A uterine leiomyoma showing both t(12;14) and del(7) abnormalities

The involvement of chromosomes 12 and 14 in uterine leiomyomas has been well established. However, in a recent report of only a del(7)(q22.1q31.32) or (q11.2q22.3) in two cases of typical uterine leiomyoma, Boghosian et al. hypothesized that this could represent a cytogenetic subgroup of uterine leiomyomas. We report a case of uterine leiomyoma with both the t(12;14) and del(7) in all the cells examined and discuss the implications of this in terms of critical chromosomal rearrangements underlying the route to benign cellular proliferation.     

Parallel karyotypic evolution and tumor progression in uterine leiomyoma

Cytogenetic evidence of clonal evolution was detected in five uterine leiomyomas. In two tumors, two clones were found, the third tumor had four, the fourth had nine, and the fifth had 12 clones. The first tumor had trisomy 12 as the primary anomaly and a sideline that also contained a del(7)(q21q31). Both clones of the second tumor had three structural changes in common but differed by the presence in the more advanced clone of an inv(7)(q31q34). Two cytogenetically unrelated pairs of clones were seen in the third tumor. One clone had a stemline of 46 and an r(1); a sideline had developed through duplication of this clone. The other pair had a del(7)(q21q31) in common. The last two tumors both had t(12;14)(q14-15;q23-24) as the primary abnormality. They also had a high frequency of telomeric associations that involved certain chromosome arms only. One of the secondary changes in the fourth tumor was a del(7)(q21q31); the principal secondary change in the fifth case was a ring chromosome 1 of variable size in the different clones. The analysis of these five uterine leiomyomas and the collation of the results with previously obtained data lead us to conclude that del(7)(q21q31) is secondary to t(12;14) and + 12 in this tumor type, and that ring formation involving chromosome 1 material, often with duplication of segments, is a common phenomenon during clonal evolution. The fact that the tumors were classified as cellular and had an increased mitotic rate indicates a parallel development between histologically detectable tumor progression and cytogenetically recognizable clonal evolution in uterine leiomyomas.     

Uterine leiomyoma cytogenetics

Uterine leiomyoma--a benign smooth muscle tumor--has recently been found to contain tumor-specific chromosome aberrations. Although only normal karyotypes were detected in 50 to 80% of cytogenetically investigated tumors, 104 leiomyomas with karyotypic aberrations have already been reported. At least four cytogenetically abnormal subgroups have been identified thus far, characterized by rearrangements of 6p, del(7)(q21.2q31.2), +12, and t(12;14)(q14-15;q23-24). The remaining abnormal tumors have had various nonrecurrent anomalies. Secondary karyotypic rearrangements, sometimes including ring chromosomes, have been found in one-third and reflect clonal evolution. Occasional leiomyomas have contained multiple numerical and structural rearrangements. Though benign, these cytogenetically grossly aberrant tumors often displayed more atypical histological features than are usually seen in leiomyoma. Multiple leiomyomas have been investigated from 69 patients, with detection of chromosome anomalies in at least two separate tumors from the same uterus in ten cases. In half of these patients unrelated aberrations were found in different leiomyomas from the same uterus. On other occasions the aberrations were identical, indicating that although some uterine leiomyomas originate independently, others may develop by intra-myometrial spreading from a common neoplastic clone. Some common features are discernible between the karyotypic pictures of uterine leiomyoma and angioleiomyoma; rearrangements of 6p, 13q, and 21q have been described in both tumor types. The cytogenetic similarities so far detected between leiomyoma and the malignant muscle tumors--leiomyosarcoma and rhabdomyosarcoma--are few and may be fortuitous. The cytogenetic profiles of leiomyoma and lipoma are strikingly similar; both tumor types have nonrandom rearrangements of 12q13-15, t(12;14) in leiomyoma and t(3;12) in lipoma, as well as variant rearrangements of the same 12q segment. Both also have cytogenetic subgroups characterized by changes in 6p and ring chromosomes. Finally, karyotypic similarities exists also between leiomyoma and pleomorphic adenoma of the salivary gland, which includes a subset of tumors with anomalies of 12q13-15, and with myxoid liposarcoma, which has t(12;16)(q13;p11) as a tumor-specific rearrangement.     

