RESUMO
Previous loss-of-heterozygosity studies in endometrial carcinoma mapped a putative tumor suppressor gene to 10q25.3-26.1. An analysis of genomic sequences for the deletion interval showed several expressed sequence tags and the homeodomain gene EMX2, a homologue of Drosophila melanogaster empty spiracles. Expression studies showed that EMX2 transcripts are abundant in the adult uterus and that message levels seem to be inversely correlated with endometrial proliferation. EMX2 RNA was more abundant in quiescent postmenopausal endometrium than in premenopausal endometrium. We found decreased EMX2 expression in a subset of primary endometrial tumors, and four of six endometrial cancer cell lines investigated failed to express EMX2. The predicted protein showed extensive amino acid conservation with EMX2 sequences from several vertebrates. There was also considerable evolutionary conservation in the 3' untranslated region. To examine the potential function of EMX2 in endometrial tumorigenesis, we investigated 20 primary tumors and 6 endometrial cancer cell lines for mutations. Two primary tumors had mutations. Inactivation or reduced expression of EMX2 in cancers, coupled with increased expression in the quiescent endometrium, indicate that this homeodomain gene is involved in maintenance of the differentiated state.
Assuntos
Sequência Conservada/genética , Neoplasias do Endométrio/genética , Genes Homeobox/genética , Proteínas de Homeodomínio/biossíntese , Proteínas de Homeodomínio/genética , Adenocarcinoma/genética , Sequência de Aminoácidos , Sequência de Bases , Análise Mutacional de DNA/métodos , DNA de Neoplasias/genética , Evolução Molecular , Feminino , Perfilação da Expressão Gênica , Genes Supressores de Tumor/genética , Humanos , Tumor Mulleriano Misto/genética , Dados de Sequência Molecular , Mutação/genética , Polimorfismo Genético/genética , Fatores de Transcrição , Células Tumorais CultivadasRESUMO
Frequent loss of chromosome 10q sequences in endometrial cancers suggests the involvement of a tumor suppressor gene. Previous loss-of-heterozygosity (LOH)studies have pointed to the 10q25-q26 region as the likely site of a tumor suppressor involved in endometrial tumorigenesis (S. L. Peiffer et al., 1995, Cancer Res. 55: 1922-1926; S. Nagase et al., 1996, Br. J. Cancer 74: 1979-1983; S. Nagase et al.,1997, Cancer Res. 57: 1630-1633). In an attempt to define further the localization of a tumor suppressor gene at 10q25, we screened a panel of 123 endometrioid adenocarcinomas for loss of heterozygosity of 10q25.3 sequences. Forty-three (35%) revealed LOH at one or more loci. The observed patterns of allelic loss define a minimum consensus region of deletion between D10S221 and D10S610. A sequence-ready bacterial clone contig and a long-range restriction map for a 1-Mb interval spanning the deletion region were developed as the first step in experiments directed toward the discovery the 10q25 tumor suppressor.