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Notch-1 staining intensity and survival in patients with renal cell carcinoma
Shaun E. L. Wason, MD1, Renee Robinson, MD1, Tom Schwaab, MD2, Maudine Waterman, HT1, Peter L. Steinberg, MD1, John D. Seigne, MD1, Alan Schned, MD1, Marc Ernstoff, MD2.
1Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA, 2Immunology and Cancer Immunotherapy Research Program, Lebanon, NH, USA.

BACKGROUND: The Notch signaling pathway is a key pathway essential for vascular development and recent studies have elucidated the role of its ligand, DII4, in angiogenesis. Notch signaling is dysregulated in many cancers. The role of Notch-1 in renal cell carcinoma is unclear. The recent success of tyrosine kinase inhibitors in treating renal cell carcinoma has prompted investigation into exploring alternate avenues of angiogenesis that may potentially be therapeutic targets. The purpose of this study was to analyze the expression of Notch-1 in renal cell carcinoma and to assess its prognostic significance.
METHODS: The expression of Notch-1 was analyzed by immunohistochemistry in a cohort of 77 patients undergoing nephrectomy for renal cell carcinoma using tissue microarray analysis. Pearson correlation was used to explore the relationship between staining intensity (none, mild, moderate, strong) and staining percentage (0%, <33%, 34%-66%, >67%) with established clinical parameters such as nuclear grade, pathological stage, lymph node invasion, extracapsular extension, vascular invasion, distant metastasis, and patients' survival.
RESULTS: There were 45 men and 32 women in the study. The mean age at diagnosis was 62 ± 13. In normal kidney tissue, intense nuclear and cytoplasmic staining for Notch-1 was uniformly observed within the distal and proximal tubules, however the glomerulus and the rest of the normal tissue did not exhibit any staining. In tumor tissue, there were varying degrees of membranous, cytoplasmic and nuclear staining. Notch-1 staining was found to be present in 73 of 77 (95%) of renal cell tumors. There was no correlation between Notch-1 staining and nuclear grade, pathological stage, lymph node invasion, extracapsular extension, vascular invasion or distant metastasis. Increased Notch-1 staining intensity however, was significantly associated with a decrease in the number of years and months lived (pearson correlation r=-0.272, p<0.05 and -0.281, p<0.05 respectively).
CONCLUSIONS: Notch-1 is expressed on renal cell carcinomas and high Notch-1 staining intensity negatively correlates with survival. This suggests that Notch-1 is involved in renal cell carcinogenesis and may be a promising target for anti-angiogenesis therapy, but is not a robust biomarker to predict survival.


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