Frequent loss of heterozygosity for chromosome 10 in uterine leiomyosarcoma in contrast to leiomyoma

Abstract

Distinction of malignant uterine leiomyosarcomas from benign leiomyomas by morphological criteria is not always possible. Leiomyosarcomas typically have complex cytogenetic abnormalities; in contrast, leiomyomas have simple or no cytogenetic abnormalities. To understand better the biological distinction(s) between these tumors, we analyzed two other potential markers of genomic instability, loss of heterozygosity (LOH) and microsatellite instability. We examined archival materials from 16 leiomyosarcomas and 13 benign leiomyomas by polymerase chain reaction for 26 microsatellite polymorphisms. Markers were selected based on previous reports of cytogenetic or molecular genetic abnormalities in leiomyosarcomas or leiomyomas and surveyed chromosomes 7, 9, 10, 11, 12, 14, 15, 16, 18, 21, and X. LOH for markers on chromosomes 15, 18, 21, and X was infrequent in leiomyosarcomas (1 of 6 tumors for each chromosome) and not observed for markers on chromosomes 7, 9, 11, 12, 14, or 16. Interestingly, 8 of 14 (57.2%) informative leiomyosarcomas had LOH for at least one marker on chromosome 10 and involved both chromosomal arms in 45.5% (5 of 11). In contrast to leiomyosarcomas, LOH for chromosome 10 was not found in 13 benign leiomyomas. Microsatellite instability was found infrequently in leiomyosarcomas and not detected in leiomyoma. Clinicopathological features (eg, atypia, necrosis, and clinical outcome) did not appear to correlate with LOH for chromosome 10. In contrast to other chromosomes studied, LOH on chromosome 10 was frequent in leiomyosarcomas and absent in benign leiomyomas.

Figure 1.

Distribution of loss of heterozygosity for chromosome 10 in uterine leiomyosarcomas. Case numbers are indicated in the left column. •, loss of heterozygosity; ○, retention of heterozygosity; —, uninformative (homozygosity); ★, microsatellite instability; blank, not determined. Numbers above the 550 band resolution idiogram of chromosome 10 label cytogenetic bands and bars below show the approximate cytogenetic localization of microsatellite markers. The diagonal hash marks on the ideogram correspond to the centromere between the short (p) and long (q) chromosomal arms. The double lines beneath the idiogram mark the cytogenetic localization of the PTEN gene in band q23. Rows 3a and 3b correspond to different portions of the same tumor and analysis of selected microsatellites is illustrated in Figure 2 ▶ (lanes A and B, respectively).

Figure 2.

Heterogeneity of allelic losses for chromosome 10 markers in one leiomyosarcoma. Microsatellite polymorphisms from the telomeric region of 10p (D10S1435) and the central and subtelomeric regions of 10q (D10S218 and D10S1213) were analyzed from different portions (tumor, lanes A and B; normal myometrium, lane M) of case 3 (rows 3a and 3b, respectively, in Figure 1 ▶ ). LOH for D10S1435 was limited to sample A. In contrast, both tumor samples showed LOH for markers from 10q, but the tumor samples differed with respect to the particular copy of chromosome 10 that was lost. This complex pattern of allelic loss is not consistent with an initial event but rather suggests clonal evolution with several acquired losses of chromosome 10 material. Normal myometrium is analyzed in lane M.