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. Accordingly, investigations of clonality with G6PD isoforms used as a marker for X chromosome inactivation have suggested independent origins for multiple tumors within individual uteri. However, results from a recent study assessing methylation differences between DNA of active and inactive 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 receptor gene. As shown by this assay, all informative leiomyomata were monoclonal in origin. In patients with multiple leiomyomata, a random distribution of inactivation between the X homologs was noted, consistent with an independent origin of each tumor. Cytogenetic analysis was also performed on short-term cell cultures of 27 of the 36 tumors. In each of two tumors that had both cells with a clonal karyotypic abnormality and karyotypically normal cells, DNA prepared from short-term cultures showed a monoclonal pattern of X inactivation identical to that of 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.
Mashal
R D
RD
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115.
Fejzo
M L
ML
Friedman
A J
AJ
Mitchner
N
N
Nowak
R A
RA
Rein
M S
MS
Morton
C C
CC
Sklar
J
J
D000483:Alleles; D001483:Base Sequence; D002869:Chromosome Aberrations; D002999:Clone Cells; D004273:DNA, Neoplasm / Q000235:genetics*; D004303:Dosage Compensation, Genetic; D005260:Female; D006801:Humans; D007621:Karyotyping; D018231:Leiomyomatosis / Q000235:genetics* / Q000473:pathology; D018598:Minisatellite Repeats; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000737:chemistry / Q000473:pathology; D011110:Polymorphism, Genetic; D011944:Receptors, Androgen / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000235:genetics* / Q000473:pathology
D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D011944:Receptors, Androgen