A malignant triton tumor with an unbalanced translocation (1;13)(q10;q10) and an isochromosome (8)(q10) as the sole karyotypic abnormalities.

The karyotype of a malignant nerve sheath tumor with rhabdomyosarcomatous differentiation (malignant triton tumor) of a 58-year-old woman is reported. The tumor revealed an isochromosome for the long arm of chromosome 8 and an unbalanced translocation (1;13)(q10;q10) leading to a gain of the long arm of chromosome 1 as the sole karyotypic abnormalities.

Chromosomal translocations affecting 12q14-15 but not deletions of the long arm of chromosome 7 associated with a growth advantage of uterine smooth muscle cells.

Cytogenetically, uterine leiomyomata are the best investigated human tumours. The most frequent clonal abnormalities are structural rearrangements involving 12q14-15 and deletions of part of the long arm of chromosome 7. The present study investigated a possible growth advantage conferred by these abnormalities, when compared with myomata having an apparently normal karyotype. A total of 155 myomata were included in the study. All samples were obtained after hysterectomy enabling karyotype analysis of all detectable tumours. Myomata with clonal chromosome abnormalities were significantly larger than those with a normal karyotype (6.8 +/- 5.3 versus 3.4 +/- 2.1 cm; P < 0.001). However, when differentiating between the two main aberrations, this was found to be true for the myomata with 12q14-15 changes affecting the high mobility group protein IC (HMGIC) gene (8.9 +/- 5.6 cm), but not for the group of tumours characterized by deletions of chromosome 7 (3.5 +/- 2.0 cm). The results are compatible with the hypothesis that myomata develop due to an unknown event, whereas the chromosomal abnormalities act as secondary changes, with those affecting the HMGIC gene increasing the growth potential of the corresponding tumours.

Karyotype evolution in a case of uterine angioleiomyoma.

Clonal karyotypic alterations of a uterine angioleiomyoma of a 41-year-old woman are reported. Cytogenetically a stemline of the tumor and two related subclones with additional abnormalities due to karyotypic evolution were identified: 46,X,t(X;11)(p11.4;p15)/46, idem,inv(2)(p15q13)/46, idem,inv(2)(p15q13),t(5;20)(q13;q13.2). None of the aberrations observed in the present case has been reported in uterine smooth muscle tumors before.

A third case of a low-grade endometrial stromal sarcoma with a t(7;17)(p14 approximately 21;q11.2 approximately 21).

Cytogenetic analysis of a low-grade endometrial stromal sarcoma of the uterus in a 52-year-old woman revealed the karyotype 46,XX,t(7;17)(p14 approximately 21;q11.2 approximately 21),der(7)t(7;16)(p14-15;q22)t(7;9) (q22;q22), der(9)t(7;9)(q22;q22),del(16)(q22). The t(7;17) was identical to an aberration observed in two other cases of endometrial stromal sarcomas, thus confirming the idea that it constitutes a non-random aberration for this type of tumor.

HMGIC expressed in a uterine leiomyoma with a deletion of the long arm of chromosome 7 along with a 12q14-15 rearrangement but not in tumors showing del(7) as the sole cytogenetic abnormality.

Cytogenetic studies on uterine leiomyomas have shown that more than 60% of these tumors possess a normal karyotype and that 30% have clonal chromosomal aberrations. The most frequent changes are aberrations involving 12q14-15 and show rearrangements of the long arm of chromosome 7. Recently, we were able to demonstrate that in a variety of mesenchymal tumors showing 12q14-15 aberrations the HMGIC gene is rearranged thus playing a role in tumorigenesis. Here we report the results of HMGIC expression studies by RT-PCR of five uterine leiomyomas with different karyotypes. The RT-PCR studies were performed on two primary tumors showing a 12q14-15 aberration, one of which with an additional del(7) and three tumors with del(7) as the sole aberration. The tumor with the 12q14-15 aberration as the sole alteration and the leiomyoma with 12q14-15 rearrangement plus deletion of the long arm of chromosome 7 were shown to express HMGIC. In contrast, in all three tumors with the del(7) as the sole aberration no expression of HMGIC was noted.

HMGI-C expression patterns in human tissues. Implications for the genesis of frequent mesenchymal tumors.

Cytogenetically visible aberrations of chromosomal region 12q14-15 in a variety of frequent benign human tumors reflect rearrangements of the HMGI-C gene. The mechanisms by which the HMGI-C gene contributes to tumorigenesis are mostly unknown, although frequently aberrant transcripts containing exons 1 to 3 of HMGI-C and ectopic sequences from other genes due to breaks within the third intron of HMGI-C are detectable. This is the first report analyzing human tissue samples mainly of mesenchymal origin by a highly sensitive polymerase-chain-reaction-based approach detecting HMGI-C expression. We found HMGI-C expression in embryonic tissue but no expression in any of several adult tissues tested except for two myometrial tissues. These data suggest that HMGI-C is mainly expressed in human tissues during embryonal and fetal development. Thus, its particular role for tumor development may be due to the expression of at least exons 1 to 3 rather than to the formation of fusion transcripts.

Rearrangements of the high mobility group protein family genes and the molecular genetic origin of uterine leiomyomas and endometrial polyps.

