ANALYSIS OF ANDROGEN RECEPTOR DNA REVEALS THE INDEPENDENT CLONAL ORIGINS OF UTERINE LEIOMYOMATA AND THE SECONDARY NATURE OF CYTOGENETIC ABERRATIONS IN THE DEVELOPMENT OF LEIOMYOMATA

Uterine leiomyomata are thought to be monoclonal neoplasms. Accordingl y, investigations of clonality with G6PD isoforms used as a marker for X chromosome inactivation have suggested independent origins for mult iple tumors within individual uteri. However, results from a recent st udy assessing methylation differences between DNA of active and inacti ve X chromosomes have been interpreted to suggest that multiple tumors may arise from a common precursor. We have examined the clonality of 36 leiomyomata from 16 patients by analyzing X chromosome inactivation as indicated by the methylation status of the X-linked androgen recep tor gene. As shown by this assay, all informative leiomyomata were mon oclonal in origin. In patients with multiple leiomyomata, a random dis tribution of inactivation between the X homologs was noted, consistent with an independent origin of each tumor. Cytogenetic analysis was al so performed on short-term cell cultures of 27 of the 36 tumors. In ea ch of two tumors that had both cells with a clonal karyotypic abnormal ity and karyotypically normal cells, DNA prepared from short-term cult ures showed a monoclonal pattern of X inactivation identical to that o f the leiomyoma from which they were derived. These data suggest that karyotypically normal cells present in short-term cultures of uterine leiomyomata are part of the tumor clone, and that clonal expansion of tumor cells precedes the development of cytogenetic aberrations. (C) 1 994 Wiley-Liss, Inc.