Chromosomal abnormalities in giant cell tumors of bone.

Cytogenetic analysis of short-term cultures from ten giant cell tumors of bone revealed clonal and nonclonal chromosome abnormalities in three tumors and nonclonal changes only in seven. None of the clonal aberrations, inv(21)(p11q21) in one tumor, +5 in another, and t(15q22q), dic(4;22)(p16;p1?), double minutes, dicentrics, and ring chromosomes present in three separate clones in the third tumor, were identical to previously reported clonal changes in giant cell tumors. Telomeric associations were found in five tumors. The telomeres of chromosome arms 19q and 15p were particularly frequently involved.     

Cytogenetic aberrations in 188 benign and borderline adipose tissue tumors

Chromosome studies of lipomas have revealed an extensive cytogenetic heterogeneity. To investigate the frequencies of previously recognized cytogenetic subgroups and to find out if more recurrent rearrangements can be identified, we have analyzed cytogenetically short-term tissue cultures of 237 samples from 188 adipose tissue tumors obtained from 142 patients. Only one of 58 tumors from 18 patients with multiple lipomas (more than two tumors) had karyotypic changes. Among the sporadic lipomas, 20 tumors had supernumerary ring chromosomes of unknown origin, 55 had different aberrations involving chromosome segment 12q13-15, 11 had changes of 6p or chromosome 13, but no rings or 12q13-15 changes, and 14 had various other aberrations. Ring chromosomes were found in all cytogenetically abnormal lipomas histologically classified as atypical and in nine tumors classified as typical lipoma or spindle cell lipoma. Recombinations between 12q 13-15 and a few other bands or segments were seen more than once: 3q27-28 (15 tumors), 2p22-24 and 2q35 (four tumors), 1 p32-34 and 13q 12-14 (three tumors), and 5q33 (two tumors). Recombinations of 12q 13-15 with 2q35 and 13q 12-14 have not been described before. Of eight tumors with chromosome 13 aberrations, five had loss of 13q material. Aberrations of 12q 13-15, 6p, and/or chromosome 13 were found simultaneously in nine tumors. Two to four samples from the same tumor were investigated in 29 tumors with clonal aberrations. Thirteen of these tumors displayed clonal evolution, also noted in another 17 tumors in which only one sample had been investigated. Thus clonal evolution occurred in 30% of the tumors and was particularly frequent in atypical lipomas. Genes Chrom Cancer 9:207-215 (1994). © 1994 Wiley-Liss, Inc.     

Cytogenetic Characterization of Ten Malignant Fibrous Histiocytomas

We examined 10 malignant fibrous histiocytomas (MFHs) using metaphase preparations. Six tumors showed clonal structural and/or numerical chromosomal aberrations, and four tumors had normal karyotypes. For the most part, chromosomes 1, 3, 6, 9, 12, 16, 18, and 20 were involved in structural aberrations. The breakpoint regions most frequently were in 1p32, 3p25, and the centromeric region of chromosomes 1 and 16. There was a conspicuous loss in chromosome 18. We detected ring chromosomes in two tumors. One tumor showed a high percentage of near-haploid cells. Our results show many parallels to data which have already been published. MFHs include a broad spectrum of tumors of widely different histology and clinical course. So it is not surprising to find a cytogenetic diversity of chromosomal aberrations in this study.     

Osteoid osteomas with chromosome alterations involving 22q

Cytogenetic analysis was performed in two osteoid osteomas. In both, the modal chromosome number was 46. One of the cases presented a del(22)(q13.1) as the sole clonal chromosome alteration. The other had clonal monosomies of chromosomes 3, 6, 9, 17, 19, and 21, as well as a +del(22)(q13.1) was detected as a non-clonal chromosome alteration. There is only one osteoid osteoma reported so far showing clonal karyotypic alterations. The cytogenetic behavior of osteoid osteomas described here was different from that of the osteoid osteoma of the literature. Numerical alterations of chromosomes 3, 6, 9, 17, 19, 21 and 22 have been described in several neoplasias including bone tumors. The breakpoint of chromosome 22 involves a region where important genes for the regulation of the cell cycle have been mapped.     

