CD31, EDNRB and TSPAN7 are promising prognostic markers in clear-cell renal cell carcinoma revealed by genome-wide expression analyses of primary tumors and metastases.

Currently used clinicopathological parameters are insufficient for a reliable prediction of metastatic risk and disease-free survival (DFS) of patients with clear-cell renal cell carcinoma (ccRCC). To identify prognostic genes, the expression profiles of primary ccRCC obtained from patients with different DFS--eight synchronously, nine metachronously and seven not metastasized tumors--were determined by genome-wide expression analyses. Synchronously and metachronously metastasized primary ccRCC differed in the expression of 167 genes. Thirty-six of these genes were also differentially expressed in synchronously vs. metachronously developed pulmonary metastases analyzed in a previous study. Because of their DFS-associated deregulation that is concordant in metastases and primary ccRCC, these genes are potentially functionally involved in metastatic tumor growth and are also prognostically useful. A prognostic impact was confirmed for the genes CD31, EDNRB and TSPAN7 at the mRNA level (n=86), and for TSPAN7 at the protein level (n=106). Patients with a higher gene expression of EDNRB or TSPAN7, or with TSPAN7-positive vessels in both cores investigated on tissue microarrays had a significantly longer DFS and tumor-specific survival (TSS). Patients with a higher CD31 gene expression showed a significantly longer TSS. EDNRB was an independent prognostic marker for the DFS. CD31, EDNRB and TSPAN7 had an independent impact on the TSS. In summary, comparative analysis of primary tumors and metastases is appropriate to identify independent prognostic markers in ccRCC. Gene expression of CD31 and EDNRB, and endothelial TSPAN7 protein level are potentially useful to improve outcome prediction because of their independent prognostic impact.

Wuttig D ，Zastrow S ，Füssel S ，Toma MI ，Meinhardt M ，Kalman K ，Junker K ，Sanjmyatav J ，Boll K ，Hackermüller J ，Rolle A ，Grimm MO ，Wirth MP ... -  《-》

MicroRNAs with prognostic potential for metastasis in clear cell renal cell carcinoma: a comparison of primary tumors and distant metastases.

Heinzelmann J ，Unrein A ，Wickmann U ，Baumgart S ，Stapf M ，Szendroi A ，Grimm MO ，Gajda MR ，Wunderlich H ，Junker K ... -  《-》

Alpha-enolase is a potential prognostic marker in clear cell renal cell carcinoma.

White-Al Habeeb NM ，Di Meo A ，Scorilas A ，Rotondo F ，Masui O ，Seivwright A ，Gabril M ，Girgis AH ，Jewett MA ，Yousef GM ... -  《-》

PLAGL1 (ZAC1/LOT1) Expression in Clear Cell Renal Cell Carcinoma: Correlations with Disease Progression and Unfavorable Prognosis.

Pleiomorphic adenoma gene-like 1 (PLAGL1) protein was originally shown to induce cell-cycle arrest and promote apoptosis in several types of human tumors and therefore it was considered a candidate tumor suppressor. The involvement of PLAGL1 gene in the etiology and pathogenesis of clear cell renal cell carcinoma (ccRCC) has not been evaluated. The purpose of the present study was to determine the expression level of PLAGL1 in ccRCC and to investigate its potential utility as a prognostic factor. We applied quantitative real-time polymerase chain reaction (QPCR), western blotting and immunohistochemistry to measure PLAGL1 mRNA/protein contents in paired tumor and kidney specimens of 40 patients with ccRCC. PLAGL1 mRNA and protein levels were increased in tumor tissues as determined by QPCR and immunohistochemistry, respectively. The average content of PLAGL1 protein measured by western blotting did not differ between tumor and non-cancerous kidney tissues. However, increased PLAGL1 protein level in ccRCC tissue positively correlated with the presence of distant metastases and worse patient outcome. These results suggest an oncogenic role of PLAGL1 in the progression of ccRCC and its potential value as a prognostic marker.

Godlewski J ，Krazinski BE ，Kowalczyk AE ，Kiewisz J ，Kiezun J ，Kwiatkowski P ，Sliwinska-Jewsiewicka A ，Maslowski Z ，Kmiec Z ... -  《-》

Reduced expression of growth and differentiation factor-9 (GDF9) is associated with aggressive behaviour of human clear-cell renal cell carcinoma and poor patient survival.

Growth and differentiation factor-9 (GDF9) is a member of the bone morphogentic protein (BMP) family. GDF9 was recently shown to be a regulator of the development and spread of cancer cells, including kidney cancer cells. However, the clinical implication of GDF9 in human clear-cell renal cell carcinoma (CCRCC) remains unknown. In the present study, the expression of GDF9 in human CCRCC tissues, and correlation between GDF9 and pathological grade and stage of the tumours were examined in CRCC specimens. The expression of GDF9 was examined in paired human normal renal and CCRCC tumour tissues (n=86). The expression of GDF9 in human renal tissues was assessed at both the mRNA and protein levels using reverse transcription-polymerase chain reaction and western blot. Furthermore, the survival curve was constructed using Kaplan-Meier method. Decreased GDF9 protein levels were seen in CCRCC tissues compared with normal tissues. Low protein levels were seen in tumours with high clinical stages and with high pathological nuclear grade of CCRCC. Likewise, levels of GDF9 transcript in normal renal specimens was significantly higher than that in CCRCC tissues. The transcript levels of GDF9 differed significantly amongst different clinical stages and different pathological nuclear grade of CCRCC: The higher the clinical stage or pathological nuclear grade of CCRCC, the lower the transcript level of GDF9. Cumulative survival curves indicated that GDF9 mRNA expression was negatively correlated with cumulative survival time. Patients with high level of GDF9 had significantly longer survival time than the patients with low level of GDF9 (p<0.001). GDF9 expression is markedly decreased in CCRCC, and is linked to pathological grade, clinical stage and long-term survival of the patients. This suggests that GDF9 is a potential tumour suppressor in CCRCC.

Du P ，Ye L ，Yang Y ，Jiang WG ... -  《-》