Sonic (Shh), Desert (Dhh) and Patched (PTCH1) Hedgehog Pathway Protein Expression Correlates with Aggressive Disease in Gastric/GE Junction Carcinomas (GCA)
Konstantinos Linos, Christine Sheehan, Jeffrey Ross. Memorial Sloan-Kettering Cancer Center, New York, NY; Albany Medical College, Albany, NY
Background: Activation of hedgehog signaling pathway is implicated in embryonic development and the differentiation, proliferation and maintenance of multiple adult tissues. Altered expression of Shh, Dhh and PTCH1 has been linked to Barrett's metaplasia in the esophagus and neoplastic transformation in the stomach, but has not been related to clinical outcome in GCA.
Design: Formalin-fixed, paraffin-embedded tissue sections of 126 GCA were immunostained by automated methods (Ventana Medical Systems Inc., Tucson, AZ) using goat polyclonal Shh, Dhh and PTCH1 antibodies (Santa Cruz Biotechnology, Santa Cruz, CA). Cytoplasmic immunoreactivity was scored based on staining intensity (weak, moderate, strong) and percentage of positive cells (focal <= 10%, regional 11-50%, diffuse >50%). Results were correlated with clinicopathologic variables.
Results: Immunoreactivity for Shh, Dhh and PTCH1 was predominately cytoplasmic. Shh overexpression was noted in 47% tumors and correlated with high grade [53% grade 3 vs 41% grade 2 vs 0% grade 1, p=0.042] and advanced stage [67% advanced vs 24% early, p=0.001]. Dhh overexpression was noted in 42% tumors and correlated with advanced stage [55% advanced vs 18% early, p=0.007], with a trend toward association with high grade [47% grade 3 vs 38% grade 2 vs 0% grade 1, p=0.089]. PTCH1 overexpression was noted in 84% tumors and correlated with high grade [83% grade 3 vs 90% grade 2 vs 40% grade 1, p=0.017]. On multivariate analysis, advanced stage [p=0.004] independently predicted shortened survival.
Conclusions: Protein expression of the Shh, Dhh, and PTCH1 members of the hedgehog pathway are associated with aggressive disease in GCA. Further study of hedgehog (Hh) signaling pathway in GCA appears warranted.
Monday, March 19, 2012 1:00 PM
Poster Session II # 94, Monday Afternoon