Trisomy 7 in short-term cultures of colorectal adenocarcinomas

Cytogenetic analysis of short-term cultures from six adenocarcinomas of the colon revealed trisomy 7 as a recurrent clonal chromosomal abnormality. In three tumors, +7 was the sole change. In the fourth carcinoma, two aberrant clones with simple numerical aberrations were detected; one with +7 and one with +3. Tumors 5 and 6 both displayed two completely different abnormal clones; one had numerous numerical and structural abnormalities and thus was undoubtedly representative of the cancer parenchyma, and the other had only +7. The karyotypic differences between the coexisting clones in the latter two cases seem to argue against an evolutionary scenario in which the karyotypically more complex clones have evolved from the clones carrying trisomy 7 only. Furthermore, in tumor 6 the metaphases with trisomy 7 were found in colonies of fibroblast-like cells whereas those with a large number of abnormalities grew in colonies of epithelial-like cells. The combined results indicate that mitoses with trisomy 7 as the sole chromosomal change do not represent the neoplastic parenchyma of colorectal adenocarcinomas.     

On the significance of trisomy 7 and sex chromosome loss in renal cell carcinoma

Cytogenetic analysis of 30 renal cell carcinomas showed 3p aberrations in nine tumors, trisomy 7 in 17 tumors, and clonal loss of one sex chromosome in 14 tumors. The 3p aberrations and trisomy 7 were present in the same clone in two tumors and in separate clones in three tumors. Loss of one sex chromosome was present together with 3p aberrations in the same clone in one tumor and occurred in seemingly unrelated clones in two tumors. It occurred as the sole change in five tumors. Clones with trisomy 7 as the only change were present in six tumors. Trisomy 7 and loss of one sex chromosome were present in separate clones in four tumors and in the same clone in one tumor. Because +7 and -X/-Y were thus rarely present together with clonal structural abnormalities, in particular 3p changes, our findings make it highly unlikely that loss of one sex chromosome or trisomy 7 represents a primary change in renal cell carcinoma. We instead suggest that there is a tendency for normal kidney cells to lose an X or a Y chromosome and also to gain an extra copy of chromosome 7. This tendency is retained by renal carcinoma cells; therefore, trisomy 7 and sex chromosome loss should not be viewed as tumor-specific abnormalities in this context. Whether these simple numerical aberrations reflect in vivo mosaicism or are acquired in vitro remains unresolved.     

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.     

Trisomy 12 is a consistent chromosomal aberration in benign ovarian tumors

Clonal karyotypic abnormalities were detected in 7 of 42 cytogenetically analyzed benign ovarian tumors. An adenofibroma had -X and a mucinous cystadenoma had t(1;11)(q25;q23) as the sole abnormality. Trisomy 12 was found in the remaining five tumors. It was the only change in two fibromas and a serous cystadenoma; the fourth tumor, a mucinous cystadenoma, had one clone with +12 and one with +12 and +10, and the fifth tumor, a fibrothecoma, had +4,+9,+12. The finding of trisomy 12 in five of seven karyotypically aberrant tumors suggests that this aberration characterizes a hitherto unrecognized cytogenetic subgroup of benign ovarian neoplasms.     

Chromosome analysis of 20 breast carcinomas: Cytogenetic multiclonality and karyotypic-pathologic correlations

Short-term cultures from 20 breast carcinomas were analyzed cytogenetically. A normal female chromosome complement was found in 4 cases. Clonal chromosome aberrations were detected in 16 tumors. In 10 tumors, multiple cytogenetic clones were found; in 2 cancers the clones were related, reflecting clonal evolution, but in the remaining 8 tumors the clones were cytogenetically unrelated, indicating clonal heterogeneity in the origin of the tumor parenchyma. Correlation analysis between karyotypic and pathologic parameters indicated that cases with complex karyotypes and/or cytogenetically unrelated clones, when compared with cases with a single simple karyotypic abnormality, were generally of higher histologic malignancy grade, had more mitoses in the histologic sections, and also more often had carcinoma in situ lesions in the same breast. © 1993 Wiley-Liss, Inc.     

