Placental S100 (S100P) and GATA3: Markers for Transitional Epithelium and Urothelial Carcinoma Discovered by Complementary DNA Microarray

Department of Biochemistry, Stanford University, Stanford, California, United States
American Journal of Surgical Pathology (Impact Factor: 5.15). 06/2007; 31(5):673-80. DOI: 10.1097/01.pas.0000213438.01278.5f
Source: PubMed


The morphologic distinction between prostate and urothelial carcinoma can be difficult. To identify novel diagnostic markers that may aid in the differential diagnosis of prostate versus urothelial carcinoma, we analyzed expression patterns in prostate and bladder cancer tissues using complementary DNA microarrays. Together with our prior studies on renal neoplasms and normal kidney, these studies suggested that the gene for placental S100 (S100P) is specifically expressed in benign and malignant urothelial cells. Using tissue microarrays, a polyclonal antiserum against S100P protein stained 86% of 295 urothelial carcinomas while only 3% of 260 prostatic adenocarcinomas and 1% of 133 renal cell carcinomas stained. A commercially available monoclonal antibody against S100P stained 78% of 300 urothelial carcinomas while only 2% of 256 prostatic adenocarcinomas and none of 137 renal cell carcinomas stained. A second gene, GATA3, also showed high level expression in urothelial tumors by cDNA array. A commercially available monoclonal antibody against GATA3 stained 67% of 308 urothelial carcinomas, but none of the prostate or renal carcinomas. For comparison, staining was also performed for p63 and cytokeratin 5/6. p63 stained 87% of urothelial carcinomas whereas CK5/6 stained 54%. Importantly, when S100P and p63 were combined 95% of urothelial carcinomas were labeled by one or both markers. We conclude that the detection of S100P and GATA3 protein expression may help distinguish urothelial carcinomas from other genitourinary neoplasms that enter into the differential diagnosis.

