High level of EZH2 expression is linked to high density of CD8-positive T-lymphocytes and an aggressive phenotype in renal cell carcinoma.

PURPOSE: Enhancer of zeste homolog 2 (EZH2), the catalytic part of the Polycomb repressive complex 2 (PRC2), has a prognostic role in renal cell carcinoma (RCC) and was recently shown to modulate the immune response by reducing tumor cell immunogenicity. METHODS: To investigate whether the prognostic role of EZH2 might be driven by a modified immune environment, more than 1800 RCCs were analyzed in a tissue microarray for EZH2 expression and CD8 positive lymphocytes were quantitated by automated digital imaging. RESULTS: EZH2 positivity was found in 75.2% of 1603 interpretable tumors. In clear cell RCC, high EZH2 expression was significantly linked to high ISUP, Furmann, and Thoenes grade (p < 0.0001 each), advanced stage (p < 0.0001), nodal (p = 0.0190) and distant metastasis (p < 0.0001) as well as shortened overall (p < 0.0027) and recurrence free survival (p < 0.0001). The density of CD8+ cells varied from 0 to 5048 cells/mm2 (Median 120 cells/mm2). A high CD8+ count was significantly associated with high ISUP, Fuhrmann, and Thoenes grade (p < 0.0001 each), advanced tumor stage (p = 0.0041), distant metastasis (p = 0.0026) as well as reduced overall survival (p = 0.0373) and recurrence free survival (p = 0.0450). The density of CD8+ cells continuously increased with raising EZH2 levels (p < 0.0001). CONCLUSION: Our data support a striking prognostic role of both EZH2 expression and the density of CD8+ cells in RCC. The tight relationship of EZH2 expression and CD8+ cell counts in RCC is consistent with models suggesting that EZH2 overexpression can be caused by high lymphocyte content in certain tumor types. Such a mechanism could explain the unique finding of high lymphocyte counts driving poor prognosis in RCC patients.

Chromosomal deletion of 9p21 is linked to poor patient prognosis in papillary and clear cell kidney cancer.

BACKGROUND: The ongoing approval of adjuvant systemic therapy in high-risk kidney tumor will increase the demand for prognostic assessment in these tumors. 9p21 deletion has been suggested as a possible prognostic feature in clear cell kidney cancer. MATERIAL AND METHODS: To learn more on the prognostic relevance of 9p21 deletions in clear cell and other kidney tumors, 1,809 kidney tumor specimens were analyzed by dual-labeling fluorescence in situ hybridization (FISH) with probes for 9p21 and centromere 9 in a tissue microarray format. Results were compared to histologic tumor type, pT stage, grade, and patient outcome. RESULTS: A total of 1,341 (74%) of tumor samples had interpretable FISH results. 9p21 deletion was found in 4.4% of 894 clear cell, 5.1% of 197 papillary, and 4.2% of 71 chromophobe carcinomas. 9p21 deletions were not found in 112 oncocytomas and in 21 clear cell tubulo-papillary cancers. In clear cell carcinomas, 9p deletions were associated with advanced stage (P = 0.009) and nodal metastasis (P = 0.0067), but not with ISUP grade (P = 0.1039) and distant metastasis (P = 0.4809). Also, in papillary carcinomas, 9p deletions were associated with advanced stage (P = 0.0008) and nodal metastasis (P = 0.0202) but not with ISUP grade (0.0904) and distant metastasis (P = 0.2022). Follow-up data were available for 789 clear cell and 177 papillary cancers. In both tumor entities, 9p21 deletions were associated with shortened overall survival, tumor-specific death, and progression-free survival in univariate analysis (P < 0.02 each). In a multivariate analysis, 9p21 deletion was an independent predictor of early tumor recurrence (P = 0.04). CONCLUSION: 9p21 deletions, 9p21 deletions identify a small subset of aggressive renal carcinomas. 9p deletion assessment may be clinically useful to identify high-risk renal cell carcinomas.