Nonrandom karyotypic features in basal cell carcinomas of the skin.

Cytogenetic analysis of short-term cultured 44 basal cell carcinomas (BCC) revealed clonal karyotypic abnormalities in 38 tumors. Relatively complex karyotypes (at least four structural and/or numerical changes per clone) with unbalanced structural as well as numerical aberrations were found in eight (approximately 21%) of the BCC, while the remaining BCC (79%) had simple karyotypes (1 to 3 aberrations per clone). Numerical changes only were found in 16 tumors, 15 BCC displayed both numerical and structural aberrations, and the remaining 7 BCC showed only structural aberrations. Extensive intratumoral heterogeneity, in the form of cytogenetically unrelated clones, was found in 21 tumors, whereas related subclones were present in 10 tumors. In order to obtain an overall karyotypic picture in BCC, the findings of our previously published 25 BCC have been reviewed. Our combined data indicate that BCC are characterized by nonrandom karyotypic patterns. A large subset of BCC is characterized by nonrandom numerical changes, notably, +18, +X, +7, and +9. Structural rearrangements often affect chromosomes 1, 4, 2, 3, 9, 7, 16, and 17. A number of chromosomal bands are frequently involved, including 9q22, 1p32, 1p22, 1q11, 1q21, 2q11, 4q21, 4q31, 1p36, 2q37, 3q13, 7q11, 11p15, 16p13, 16q24, 17q21, and 20q13. When the genomic imbalance is assessed, it has been shown that several chromosome segments are repeatedly involved in losses, namely loss of the distal part of 6q, 13q, 4q, 1q, 8q, and 9p. A correlation analysis between the karyotypic patterns and the clinico-histopathologic parameters has been undertaken in the 44 BCC of the present series. The cytogenetic patterns show a significant correlation with tumor status (P=.025), that is, that cytogenetically more complex tumors are also those clinically the most aggressive. Also, the frequency of cytogenetically unrelated clones is significantly higher in recurrent BCC than that in primary lesions (P=.05). No clear-cut association has been found between the karyotypic patterns and histologic subtypes or tumor sites.     

Genomic defects in nonfamilial renal cell carcinoma. Possible specific chromosome change

Using a newly developed combined method of enzymatic technique and short-term tissue culture, 30 tumor specimens from 26 patients with nonfamilial renal cell carcinoma were subjected to cytogenetic analysis. Of the 26 patients, 19 had chromosomally abnormal tumors, four (including two oncocytomas) were normal, and three did not grow. The modal chromosome numbers ranged from 44 to 98 (including two pseudotetraploids). Banding analysis revealed 38 clonal aberrations and ten nonclonal aberrations. Abnormalities were of structure and number. The most consistent clonal abnormality was a trisomy or tetrasomy chromosome 7 occurring in tumors from 15 of the 19 patients with cytogenetically abnormal tumors. In four cases, trisomy 7 was the only visible abnormality observed, and in an additional five it was the only abnormality in two or more cells. An abnormal chromosome 3 was found in ten (38%) of the cases. Two were trisomic for #3, two were monosomic, three were hyperdiploid, and three had interstitial deletions with breakpoints clustered from p11 to p25. In only one case was a deleted #3 the only abnormality observed in a clone of cells. Loss of the sex chromosome was seen in eight (35%) of the 23 chromosomally abnormal cases including all four (100%) patients with bilateral disease. One of the patients with bilateral disease had an abnormal clone with monosomy X as the only abnormality. These data suggest that trisomy or tetrasomy 7 more often represents the specific primary abnormality than abnormalities of either chromosome 3 or the sex chromosomes. From this, a model of chromosomal progression may be constructed for nonfamilial renal cell carcinoma, which could assist in pathologic classification and prognostic and therapeutic considerations.     

Trisomy 7 and sex chromosome loss need not be representative of tumor parenchyma cells in malignant glioma.