Chromosome rearrangements at 12q13 in two cases of chondrosarcomas.

We analyzed the karyotypes of two moderately differentiated (grade 2) chondrosarcomas. Case 1 had a reciprocal translocation between chromosomes 6 and 12, t(6;12)(q25;q13) in most of the cells analyzed, as well as trisomies of chromosomes 7, 8, 11, 17, 19, and 21 and tetrasomy of chromosome 19. A reciprocal translocation involving chromosomes 12 and 19, t(12;19)(q13;q13), was noted as a highly clonal abnormality in the other case. Some cells had t(12;19) as the sole chromosome abnormality. Thus, chromosome rearrangements involving the long arm of chromosome 12 at the same region (q13) were commonly identified in the two tumors. These findings suggest that the rearrangements at 12q13 are nonrandom acquired changes that characterize a subgroup of chondrosarcomas.     

Cytogenetic analysis of 57 primary prostatic adenocarcinomas.

Cytogenetic analysis after short-term culture in vitro of primary tumor samples was attempted in 82 patients with prostatic cancer. Tumor material was obtained by radical prostatectomy or transurethral resection. Successful cytogenetic studies were performed on 57 tumors of which five were well, 30 moderately, and 22 poorly differentiated adenocarcinomas. Only normal karyotypes were found in 24 tumors. Structural nonclonal aberrations were detected in 18 and clonal karyotypic abnormalities in 15 tumors. The most common clonal numerical aberration was loss of the Y chromosome; a missing Y was found in six tumors, in three of these as the sole anomaly. Clonal structural chromosomal rearrangements, usually accompanied by numerical changes, were detected in 12 tumors. The rearrangements involved 18 of the 22 autosomes and the X chromosome. Chromosomes 1, 7, and 10 were most frequently affected. Deletions, duplications, inversions, insertions, and balanced as well as unbalanced translocations were represented. The breakpoints in chromosome 1 were scattered along both the short and long arms with no obvious clustering, whereas those in chromosomes 7 and 10 were clustered at bands 7q22 (two deletions and two duplications in four different tumors) and 10q24 (two translocations, one deletion, and one inversion in four tumors). One additional tumor displayed a derivative chromosome 10 with a breakpoint in 10q23, and one had monosomy 10. Altogether, these abnormalities resulted in loss of 10q24----qter in five tumors. Monosomy 8 and rearrangements of the short arm of chromosome 8 leading to loss of 8p21----pter were seen in four tumors. Double minute chromosomes were found in two tumors.     

Clonal chromosome rearrangements in a uterine myoma

A cytogenetic study of a myoma of uterus with extensive hyaline, myxoid, and cystic degeneration revealed a clonal karyotype with a complex structural rearrangement involving chromosomes #3, #12, #14, #17, and #22. The modal chromosome number of the tumor was 45 due to monosomy #22. Analysis of seven additional myomas of the uterus including five tumors with typical histology and two with degenerative changes showed no clonal abnormalities. Single metaphases with a trisomy and a translocation were detected in two tumors. We conclude that although many uterine myomas appear to have normal karyotypes, clonal chromosome abnormalities are present in some of these tumors.     

Spectral karyotyping and chromosome banding studies of primary breast carcinomas and their lymph node metastases

Three primary breast tumors and their lymph node metastases were characterized by G-banding, spectral karyotyping (SKY), and fluorescence in situ hybridization (FISH). In each case, the karyotypic abnormalities detected were similar in the primary tumor and its matched metastasis. Two of the pairs had near-diploid karyotypes with three to four chromosomal aberrations, whereas the third pair had a near-pentaploid chromosome content and many marker chromosomes in the primary tumor and a near-tetraploid chromosome number with almost the same marker chromosomes in the metastasis. SKY and FISH confirmed the karyotypic similarities between the primary tumors and their metastases and, in addition, improved the identification and characterization of marker chromosomes. One of the tumor pairs with near-diploid karyotypes had gain of 8q, 16q, and 17q, whereas the other had gain of 1q and chromosome 8 material in the form of ring chromosomes. The third pair had more complex chromosomal translocations and numerical changes resulting in net gain of material from chromosomes X, 1, 2, 6, 7, 14, 16, 19, and 20, and chromosome arms 8q and 11q, as well as net loss of material from chromosomes 3, 13, 18, 21, and 22. The present study underscores the need to combine conventional chromosome banding and molecular cytogenetic techniques in the cytogenetic analysis of solid tumors.     

