Hedgehog Pathway Gene Product Expression in Renal Cell Carcinomas (RCC).
Kelly A Kim, Jennifer L Garbaini, Christine E Sheehan, Ronald P Kaufman, Jeffrey S Ross, Alida M Hayner-Buchan. Albany Medical College, NY
Background: The hedgehog signaling pathway is involved in embryonic development and stem cell renewal in a variety of tissues. Recent studies demonstrate reactivation of this normal developmental signaling pathway in RCC, suggesting a role for the hedgehog pathway in RCC tumorigenesis. This study investigates the expression of these and other hedgehog pathway gene products in RCC.
Design: Tissue sections from 94 formalin-fixed, paraffin-embedded cases of RCC were immunostained by an automated method (Ventana Medical Systems Inc., Tucson, AZ) using Santa Cruz goat polyclonal antibodies to Desert hedgehog (N-19) and Sonic hedgehog (N-19), and Santa Cruz rabbit polyclonal antibodies to Fox M1 (K-19) and patched (H-267). Cytoplasmic immunoreactivity based on intensity and distribution was semiquantitavely scored and the results were correlated with clinical and morphologic variables.
Results: Sonic hedgehog (SHH) overexpression was noted in 39/94 (42%) tumors, including 26/77 (34%) clear cell carcinomas and correlated with high grade (p=0.035 for all tumors, p=0.007 for clear cell carcinomas). Patched overexpression was identified in 52/94 (55%) tumors, including 36/77 (47%) clear cell carcinomas and correlated with high grade (p=0.002 for all tumors, p=0.01 for clear cell carcinomas), shortened length of survival (p=0.04) and showed a trend toward association with advanced stage (p=0.06). Fox M1 overexpression was noted in 52/94 (55%) tumors and showed a trend toward correlation with high grade (p=0.071 for all tumors, p=0.085 for clear cell carcinomas). Desert hedgehog (DHH) was overexpressed in 43/94 (46%) tumors and showed a trend toward correlation with advanced stage (p=0.09). There was significant coexpression of each of the proteins with one another (p≤0.002). In addition, there was significant co-overexpression of SHH and patched within high grade tumors (p=0.024 for all tumors, p=0.037 for clear cell carcinomas). On multivariate analysis, tumor grade (p=0.01) and stage (p=0.012) independently predicted overall survival.
Conclusions: The hedgehog signaling pathway appears to be upregulated in high grade RCCs and associated with aggressive disease (advanced stage and shortened survival). Further, these pathway members (SHH, DHH, patched and Fox M1) appear to be co-expressed. Additional studies to further characterize the role of the hedgehog pathway in RCC are indicated.
Category: Genitourinary (including renal tumors)
Wednesday, March 2, 2011 9:30 AM
Poster Session V # 99, Wednesday Morning