We describe the cytogenetic findings in short-term cultures from 40 malignant gliomas, all of which had at least one clone with a simple numerical chromosome aberration. More than one aberrant clone was found in 17 tumors. The most frequent changes were loss of a gonosome (sole aberration in 38 clones), trisomy 7 (sole aberration in four clones), and combinations thereof (the aberrations +7 and -X or -Y were found together as the only changes in four clones). Clones with solitary trisomies for other autosomes--3, 5, 6, and 18--were seen in five tumors. Clones with structural rearrangements were found in nine tumors. The bands most commonly involved were lp36, 7p22, 9p22, 17p13, and 19q13. An extra copy of chromosome 7 was seen as part of a structurally abnormal clone in five tumors. In one case, trisomy 7 and even tetrasomy 7 were found in clones with simple numerical changes, but not in the clone with structural rearrangements. Likewise, the clonal loss of a gonosome was in six tumors, with structural abnormalities not present in the structurally aberrant clones; on the other hand, in two clones with structural aberrations a sex chromosome had been lost. The combined findings indicate that loss of a sex chromosome and trisomy 7 should not be seen as tumor-specific aberrations in gliomas. Instead, both glioma parenchyma cells and nonneoplastic cells in brain tumors may have a propensity to acquire extra copies of chromosome 7 and to lose gonosomes.     

Trisomy 21 as the sole acquired karyotypic abnormality in an adult patient with CD7-positive acute myeloid leukemia.

We report a unique case of acute myeloid leukemia (AML) in which trisomy 21 was the sole acquired karyotypic abnormality. The blasts were positive for myeloperoxidase, and phenotypic analysis of peripheral blood cells by flow cytometry demonstrated positivity for CD7, CD13, CD33, and CD34. chromosomal analysis of peripheral blood and bone marrow cells showed trisomy 21; however, that of the buccal mucosal membrane revealed a normal karyotype. A diagnosis of CD7+AML (M2) with trisomy 21 was diagnosed and the patient achieved complete remission following treatment with Japan Adult Leukemia Study Group-AML97 protocol. This is the first reported case of CD7+AML with trisomy 21 as the sole cytogenetic abnormality.     

Trisomy 7 accumulates with age in solid tumors and non-neoplastic synovia

Trisomy 7 is a common finding in benign and malignant solid tumors, in several non-neoplastic lesions (for example, osteoarthritis and rheumatoid arthritis), and in apparently normal tissues as well, suggesting that the occurrence of +7 might be associated with factors other than the disease process itself. To find out whether the frequency of +7 varies with a patient's age, we cytogenetically analyzed short-term-cultured synovial samples from elderly persons without signs of arthritis and from young patients affected by juvenile chronic arthritis (JCA). In normal synovia, gain of a chromosome 7 was present as a clonal change in five of 10 cases and in single cells in four of the five remaining cases. In synovia from patients with JCA, cells with +7 were detected in only one of nine cases, representing the oldest patient in the series. Furthermore, we reviewed the cytogenetic literature on tumors of the brain, breast, colon, kidney, lung, skin, thyroid, and upper aerodigestive tract. In the majority (six of eight) of these tumor types, the frequency of cases displaying a clone with +7 as the sole aberration increased with age. Taken together, the results presented here suggest that the acquisition of trisomy 7 in some neoplastic and non-neoplastic tissues might be associated with age rather than with disease. The finding of a completely different frequency distribution in two of the tumor types (tumors of the brain and the thyroid gland), however, emphasizes the heterogeneity of +7 and indicates that other, possibly tissue-specific, factors might influence the occurrence of this mutation.     