Chromosome analysis of 96 uterine leiomyomas

From September 1989 to May 1990, we attempted cytogenetic analysis on 96 uterine leiomyomas removed from 64 women. Of the 90 tumors in which analysis was successful, 59 had a normal karyotype while 31 had clonal abnormalities. The most common aberration (13 tumors) was 7q-, mostly del(7)(q21.2q31.2); in two tumors with +12 and t(12;14) as the primary abnormalities, the 7q- was obviously a secondary change since it was found only in a subclone. A t(12;14)(q14-15;q23-24) was detected in two tumors, complex aberrations involving both 12q14-15 and 14q23-24 were also present in two, and rearrangements of 12q without concomitant 14q changes were seen in another two myomas. Rearrangements of 6p were present in five tumors, and trisomy 12 was found in two. More than one abnormality could be detected in 17 leiomyomas. Evidence of clonal evolution in the form of subclones was found in eight tumors, all of which were cellular and had histologically detectable mitotic activity. In addition to their clonal complexity, these myomas also frequently exhibited clonal telomeric associations (four tumors) and ring chromosome formation (three tumors; twice affecting chromosome 1). Monosomy 22 occurred as a secondary abnormality in three tumors; it, too, may reflect a preferred pathway in the karyotypic evolution of uterine leiomyomas.     

Identification of CUX1 as the recurrent chromosomal band 7q22 target gene in human uterine leiomyoma

Uterine leiomyomas are benign solid tumors of mesenchymal origin which occur with an estimated incidence of up to 77% of all women of reproductive age. The majority of these tumors remains symptomless, but in about a quarter of cases they cause leiomyoma‐associated symptoms including chronic pelvic pain, menorrhagia‐induced anemia, and impaired fertility. As a consequence, they are the most common indication for pre‐menopausal hysterectomy in the USA and Japan and annually translate into a multibillion dollar healthcare problem. Approximately 40% of these neoplasms present with recurring structural cytogenetic anomalies, including del(7)(q22), t(12;14)(q15;q24), t(1;2)(p36;p24), and anomalies affecting 6p21 and/or 10q22. Using positional cloning strategies, we and others previously identified HMGA1, HMGA2, RAD51L1, MORF, and, more recently, NCOA1 as primary target (fusion) genes associated with tumor initiation in four of these distinct cytogenetic subgroups. Despite the fact that the del(7)(q22) subgroup is the largest among leiomyomas, and was first described more than twenty years ago, the 7q22 leiomyoma target gene still awaits unequivocal identification. We here describe a positional cloning effort from two independent uterine leiomyomas, containing respectively a pericentric and a paracentric chromosomal inversion, both affecting band 7q22. We found that both chromosomal inversions target the cut‐like homeobox 1 (CUX1) gene on chromosomal band 7q22.1 in a way which is functionally equivalent to the more frequently observed del(7q) cases, and which is compatible with a mono‐allelic knock‐out scenario, similar as was previously described for the cytogenetic subgroup showing chromosome 14q involvement. © 2012 Wiley Periodicals, Inc.     

Ring formation and structural rearrangements of chromosome 1 as secondary changes in uterine leiomyomas with t(12;14)(q14-15;q23-24)

