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Activating Mutation of the Stimulatory G Protein (gsp) as a Putative Cause of Ovarian and Testicular Human Stromal Leydig Cell Tumors¹

Division of Endocrinology, Developmental Endocrinology Unit and Hormone and Molecular Genetics Laboratory (M.C.B.V.F., A.C.L., J.A.M.M., V.S.L., E.T.F., B.B.M., S.M.F.V.), Department of Pathology (F.M.C., M.C.N.Z.), Hospital das Clínicas, São Paulo University School of Medicine, São Paulo; Unit of Endocrinology, Hospital Universitário Professor Edgard Santos, Bahia University School of Medicine (L.M.B.A.), Salvador, Brazil

Address all correspondence and requests for reprints to: Dr. Sandra M. F. Villares, Hospital das Clínicas, Endocrinologia, Caixa Postal 3671, CEP 01060–970, Sao Paulo, Brazil. E-mail: smvillar{at}usp.br

Activating mutations of the G protein genes have been associated with the development of several endocrine neoplasms. Such activating mutations, gip2, affecting the -subunit of the G_i2 protein were previously described by a single group in 30% of ovarian sex cord stromal tumors. Other activating mutations of the -subunit of the G_s (gsp) have been identified in GH-secreting and nonfunctioning pituitary tumors, autonomous thyroid adenomas, and all affected McCune-Albright tissues, but not in sex cord stromal tumors. In the present study, we investigated the presence of gip2 and gsp mutations in 14 human sex cord stromal tumors. Six Leydig cell tumors (4 ovaries and 2 testes), 2 thecomas, 2 granulosa cell tumors, 3 androblastomas, and 1 gonadoblastoma (sex cord and germ cell) were included in this study. Genomic DNA was obtained from either fresh-frozen tumor tissues or paraffin-embedded sections and in some cases from blood samples. Using PCR, denaturing gradient gel electrophoresis, and direct sequencing, we detected 4 tumors (66.6%) with the gsp mutation (R201C) in our series of ovarian and testicular Leydig cell tumors. In contrast, no gip2 mutations were found in any of the sex cord stromal tumors studied. In conclusion, our findings suggest that the putative oncogene gsp may play a significant role in the molecular mechanism of these tumors.

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