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Loss of Rap1GAP in Papillary Thyroid Cancer

Departments of Medicine (A.N., M.S.B.), Otorhinolaryngology: Head and Neck Surgery (K.Pa., C.M., Y.W., K.Pu., A.U.I., S.R.F., M.S.B.), Pharmacology (O.M.T., J.L.M.), Biostatistics and Epidemiology (A.B.T.) and Pathology (M.D.F.), University of Pennsylvania, Philadelphia, Pennsylvania 19104; and Department of Pathology (Y.L.), Capital University of Medical Sciences, 100069 Beijing, China

Address all correspondence and requests for reprints to: Marcia S. Brose, M.D., Ph.D., Department of Otorhinolaryngology: Head and Neck Surgery, Department of Medicine, Division of Hematology/Oncology, Abramson Comprehensive Cancer Center The University of Pennsylvania, Clinical Research Building, Room 127, 415 Curie Boulevard, Philadelphia, Pennsylvania 19104. E-mail: brosem{at}mail.med.upenn.edu.

Context: Rap1 GTPase-activating protein (GAP) regulates the activity of Rap1, a putative oncogene. We previously reported Rap1GAP was highly expressed in normal human thyroid cells and decreased in five papillary thyroid carcinomas (PTCs).

Objectives: To confirm the significance of these findings, we analyzed Rap1GAP expression in a larger set of benign tumors (adenomas and hyperplastic nodules) and PTCs. We determined whether the presence of the BRAF^V600E mutation or allelic loss of Rap1GAP related to changes in Rap1GAP protein expression. To determine the consequences of Rap1GAP loss, we targeted Rap1GAP in culture using small interfering RNA.

Design, Patients, and Methods: A highly specific Rap1GAP antibody was applied to sections of 55 human thyroid tissues. Genomic DNA was analyzed for the presence of the BRAF^V600E mutation, and loss of Rap1GAP. Rap1GAP expression in rat thyroid cells was abolished using small interfering RNA.

Results: We observed that down-regulation of Rap1GAP in benign lesions and PTCs was common. Rap1GAP expression was more severely decreased in PTCs. Loss of Rap1GAP expression was observed in multiple histological variants of PTCs. Approximately 20% of PTCs and adenomas exhibited allelic loss of Rap1GAP. Loss of Rap1GAP was not associated with the presence of the BRAF^V600E mutation. In vitro, loss of Rap1GAP was sufficient to increase Rap1 activity in thyroid cells.

Conclusions: These data indicate that loss of Rap1GAP is a frequent event in PTC. The more frequent and greater down-regulation of Rap1GAP in PTCs compared with adenomas suggests a role for Rap1GAP depletion in the progression of human thyroid tumors, possibly through unrestrained Rap activity.