Cytogenetic analysis of short-term cultures from two uterine leiomyomas revealed, in addition to the primary abnormality, the reciprocal translocation t(12;14)(q14-15;q23-24), secondary structural changes that in both cases included ring chromosomes and rearrangements of chromosome 1. One tumor had the karyotype 46,XX,r(1)(p34q32),ins(8;9)(q13;q13q22),t(12;14)(q14-15;q23- 24). Massive numerical rearrangements were found in the second leiomyoma, with chromosome numbers ranging from 47 to 92. In spite of this variability, two main cell populations could be discerned, one near-diploid, the other hypotetraploid, with most mitoses having chromosome numbers between 80 and 88. These findings were corroborated by flow cytometry, which revealed two peaks corresponding to DNA indexes of 0.97 and 1.77. The structural abnormalities t(1;1)(p31;q44) and t(12;14)(q14-15;q23-24) were present in all karyotypically abnormal cells, and one or more unidentified ring chromosomes were observed in most of the hypotetraploid mitoses. In no cells were double copies of the t(1;1) and t(12;14) rearrangements detected. The similarity between the secondary changes in the cases reported here suggests that clonal evolution in uterine leiomyoma is nonrandom.     

Inversion (X)(p22q13) in a uterine leiomyoma.

We report a case of uterine leiomyoma which showed a karyotype 46,X,inv(X)(p22q13) as the only clonal change in most of the cells. A few cells had an additional del(7), though del(7) has been found to be a primary change in leiomyomas. These findings indicate that the abnormality involving the X chromosome and particularly Xp22 can be considered as a primary chromosomal abnormality. We discuss the findings together with few reports of cases involving chromosome X in leiomyomas.     

A specific translocation,t(12;14)(q14–15; q23–24), characterizes a subgroup of uterine leiomyomas

We have cytogenetically investigated short-term cultures initiated from 34 uterine leiomyomas, all of which were histologically completely benign. Clonal chromosome abnormalities were detected in five cases, a normal female complement in 22, whereas, in the remaining seven tumors no karyotype could be established. Apparently identical reciprocal translocations, t(12;14)(q14–15;q23–24), were found as the sole abnormality in four tumors. The fifth abnormal case contained a t(2;14)(p11;p11). We conclude that chromosome aberrations may be found in myomas of the uterus, and that t(12;14)(q14–15;q23–24) characterizes a subset of these tumors.     

Deletion of chromosome 13 in leiomyomas of the uterus

We report two cases of leiomyomas of the uterus with a deletion of the long arm of chromosome 13. To our knowledge this cytogenetic abnormality as a single change has not been reported previously. One of our cases showed a del(13)(q14q32) and the other a del(13)(q13q33). We discuss the cases and compare our findings with previous ones reported in the literature.     

Leiomyoma of the urinary bladder: a cytogenetic study of a case

We report the first case of a leiomyoma of the urinary bladder studied by cytogenetics. In comparison with cytogenetic changes of leiomyomas of other sites, the karyotype of the tumor was unusual: 47,XX,+7/89 approximately 93,XXXX,-1,+7,+7,add(12)(q23.4),+add(12)(q23.4),-18,-21,+idic(21)(p11.2),-22.     

Nonrandom cytogenetic changes in leiomyomas of the female genitourinary tract. A report of 35 cases

Cytogenetic analysis of short-term cultures from 35 leiomyomas of the female genitourinary tract showed abnormal karyotypes in 14 cases. In 11 of 14 aberrant tumors, normal cells were also observed. Structural changes were most frequent, resulting in modal chromosome numbers in the diploid range. Our data confirm preferential breakpoint clusters at 7q, 12q14-15, and 14q23-24, mainly resulting from consistent, specific chromosome rearrangements such as t(12;14)(q14-15;q23-24) and del(7)(q21) or del(7)(q22q32). Together with previously published cases, we describe trisomy 12, ring chromosomes, and monosomy 22 as new additional recurrent findings in myomas. Statistical analyses of possible coherencies between tumor karyotype (abnormal versus normal) and clinicopathologic data, as well as age of the patients, menopausal status, and tumor size showed no correlations.     