The results of cytogenetic studies of uterine leiomyomas have revealed that approximately 50% of these tumours are characterized by clonal chromosomal alterations. These karyotypic deviations are dominated by rearrangements involving a particular part of chromosome 12, i.e. region 12q13-15. We recently showed that the multiple aberration region on chromosome 12q15 harbours recurrent breakpoints frequently found in a variety of benign solid tumours. Within this region a gene encoding for a member of the so called high mobility group family proteins (HMG) was mapped. Further investigation revealed that this gene i.e. HMGI-C is often truncated by the chromosomal aberrations and fused to ectopic DNA sequences leading to fusion genes. Therefore, the results suggest a causal relationship between mutations of the HMGI-C gene and the development of uterine leiomyomas. Apparently identical mutations have been found also in endometrial polyps. Furthermore, there is an obvious coincidence between the chromosomal assignment of other members of the HMG family and the breakpoints of other non-random chromosome abnormalities seen in uterine leiomyomas.

Structural aberrations of chromosome 6 in three uterine smooth muscle tumors.

Clonal karyotypic alterations of chromosome 6 in three uterine smooth muscle tumors are reported. In all cases an apparently identical breakpoint on the short arm of chromosome 6 was found. Two cases displayed the histologic features of cell-rich myomas with severe nuclear atypia but no clear evidence for malignancy. The remaining case was a primary uterine leiomyosarcoma of an 80-year-old patient showing an apparently balanced reciprocal chromosomal translocation, t(1;6)(p32-33;p21.3), as the sole karyotypic abnormality. This type of aberration has not been reported before in leiomyosarcomas. Because of the nuclear atypia in the other myomas with a breakpoint involving the short arm of chromosome 6 we feel that this cytogenetically recognizable but rare subgroup of uterine smooth muscle tumors warrants a careful clinical follow-up.

Description of a novel fusion transcript between HMGI-C, a gene encoding for a member of the high mobility group proteins, and the mitochondrial aldehyde dehydrogenase gene.

Aberrations involving the chromosomal region 12q24 are a nonrandom cytogenetic abnormality in frequent benign tumors mainly of mesenchymal origin, e.g., uterine leiomyomas, pleomorphic adenomas of the salivary gland, lipomas, or hamartomas of the lung. Mostly, these 12q24 abnormalities occur as a result of inversions also affecting chromosomal region 12q14-15. In addition to the frequent tumors mentioned above, these abnormalities have also been found in rare mesenchymal tumors, e.g., hemangiopericytomas. Although recently the molecular basis of the aberrations of chromosomal region 12q14-15, i.e., a rearrangement of the HMGI-C gene has been identified, the molecular roots of the 12q24 changes still remain to be elucidated. Herein we report on 3' rapid amplification of cDNA ends PCR results on cDNA from a primary uterine leiomyoma. As an ectopic sequence fused to exon 3 of the HMGI-C gene, we have identified a cDNA sequence that revealed 100% homology to exon 13 of the human mitochondrial aldehyde dehydrogenase gene (ALDH 2). Because ALDH 2 maps to 12q24.1, this fusion transcript is a good candidate underlying the chromosomal rearrangements involving 12q24.

Telomere repeat fragment sizes do not limit the growth potential of uterine leiomyomas.

We have compared the length of telomere repeat fragments (TRF's) in 19 uterine leiomyomas from 6 patients with the corresponding myometrium. The advantage of this study of TRF length is that cells from uterine leiymyoma and cells from corresponding myometrium do not contain any considerable proportions of other cells as revealed by analysis of clonality. In all tumor samples a loss of TRF length ranging from 1120 to 4690 bp was noted. There was no correlation between tumor volume or size of tumor population as revealed by histological examination and loss of TRF length. From the obtained TRF length data (an average myometrial TFR length of 13 kb and an average loss of TRF length in myoma cells of 83 bp per cell division) we concluded that TRF length reduction does not limit the growth potential of uterine leiomyomas.

Molecular-cytogenetic refinement of the 12q14-->q15 breakpoint region affected in uterine leiomyomas.

Recent molecular and cytogenetic studies on uterine leiomyoma cell lines with aberrations in 12q14-->q15 have shown that the chromosome 12 breakpoints seem to cluster in a 260-kb region designated as ULCR 12 (uterine leiomyoma cluster region of chromosome 12 breakpoints). Here we report the results of fluorescent in situ hybridization (FISH) studies using a molecular probe composed of five different cosmids that cover a 700-kb region encompassing ULCR 12. The FISH studies were performed on primary tumor specimens of uterine leiomyomas. With the exception of one case, our results demonstrated that the cosmid pool bridges the breakpoint region 12q14-->q15 in primary tumors as well. In the remaining case signal was localized distal to the breakpoint, indicating a breakpoint outside the region covered by the cosmid pool or a deletion in the region surrounding the chromosome 12 breakpoint. Individual cosmid probes from the pool were then used to narrow the localization of the breakpoint region in both the primary leiomyomas and established cell lines. The results showed that the breakpoints involving 12q14-->q15 in the primary uterine leiomyomas and derived cell lines are clustered in a single 170-kb breakpoint region within ULCR 12. For three of the cell lines studied, the breakpoint map within a 40-kb segment covered by one cosmid.