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- W2246126953 abstract "6059 Background: With the early success of kinase inhibitors in the treatment of differentiated thyroid cancer, we seek to better characterize the status of key cell signaling pathways. RAP1 GTPase activating protein (RAP1GAP) regulates the oncogene RAP1, which, in turn, activates the oncogene BRAF. Previously, we identified decreased expression of RAP1GAP in human thyroid cancer cell lines, and a cessation of invasion and anchorage independent proliferation upon rescue of the RAP1GAP phenotype. This study extends these in vitro findings by examining RAP1GAP expression in primary thyroid tumors. Methods: Tissue blocks from patients with papillary thyroid cancer (PTC) were obtained. Immunohistochemistry was performed using a polyclonal RAP1GAP antibody (Santa Cruz) and staining intensity was scored by two independent pathologists on a 0–3 scale. The Wilcoxon signed-rank test was used to measure differences in staining between tumor and adjacent normal tissue on the same slide. The Wilcoxon rank sum test was used to evaluate variation in staining intensity between tissue groups. Tumor genomic DNA was analyzed for the BRAFV600E mutation. Results: 55 tissue blocks were examined (36 PTC, 16 adenomas, 3 hyperplastic nodules). Mean RAP1GAP staining of adjacent normal tissue, benign nodules, and invasive cancer were 2.4 ± 0.50, 2.18 ± 0.65, 1.15 ± 0.52, respectively. Decreases in RAP1GAP staining between benign and invasive nodules and adjacent normal tissue were statistically significant (p<0.001 and p<0.002). Decreases in RAP1GAP staining were more pronounced in invasive tumors than benign lesions (p < 0.0001). BRAFV600E mutation was found in 11 of 34 sequenced PTCs. No difference in RAP1GAP staining was found between PTC tissue with and without BRAFV600E. Conclusions: Our study shows a progressive decline in RAP1GAP levels from normal tissue to benign and then to invasive thyroid lesions, implicating loss of RAP1GAP in the evolution of thyroid carcinoma. Increased activity of RAP1 due to loss of RAP1GAP may lead to tumor invasion by disruption of cell-cell or cell-basement-membrane adhesion. Our study also suggests that loss of RAP1GAP is independent from the BRAFV600E mutation. Further investigation of the control of signaling through RAP1 may lead to new therapeutic targets for thyroid cancer. No significant financial relationships to disclose." @default.
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- W2246126953 date "2008-05-20" @default.
- W2246126953 modified "2023-09-23" @default.
- W2246126953 title "Progressive loss of Rap1GAP in benign and invasive thyroid cancer" @default.
- W2246126953 doi "https://doi.org/10.1200/jco.2008.26.15_suppl.6059" @default.
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