Consistent breakpoints in region 14q22-q24 in uterine leiomyoma

The chromosomes of nine consecutive human benign leiomyomas of the uterus were studied with banding methods following short-term culture. All of the tumors had a typical benign histology. Five exhibited clonal chromosome changes including three with consistent involvement of chromosomes 12 and 14 in a translocation, t(12;14)(q14-15;q23-q24), a direct insertion, dir ins(12;14)(p11.2;q22q24.1), and a direct insertion, dir ins(14;12)(q22-q23;q14-q15q23-q24.1). Thus, this study demonstrated the presence of consistent chromosome changes in another benign proliferation. Strikingly, the breakpoint observed at 12q14-q15 in two specimens is also involved nonrandomly in other benign proliferations such as mixed salivary gland tumors and lipomas. However, region 14q22-q24, which was involved in three specimens, may contain a DNA sequence critical for the genesis of uterine leiomyoma.     

inv(12)(p11.2q13) in an endometrial polyp

A benign endometrial polyp from a 50-year-old postmenopausal woman has been cytogenetically investigated. A single clonal karyotypic anomaly, inv(12)(p11.2q13), was found in about 30% of cells analyzed after short-term culture. This finding contributes further to the hypothesis that the chromosomal segment 12q13-q14, which is also involved in chromosomal rearrangements in uterine leiomyomas, pleomorphic adenomas of the salivary glands, lipomas, and myxoid liposarcomas, contains a gene or genes that are related to cellular proliferation rather than to malignant transformation.     

Uterine leiomyoma cytogenetics. II. Report of forty cases

Chromosome analysis of 40 cultured uterine leiomyomas revealed the presence of clonal changes in 32.5% of them, confirming the cytogenetic heterogeneity within this type of tumor, mostly referable to a few cytogenetic subgroups. Preferential involvement of 12q14-15 and 14q23-24 bands in reciprocal and complex translocations was most commonly observed. Deletions of chromosome 7 and changes of chromosomes 1, 2, and to a lesser extent, chromosomes 19 and 22 were also found. Constitutional karyotype of patients bearing tumors with karyotypic abnormalities was examined. In one patient, two cells were found with t(12;14)(q14-15;q23-24) translocation and two with del(14)(q13q23-24). The latter rearrangement was also present as a clonal change in the tumor.     

Molecular cytogenetic characterization of del(7q) in two uterine leiomyoma-derived cell lines

Uterine leiomyoma cytogenetically exhibits at least six chromosomally abnormal subgroups. The largest subgroup is characterized by deletions of the long arm of chromosome 7. Few molecular and fluorescence in situ hybridization data are available that have aimed at a better definition of the lesion. Here, we report the results of a partial molecular cytogenetic characterization of two del(7q) chromosomes that were derived from cell lines established from two uterine leiomyomas with del(7)(q22q32). By using a large series of ordered 7q markers, we were able to identify the most proximal and the most distal conserved markers, which delineate the size of the deletion and which allow for a more targeted approach to the nature and function of genes that are possibly relevant for the pathogenesis of the disorder. Genes Chromosom. Cancer 18:155–161, 1997. © 1997 Wiley-Liss, Inc.     