Cytogenetic findings in 31 papillary thyroid carcinomas

Chromosome studies performed on 3I papillary thyroid carcinomas (PTCs) revealed clonal numerical and structural abnormalities in I2 tumors. The numerical clonal aberrations found were trisomy 2, trisomy 7, and loss of the Y chromosome. A nonrandom telomeric association, tas( I5; I6)(p I3; p I3), was observed in one carcinoma. Structural alterations with a breakpoint at I0q II.2 were detected in two tumors. Other chromosomes involved in rearrangements were chromosomes I, 2, 3, 5, 7, 9, II, 12, and 14. The observation of clonal changes of chromosome 2 [i(2)(qI0) and trisomy 2] in two tumors, which were both histologically classified as tall-cell PTC variants, suggests that gain of 2q may be important in the development of this morphological variant. © 1995 Wiley-Liss, Inc.     

Chromosome alterations associated with positive and negative lymph node involvement in breast cancer

Genetic heterogeneity is high in breast cancer, and hence it is difficult to link a specific chromosome alteration to a specific clinicopathologic feature. We examined clonal chromosome alterations in 45 breast carcinomas and statistically correlated the findings with clinical-histopathological parameters of the patients. The most common abnormalities were losses of chromosomes 19, 22, 21, X, and 17 and gains of chromosomes 9 and 18. A statistically significant correlation was found between clonal aberrations in chromosomes 17, 20, and 21 and positive lymph node involvement (LN+) and between clonal aberrations in chromosomes X and 6 and negative involvement (LN-). The average number of chromosome abnormalities was the same for both LN- and LN+ groups, and numerical and structural alterations were equally distributed. The mean number of chromosome aberrations did not differ significantly among tumor grades, but when aberrations were analyzed as monosomies, trisomies, and structural aberrations, a heterogeneous distribution was observed. Further cytogenetic investigation of breast tumors and their variable pathological features is undoubtedly necessary. The recognition and ultimately the molecular understanding of these abnormalities may improve breast cancer taxonomy and provide important prognostic information for both the patient and clinician.     

Aberrations of chromosome 8 in mixed salivary gland tumors--cytogenetic findings on seven cases

Cytogenetic findings on seven mixed salivary gland tumors are reported herein. The involvement of chromosome #8 in clonal chromosome aberrations in five of the seven tumors was particularly noteworthy. Four tumors had translocations involving chromosome #8 and one or two other chromosomes (#3, #7, #9, #13). The fifth showed a deletion of parts of the long arm of chromosome #8. In an attempt to define the critical segment on chromosome #8, we have identified the part between 8q11 and 8q13 as the critical region involved in all rearrangements. Thus far, our results confirm the results of the Swedish group, though the percentage of cases having #8 abnormalities is somewhat higher in our small series. The relationship between the two groups of cases, those with and those without chromosome abnormalities, will be discussed.     

Chromosomal organization of amplified chromosome 12 sequences in mesenchymal tumors detected by fluorescence in situ hybridization

The chromosomal organization of amplified chromosome 12 sequences was studied with fluorescence in situ hybridization in six mesenchymal tumors: two osteosarcomas, one lipoma, two liposarcomas, and one fibrosarcoma. All except the fibrosarcoma contained ring and/or giant marker chromosomes. Amplification of chromosome 12 sequences, demonstrated with whole-chromosome paint in all cases, was confined to ring and giant marker chromosomes in four tumors. In one of the osteosarcomas and in the fibrosarcoma, amplified sequences were added to chromosome 12 and to chromosomes 10, 12, 18, and the Y chromosome, respectively. Hybridizations with single-copy probes demonstrated considerable inter- and intracellular variation in the arrangement of chromosome 12 sequences in ring and marker chromosomes. Amplification of 12q13–15 sequences, predominantly from the HMGIC–MDM2 region, was detected in all cases, but the two osteosarcomas also contained amplification of 12p material. This finding, combined with results from previous studies, indicates that 12p amplification is a feature distinguishing osteosarcomas from adipose tissue tumors. A novel finding was the presence of positive signals for chromosome 12 alpha-satellite sequences in ring and marker chromosomes in four cases. Rod chromosomes carrying amplified material, in particular those that were relatively stable, frequently exhibited chromosome 12 negative terminal segments; two of these, present in two separate cases, were shown by C-banding to contain constitutive heterochromatin. The significant intercellular heterogeneity in the number and structure of rings and giant markers in a subset of mesenchymal tumors could be explained by continuous recombination through breakage–fusion–bridge cycles. If so, this process will continue until broken ends become stabilized, for example by acquisition of telomeric segments from other chromosomes. Genes Chromosomes Cancer 23:203–212, 1998. © 1998 Wiley-Liss, Inc.     

