Notch Overexpression in Colorectal Adenocarcinoma (CRC)
JD Choate, KA Robstad, MN Donovan, MA DiMaio, CE Sheehan, JS Ross, DM Jones. Albany Medical College, Albany, NY
Background: Notch signaling is dysregulated in a variety of cancers, including cervical, head and neck, endometrial, renal, lung and breast carcinomas and hematological malignancies. In intestinal epithelium, Notch signaling via HES1 has been shown to promote the differentiation of enterocytes from intestinal 'stem cells' while inhibiting the differentiation of secretory cells. The prognostic significance of Notch2, Notch3 and Notch4 expression in CRC has not been previously studied.
Design: Formalin-fixed, paraffin-embedded sections from 125 colorectal adenocarcinomas (CRCs) were immunostained by an automated method (Ventana Medical Systems; Tuscon, AZ) using polyclonal rabbit IgG antibodies to Notch-2 (sc-5545), Notch-3 (sc-5593) or Notch-4 (sc-5594); (Santa Cruz Biotechnology, Santa Cruz, CA). Cytoplasmic immunoreactivity was semiquantitatively evaluated based on both intensity and distribution and results were correlated with histologic and prognostic variables.
Results: Overexpression of Notch2 was observed in 43/125 (34%) of CRCs, overexpression of Notch3 was seen in 29/116 (25%), and of Notch4 seen in 27/122 (22%). With all three Notch biomarkers, increasing expression was observed with increasing grade: for Notch2 (17% of grade 1, 32% of grade 2 and 54% of grade 3, p=0.034); for Notch3 (33% of grade1, 17% of grade 2 and 42% of grade 3, p=0.030); for Notch4 (11% of grade 1, 15% of grade 2 and 50% of grade 3, p=0.001). Notch2, Notch3 and Notch4 expression did not correlate with pathologic stage, disease recurrence or overall survival. On multivariate analysis, pathologic stage at diagnosis independently predicted patient survival.
Conclusions: Notch2, 3 and 4 proteins are overexpressed in colorectal adenocarcinomas, and the expression of each biomarker correlated with aggressive tumor histology. Notch2, Notch3 and Notch4 overexpression may be useful prognostic indicators in CRC, and further investigation of these biomarkers appears warranted.
Monday, March 9, 2009 9:30 AM
Poster Session I Stowell-Orbison/Autopsy Award # 92, Monday Morning