The role of cytogenetics in the classification of soft tissue tumours

 Soft tissue tumours represent a heterogeneous group of mesenchymal lesions, and their classification is the subject of continuous debate. Chromosome analysis, molecular cytogenetics and molecular assays may become increasingly useful in diagnosis, and this review summarises advances in the cytogenetic characterisation and classification of soft tissue tumours. Among the group of fibrous lesions, superficial fibromatosis exhibits trisomy 8. This genomic change is also observed in desmoid fibromatosis in association with trisomy 20. Trisomy 11 is the most frequently observed chromosomal aberration in congenital fibrosarcoma. Dermatofibrosarcoma protuberans and giant cell fibroblastoma share a translocation t(17;22), which supports the concept of the existence of a common differentiation pathway. Adipose tissue tumours is the group in which integration of genetics and pathology has been most fruitful. Ordinary lipomas cytogenetically show an abnormal karyotype in about half the cases. Genomic changes of the 11q13 region are observed in hibernoma. Lipoblastoma exhibits a specific 8q rearrangement in 8q11-q13. Loss of material from the region 16q13-qter and 13q deletions are observed in spindle cell/pleomorphic lipomas. The well-differentiated liposarcoma/atypical lipoma group is characterised karyotypically by the presence of one extra ring and/or extra giant chromosome marker. Myxoid and round cell liposarcoma share the same characteristic chromosome change: t(12;16)(q13;p11) in most cases. In the group of smooth muscle lesions most data are derived from uterine leiomyomas, which can be subclassified cytogenetically into seven different types. Half of all leiomyomas are chromosomally normal; the other half have one of six possible consistent chromosome changes. Alveolar rhabdomyosarcoma is characterised cytogenetically by two variant translocations t(2;13)(q35;q14) and t(1;13)(p36;q14). Among tenosynovial tumours, the localised type of giant cell tumour of tendon sheath exhibits two different karyotypic changes. One involves 1p11 in a translocation with chromosome 2 or with another chromosome. A second type involves 16q24. Synovial sarcoma is characterised cytogenetically by a translocation occurring between chromosome 18 and presumably two adjacent loci on the X chromosome. In neural tumours, abnormalities of chromosome 22 have been reported in benign schwannomas and perineuriomas. Malignant peripheral nerve sheath tumours exist in two main forms: sporadic and associated with the NF-1 syndrome. Karyotypes are very complex, but chromosomes 17q and 22q are very often involved. Clear cell sarcoma is characterised cytogenetically and molecularly by a translocation t(12;22)(q13;q12). The Ewing’s sarcoma/peripheral neuroectodermal tumour category shows a central karyotypic anomaly represented by the translocation t(11;22). The two variants t(21;22) and t(7;22) are found in some cases. Among cartilaginous lesion, the most frequently described anomaly is the t(9;22)(q22;q12) in extraskeletal myxoid chondrosarcoma. Intra-abdominal desmoplastic small round cell tumour is characterised by a t(11;22)(p13;q12). Received: 5 February 1997 / Accepted: 24 February 1997     

High resolution mapping of consistent leiomyoma breakpoints in chromosomes 12 and 14 to 12q15 and 14q24.1

A substantial percentage of uterine leiomyomas are cytogenetically characterized by consistent, clonal chromosome abnormalities, including t(12;14)(q14-15;q23-24) and other rearrangements of 12q14-15 that occur without any visible 14q changes. The partly similar banding characteristics of these two regions have hitherto precluded exact mapping of the 12q and 14q breakpoints to any particular band, let alone their assignment to subbands. In the series of four myomas presented here, in which one tumor had inv(12q), two t(12;14), and one a three-way t(7;12;14), we were able to achieve high resolution banding (550 band stage) of the rearranged chromosomes in several metaphases. This enabled us to assign a 12q breakpoint to 12q15 in all tumors and, in the three cases informative in this regard, the 14q breakpoint to 14q24.1. The more precise breakpoint mapping considerably narrows down the area that must be examined with molecular genetic methods in order to identify the gene loci that are rearranged in leiomyomas with 12q and 14q aberrations. It will also help determine to what extent leiomyoma rearrangements of 12q involve the same loci that are affected in 12q changes in other tumor types, e.g., in pleomorphic adenomas of the salivary gland, in lipomas, and in myxoid liposarcomas. At present it seems that the breakpoint in 12q may be cytogenetically identical in the three benign tumors, whereas it in myxoid liposarcomas appears to be more proximal.     

Cytogenetic and histologic findings in 17 pulmonary chondroid hamartomas: Evidence for a pathogenetic relationship with lipomas and leiomyomas

Pulmonary chondroid hamartomas (PCH) are benign tumors that contain mesenchymal and epithelial components. In this series, we identified clonal chromosome aberrations in mesenchymal cells from 10 of 17 PCH. Chromosome band 12q15 was rearranged most frequently (N = 4), and one case had a t(12;14)(q15;q24) that was identical cytogenetically to the characteristic translocation in uterine leiomyomas. Histologic review revealed diverse mesenchymal populations, including undifferentiated cells, cartilage, adipose tissue, and smooth muscle, in most of the PCH. These findings suggest that PCH result from neoplastic transformation of a primitive mesenchymal cell that differentiates along chondroid, adipose, and smooth muscle pathways.