Cytogenetics of primary prostatic adenocarcinoma. Clonality and chromosome instability.

We have examined 62 prostatic adenocarcinomas by conventional cytogenetic analysis. Most were primary cultures harvested in 14 days or less. The most consistent finding was a normal male diploid karyotype, found in 87% of all cells analyzed, and as the exclusive finding in 19 tumors. Nonrandom chromosomal changes included gain of chromosome 7 and loss of the Y chromosome. In addition, clonal gains of chromosomes 8, 12, and 18, and clonal losses of chromosomes 14 and 19 were noted in individual cases. Two structural clonal aberrations, a 9p+ in one case and a t(Y;22) (q11.2;p12) in another, were also seen. Ten of 62 cultures demonstrated chromosome instability, defined herein as nonclonal gain or loss of chromosomes in more than 10% of the metaphases examined from that culture. In those cases with nonclonal numerical aberrations, loss of chromosomes was more common than gain. The distribution of apparently random numeric abnormalities was similar to that of the clonal abnormalities in that the most frequent nonclonal gain was of chromosome 7 and the most frequent nonclonal loss was of the Y chromosome. Apparently random structural aberrations were observed in less than 1% of all analyzed cells. These included a 4p-,del(3)(q13), and t(1;11). The extent of apparently random aneuploidy suggests that chromosome instability characterizes cultured prostatic adenocarcinomas. An increase in the frequency of nonclonal aberrations may be an indicator of tumor origin in a predominantly diploid cell population. The coexistence of clonally aberrant, nonclonally aberrant, and normal diploid cells in culture may reflect heterogeneity of prostate tumors in vivo.     

Cytogenetics of epithelial hyperplasias of the human breast

Generally, benign breast lesions behave like innocuous and limited proliferations; however, sometimes they can represent precancerous pathologies. The cytogenetic analysis of five mammary epithelial hyperplasias is reported. Four cases had clonal chromosome alterations. All of the cases presented a modal number of 46 chromosomes. Chromosome 9 monosomies and chromosome 1 deletions were common in these benign tumors. The study of benign proliferations of the breast may reveal a possible relationship between chromosomal alterations and the conditions of the tissue.     

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.     

X-chromatin, sex chromosomes, and ploidy in 37 germ cell tumors of the testis.

X-chromatin was present in interphase cells from nine of 14 teratomas and all of three combined tumors, but only one of 20 seminomas (which tended to have higher chromosome numbers). Eight of the 37 tumors were karyotyped; seven, only one of which (a teratoma) was X-chromatin-positive, had two X chromosomes while one, the X-chromatin-positive seminoma, had three. A possible relationship between the presence of inactive, X-chromatin-forming, X chromosomes and the number of autosomes is suggested by the data on the eight karyotyped tumors; the ratio of the number of Xs to the number of autosomes was higher for the two X-chromatin-positive tumors than for the remainder. All eight had at least one Y chromosome, and eight further tumors had one to three Y-bodies in their interphase cells. It is uncertain whether retention of the Y is a characteristic of male germ cell tumors, as tumors lacking a Y have been described by other workers. Two characteristics of these tumors, however, are high ploidy (at least 55 chromosomes), perhaps signifying an origin from a triploid or tetraploid cell, and chromosome 12 aberrations, usually resulting in an i(12p).     