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    • "Initially discovered as a urothelial lineage marker by complementary DNA expression microarrays studies [19], GATA3 has since been shown to be a sensitive marker for urothelial carcinomas including several of its variants. In a recent comprehensive evaluation of GATA3 expression status in 2500 epithelial and nonepithelial tumors, Miettinen et al [20] showed lack of GATA3 positivity in all tested neuroendocrine tumors including carcinoids, well-differentiated pancreatic neuroendocrine tumors, and high-grade neuroendocrine carcinomas. "
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    ABSTRACT: GATA3 is a sensitive marker for urothelial carcinoma. We here evaluate, for the first time, GATA3 expression in small cell carcinoma of bladder and prostate and assess its utility in the differential diagnosis with small cell carcinoma of lung primary. Archival tissues from 60 small cell carcinomas (12 bladder, 15 lung and 33 prostate primary cases) were used to build two tissue microarrays. We also assessed whole slide sections from 10 additional primary small cell carcinomas of bladder. GATA3 nuclear expression was evaluated using standard immunohistochemistry. Intensity (weak, moderate and strong) and extent of expression were assessed in each TMA spot. Extent positivity was categorized as: focal (1-25%), multifocal (>25%) and diffuse (>75%). Nuclear GATA3 expression was encountered in 7 bladder (7/22, 32%) and 2 lung (2/15, 13%) small cell carcinomas. All 33 primary prostate small cell carcinomas were negative. Among bladder tumors, strong and diffuse (>75%) GATA3 labeling was seen in 3 cases (3/22, 14%); focal positivity was observed in the 4 remaining cases (4/22, 18%). Both positive lung cases had only focal positivity. Our study is the first to reveal GATA3 expression in small subset of lung small cell carcinoma that should be taken into consideration in assigning site of origin in advanced small cell carcinoma cases. Our novel finding of GATA3 positivity in one third of bladder small cell carcinoma is of potential value in differentiating small cell carcinomas of prostate origin from those of bladder origin.
    Full-text · Article · Aug 2014 · Human pathology
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    • "Upper tract urothelial carcinoma (UT-UC) is a relatively uncommon form of kidney cancer arising from the urothelial lining of the renal pelvis and calyces. UT-UC accounts for the majority of bladder cancer; however, it only accounts for about 7% of renal neoplasms [7]. UC of the renal pelvis is an aggressive tumour, which may invade the renal parenchyma, mimicking primary renal cell carcinoma. "
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    ABSTRACT: Upper tract urothelial carcinomas (UT-UC) can invade the pelvicalyceal system making differential diagnosis of the various histologically distinct renal cell carcinoma (RCC) subtypes and UT-UC, difficult. Correct diagnosis is critical for determining appropriate surgery and post-surgical treatments. We aimed to identify microRNA (miRNA) signatures that can accurately distinguish the most prevalent RCC subtypes and UT-UC form the normal kidney. miRNA profiling was performed on FFPE tissue sections from RCC and UT-UC and normal kidney and 434 miRNAs were significantly deregulated in cancerous vs. the normal tissue. Hierarchical clustering distinguished UT-UCs from RCCs and classified the various RCC subtypes among them. qRT-PCR validated the deregulated expression profile for the majority of the miRNAs and ROC analysis revealed their capability to discriminate between tumour and normal kidney. An independent cohort of freshly frozen RCC and UT-UC samples was used to validate the deregulated miRNAs with the best discriminatory ability (AUC>0.8, p<0.001). Many of them were located within cytogenetic regions that were previously reported to be significantly aberrated. miRNA targets were predicted using the miRWalk algorithm and ingenuity pathway analysis identified the canonical pathways and curated networks of the deregulated miRNAs. Using the miRWalk algorithm, we further identified the top anti-correlated mRNA/miRNA pairs, between the deregulated miRNAs from our study and the top co-deregulated mRNAs among 5 independent ccRCC GEO datasets. The AB8/13 undifferentiated podocyte cells were used for functional assays using luciferase reporter constructs and the developmental transcription factor TFCP2L1 was proved to be a true target of miR-489, which was the second most upregulated miRNA in ccRCC. We identified novel miRNAs specific for each RCC subtype and UT-UC, we investigated their putative targets, the networks and pathways in which they participate and we functionally verified the true targets of the top deregulated miRNAs.
    Full-text · Article · Mar 2014 · PLoS ONE
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    • "PAX8 IHC has also been observed in nonneoplastic and neoplastic tissues of Müllerian and Wolffian origin as well as the endocrine pancreas, thyroid, parathyroid, and thymus [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16]. Recently, GATA3 IHC has been shown to be a sensitive marker for urothelial carcinoma (UC), ductal breast carcinoma, and transitional cell proliferations of the female genital tract [17] [18]. Sarcomatoid carcinomas are malignant neoplasms that demonstrate epithelial and mesenchymal differentiation. "
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    ABSTRACT: Immunohistochemistry for PAX8 and GATA3 are sensitive markers for renal cell carcinoma and urothelial carcinoma, respectively. However, there are limited data on these markers in sarcomatoid renal cell carcinoma (SARCRCC) and sarcomatoid urothelial carcinoma (SARCUC). Tissue microarrays (TMAs) were constructed from 45 cases of SARCRCC and 45 cases of SARCUC of the lower urinary tract, with an additional 11 SARCUCs of the upper tract. PAX8 and GATA3 were also evaluated in TMAs from 161 sarcomas from other sites, 14 atypical epithelioid angiomyolipomas (AMLs) of the kidney, 23 bladder inflammatory myofibroblastic tumors (IMTs), and 2 bladder and 4 renal leiomyosarcomas. In the SARCRCC, PAX8 and GATA3 were positive in the sarcomatoid areas in 31 (69%) and 0 (0%) of cases, respectively. In the bladder SARCUC, GATA3 and PAX8 were positive in 14 (31%) and 2 (4%) of cases, respectively. Of the 11 SARCUCs of the upper urinary tract, 2 (18%) cases were PAX8 positive and 2 (18%) separate cases were GATA3 positive. Only 1 tumor present on the sarcoma TMAs, a Ewing sarcoma/primitive neuroectodermal tumor, was PAX8 positive, and all sarcomas were GATA3 negative. Of the AMLs, IMTs, and leiomyosarcoma, only 1 case of IMT showed moderate GATA3 positivity, and all were negative for PAX8. PAX8 can be used to distinguish SARCCRCC from atypical epithelioid AMLs and primary renal or retroperitoneal sarcomas. However, in a kidney/renal pelvic tumor, PAX8 shows overlap in staining between SARCUC and SARCRCC. GATA3 lacks sensitivity but is more specific for SARCUC.
    Full-text · Article · Feb 2013 · Human pathology
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