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A Novel SMAD4 Gene Mutation in Seminoma Germ Cell Tumors¹

Institut National de la Santé et de la Recherche Médicale U407, Faculté de Médecine Lyon-Sud, 69621 Oullins Cédex [M. Bo., J. B., M. Be., R. B.]; Centre Léon Berard [E. T., J-P. D.] and Institut de Biologie et de Chimie des Protéines [P. S.], 69007 Lyon Cédex 07; and Hôpital Edouard Herriot, 69373 Lyon Cédex [R. B.], France

Transforming growth factor (TGF)-ß is known as an antiproliferative factor in the majority of mammalian cells, including stem germ cells. Lack of TGF-ß-induced growth inhibition has been associated with disruptions of TGF-ß receptors and SMADs. In the present study, we performed a mutational analysis of the TGF-ß signaling system, including TGF-ß receptor type I and type II and SMADs (SMAD1–SMAD7), in 20 seminoma germ cell tumors. Using reverse transcription-PCR, single-strand conformational polymorphism, and sequencing analysis, the COOH-terminal domain of SMAD4 was found to be mutated: a single thymine was inserted between nt 1521 and 1522 in 2 of 20 tumors analyzed. This addition of a thymine creates a frameshift and a new stop signal at codon 492, which leads to premature termination of the encoded protein. Such a mutation potentially abrogates signaling from TGF-ß as well as the other TGF-ß family members, including activin and bone morphogenetic protein, which all use the SMAD pathway. Immunohistological analysis confirmed the loss of expression of SMAD4 protein in the seminoma tissues with the insertional mutation. To our knowledge, this is the first description of a novel SMAD4 insertional mutation in seminoma testicular germ cell tumors. This mutational inactivation of SMAD4/COOH-terminal domain may cause TGF-ß unresponsiveness. It could thus provide a basis for understanding the potential role of the TGF-ß system in germ cell tumorigenesis.

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