinicopathologic parameters in the two UTUC groups (Table 3).

In our study cohort, the loss of GATA3 expression demonstrated strong association with poor survival in the CSS assay (P = 0.028) and DFS assay (P = 0.024) (data not shown). However, neither focal staining nor absence of MMR proteins showed any significant association with patient outcome.

In multivariate Cox regression analysis, only GATA3 met the qualifying criteria for inclusion in predictive modeling. Although the absence of GATA3 expression was shown to be a negative indicator for survival status in this UTUC cohort overall, the association was not observed in the multivariate analysis. Moreover, neither GATA3 nor MSI was significantly correlated with survival status in patients with muscle-invasive UTUC. However, as expected, advanced pT stage and the presence of extensive necrosis were independent prognostic factors for poor outcome (Table 4).

Analysis of GATA3 and MSI in combination

The patients were divided into four groups according to the expression patterns of GATA3 and MMR proteins as follows: GATA3⁺/MSI (n = 9), GATA3⁺/MS (n = 57), GATA3⁻/MSI (n = 11), and GATA3⁻/MS (n = 17). However, only a near-significant trend of survival difference was found within the four groups (P = 0.056 for CSS, P = 0.050 for DFS, Fig. 2). Upon further comparison of every set of two groups, the GATA3⁻/MS cohort was associated with advanced pT stage (P<0.001) and poor outcome (P = 0.019 for CSS, P = 0.016 for DFS, Fig. 3) as compared with the GATA3⁺/MSI cases. GATA3⁻/MSI patients showed unfavorable clinical outcome (P = 0.008 for CSS, P = 0.023 for DFS, Fig. 4) in contrast to cases with GATA3⁺/MSI. No significant difference in any parameter was found between the other groups. The GATA3⁻/MS group showed poorer outcome than the GATA3⁺/MSI cohort. Within the MSI group, cases without GATA3 expression showed unfavorable clinical outcome compared with cases with GATA3 expression.

Discussion

GATA3 has been used widely as a marker for urothelial differentiation [²⁰], and MMR proteins have been considered involved in the development of urothelial carcinoma [²¹]. However, to the best of our knowledge, these markers have not been evaluated together in a large number of UTUC cases in China, and whether there is a relationship between GATA3 expression and MSI status in UTUC remains unknown.

GATA3 is a well-established transcription factor marker for luminal muscle invasive bladder cancer and has been reported in several studies on bladder cancer molecular subtypes [²²–²⁴]. Similar to the findings on the cases of UTUC in western countries [¹⁶], our findings show that GATA3 expression is considerably downregulated relative to non-neoplastic urothelial tissues. GATA3 expression is considerably reduced when tumors with and without muscle-invasive UTUC are separately analyzed (data not shown).

In agreement with a previous study, which reported that GATA3 loss is related to muscle-invasive UTUC [¹⁶], our findings showed that the absence of GATA3 is associated with advanced stage UTUC. Meanwhile, no correlation was obtained among the UTUC cases. This finding is inconsistent with the findings of studies on bladder cancer [²⁵], which demonstrated that loss of GATA3 expression is associated with high-grade tumor. This might explain the more aggressive behavior of UTUC relative to that of bladder cancer [²⁶], thus resulting in a limited proportion of cases of low-grade UTUC. Although numerous studies have demonstrated the prognostic role of GATA3 in urothelial carcinoma or in breast carcinoma [⁷,²⁵,²⁷], the prognostic value of GATA3 has not been explored in UTUC cases in China. Inoue et al. reported the loss of GATA3 expression is an independent predictor of poor outcome in Japanese patients with UTUC [¹⁶]. Accordingly, we found that the absence of GATA3 indicates poor CSS and poor DFS in the univariate log rank test, but GATA3 was not identified as an independent marker of adverse prognosis in multivariate Cox regression analysis.

Although some researchers have insisted that only stains that are completely negative for MMR proteins should be interpreted as MSI tumors, more recent studies have suggested that lax criteria should be used in practice. As mentioned above, Mangold et al. [¹⁷] and Joost et al. [¹⁸] showed that tumors with focal MMR staining (less than 5% of tumor cells positive) are in fact MSI-H cases upon the evaluation with PCR-gene scan assay. In view of these controversial results, stringent criteria and lax criteria were tested in our study. When the lax criteria were used, MMR-negative staining cases were presented in 21.3% UTUC patients. This finding is similar to the findings from western countries, indicating a high level of MSI (25%, 46%) in UTUC [¹²,²⁸]. However, the correlation between MSI status and any clinicopathlogic parameter or prognosis in our UTUC cases was nonsignificant regardless of the criteria used. This result is inconsistent with the results of previous studies from other countries, which demonstrated that high MSI or inactivation of MMRs is associated with the presence of low-grade tumors and good prognosis in UTUC [²⁸–³¹]. These might be explained by the fact that Chinese UTUC exhibits unique characteristics in pathogenesis and clinicopathologic features. Although stringent MSI evaluation has no significant association with GATA3 expression, we did find an inverse correlation between lax MSI evaluation and GATA3 expression. Subsequently, in the survival analysis, a near-significant trend between patient outcome and each of the four combined expression patterns of GATA3/MSI was observed only when lax MSI criteria were used. Thus, the use of lax criteria may be effective in the evaluation of MSI status in UTUC. Focal MMR protein staining cases, which may likely contain MSI-H, should be further experimentally assessed.

We evaluated the associations among the combined expression patterns of GATA3 and MSI status to assess their predictive value for survival. The prognostic values of GATA3 expression and MSI status have been separately documented in numerous studies, but the prognostic value in combination had not been explored. As expected, the GATA3⁻/MS group was statistically associated with tumor progression and poor outcome as compared with the GATA3⁺/MSI cohort. At the same time, the GATA3⁻/MSI group was statistically correlated with tumor progression and poor outcome as compared with GATA3⁺/MSI counterparts. This correlation suggests that GATA3 is a critical factor in the evaluation of MSI patient outcome in UTUC.

To date, the relationship between GATA3 and MSI and the mechanisms underlying the coordinate function of these molecules has not been described. A previous study found that GATA3 inhibited metastases of breast cancer through abolition of the TGF-b signaling pathway [¹⁰]. Interestingly, studies on MSI-H colorectal cancers demonstrated that TGF-b signaling is ablated secondary to the high frequency of an inactivating mutation of the TGF-b receptor. Thus, the process is involved in tumorigenesis and tumor progression [¹¹,³²,³³]. Whether GATA3 interacts with MSI through the TGF-b signaling pathway to regulate UTUC progression requires further investigation.

Summary

In contrast to the absence of MMR proteins, loss of GATA3 expression was statistically associated with adverse clinicopathologic parameters and poor survival of Chinese patients with UTUC. The GATA3⁻/MS group was correlated with advanced pT stage and poor outcome compared with GATA3⁺/MSI cohort. This finding raises a question as to whether GATA3 interacts with MSI through the TGF-b signaling pathway and subsequently regulates UTUC progression.

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