Loss of 17p is a major consequence of whole-arm chromosome translocations in hematologic malignancies

To ascertain the distribution of whole-arm translocations (WATs) and their consequential imbalances in hematologic malignancies, we analyzed the imbalances related to chromosomes involved in clonal, acquired WATs in 140 consecutive tumors with WATs and near-diploid karyotypes. Tumors for analysis were obtained from a survey of the cytogenetic database in the Department of Medical Genetics, Henry Ford Health System, Detroit, MI. Of the 140 tumors, 9 had balanced WATs; the remaining 131 had WATs that rarely or never involved chromosome X, Y, 2, 3, 4, 6, 19, or 20. Chromosome arms were lost more often than they were gained, and short arms were lost more often than long arms, except for chromosomes 7 and 16 (more long arms lost than short) and chromosome 11 (both arms equally lost). The long arm of chromosome 1 was the only arm gained with substantial frequency, in 26% of tumors. Of WATs that resulted in gain of 1q, short arm of chromosome 7 and acrocentric long arms were involved in 47 and 24%, respectively. Acrocentric chromosomes were involved in acquired WATs in 45% of tumors (the D-group acrocentrics more than the G-group), and were more likely to be involved in non-Robertsonian than Robertsonian translocations (P < 0.001, normal test). Loss of 17p was the most common short-arm loss (23% of tumors) and often occurred as part of complex karyotypes suggestive of disease progression. The present findings show that acquired whole-arm chromosome translocations in hematologic malignancies are nonrandom, commonly involve acrocentric chromosomes, and often result in loss of 17p, which is often associated with advanced disease and poor prognosis in a wide spectrum of hematologic malignancies.     

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.     

Differentially amplified chromosome 12 sequences in low- and high-grade osteosarcoma.

Most osteosarcomas are highly aggressive malignancies characterized by a complex pattern of chromosome abnormalities. However, a subgroup of low-grade, parosteal tumors exhibits a relatively simple aberration pattern dominated by ring chromosomes carrying amplified material from chromosome 12. To assess whether sequences from this chromosome were differentially amplified in low- and high-grade osteosarcomas, copy numbers of the CCND2, ETV6, KRAS2, and D12S85 regions in 12p and the MDM2 region in 12q were evaluated by interphase or metaphase fluorescence in situ hybridization (FISH) in 24 osteosarcomas. Amplification of MDM2 was detected in all five low-grade and four high-grade osteosarcomas, all of which showed ring chromosomes. An overrepresentation of 12p sequences was found in 1/5 low-grade and in 9/19 high-grade tumors. Multicolor single-copy FISH analysis of metaphase cells from six high-grade tumors showed that extra 12p material either occurred together with MDM2 in ring chromosomes or was scattered over the genome as a result of complex structural rearrangements. Most tumors (8/10) not containing amplification of the assessed chromosome 12 loci exhibited a nondiploid pattern at evaluation with probes for centromeric alpha satellite sequences. These findings indicate that gain of sequences from the short arm of chromosome 12 could be a possible genetic pathway in the development of aggressive osteosarcoma.     

Nonrandom chromosome structural aberrations and oncogene loci in human malignant melanoma

Short-term cultures of 10 malignant melanomas derived from 8 patients were analyzed cytogenetically. The chromosome composition of the tumors was found to be similar in terms of modal number and structural and numerical aberrations, especially the nonrandom nature of breakpoints. Six chromosomes were consistently involved in marker formation. Aberrations of chromosomes #1 and #9 were identified in every tumor, whereas structural alterations of chromosome #2 were found in 9 tumors. In contrast, aberrations of chromosomes #6, #3, and #7 were identified in 7, 7, and 8 of the tumors, respectively. The nonrandom breakpoints on these chromosomes frequently coincided with known oncogenic loci and resulted in morphologically identical marker chromosomes. Consecutive lesions were obtained for two patients. Common markers were identified in both cases, indicating the clonal origin of the tumors. In addition, many marker chromosomes characteristic of the individual lesions were also identified. The presence of these lesion-specific markers indicates the nonrandom selective nature of the metastatic process and suggests the possible heterogeneity of the original tumor cell population.