Trisomy 15 is frequently observed as a minor clone in patients with Anemia/MDS/NHL and as a major clone in patients with AML

Trisomy 15 as the sole karyotypic aberration is an uncommon clonal cytogenetic aberration in hematological malignancies, making its significance unclear. Previous studies have reported relations of trisomy 15 with low-grade myelodysplasia or a benign age-related phenomenon associated with loss of the Y chromosome. To define the significance of trisomy 15, we conducted a retrospective study of all examples of trisomy 15 accessed in our laboratories. Trisomy 15 was observed as a clonal abnormality (> or =2 cells) in 17 cases and nonclonal (single cell) in 9 cases. The majority of cases (14/17 clonal cases) had a minor clone (5-35% of metaphase cells) of trisomy 15. The minority of cases (3/17) had a major clone (80-95% of metaphase cells) of trisomy 15. Two of these 3 cases were diagnosed as having acute myelocytic leukemia. Fluorescence in-situ hybridization (FISH) with the use of a chromosome 15-specific alpha-satellite probe was performed on 3 of 17 clonal cases and on 3 of 9 nonclonal cases. FISH results revealed the presence of a minor clone (from 3 to 5 of 700 interphase cells) in 5 of them, 2 of which had trisomy 15 in 20% of metaphase cells. These results may indicate that the 20% of trisomy 15 are very likely an overrepresentation of a very minor clone that could be transitory. In summary, the analysis of our cytogenetic and FISH results revealed the presence of two types of trisomy 15 clones: a minor clone that could be transitory or indolent and a major clone that could be of a neoplastic nature.     

Trisomy 7 in nonneoplastic focal steatosis of the liver.

Cytogenetic analysis of short-term cultures of a nonneoplastic focal steatosis of the liver showed trisomy 7 as the sole chromosomal change. This finding, especially when viewed in light of previous reports describing +7 in nonneoplastic tissues, strongly suggests that trisomy 7 cannot be considered a tumor-specific abnormality when it occurs as the only change. The cell type in which +7 is present is not yet known.     

Chromosome aberrations in tenosynovial giant cell tumors and nontumorous synovial tissue

Five tenosynovial giant cell tumors—4 pigmented villonodular synovitis (PVNS) and 1 nodular tenosynovitis (NTS)—were investigated cytogenetically. Clonal chromosome aberrations were detected in 3 of them. One PVNS had t(7;16)(q22;q24) as the sole anomaly, whereas 1 PVNS and the NTS displayed aberrations suggesting clonal evolution: t(1;19)(p11;p12)/t(1;19), + 12 and ins(5;1)(q31;p13p34)/ins(5;1),t(2;4)(p23;q21), respectively. Including our 3 cases, a total of 6 tenosynovial giant cell tumors with karyotypic changes have been reported. Apart from 2 PVNS with trisomies 5 and 7, and 2 NTS with rearrangement of chromosome band 1p13, no recurrent chromosome change has been detected. Although the detection of clonal, acquired chromosome abnormalities has formerly generally been accepted as sufficient to conclude that a lesion is neoplastic, the interpretation of the pathogenetic significance of the karyotypic aberrations in synovial tumors is obscured by the fact that we have also detected comparable aberrations in obviously nonneoplastic synovial tissue. One of 2 lesions from patients with hemorrhagic synovitis carried a clonal del(13)(q12q21), and 2 of 4 synovectomy samples from patients with rheumatoid arthritis displayed –Y and –Y together with +7. The available cytogenetic data therefore cannot be used to resolve the controversy as to whether tenosynovial giant cell tumors are truly neoplastic or only reactive, inflammatory proliferations. © 1993 Wiley-Liss, Inc.     

Chromosome change in transitional cell carcinoma of ureter

Primary transitional cell carcinoma of the ureter is a relatively rare cancer. A case of transitional cell carcinoma of the mid-portion of the ureter in an adult male has been studied cytogenetically and has been found to have trisomy of chromosome #7 (+7) as the only karyotypic abnormality. In an earlier instance of transitional cell carcinoma of the ureter, we observed trisomy 7 together with monosomy 9 and an isochromosome for 5p. The relation of this observation to the cytogenetic findings in transitional cell carcinoma of the bladder is discussed and their possible significance evaluated. The rarity of the cytogenetic findings in these tumors is stressed, as is the possible role played by the chromosomal change in this condition, which may possibly involve the c-erb B oncogene.     

Cytogenetic evolution in primary tumors,local recurrences,and pulmonary metastases of two soft tissue sarcomas

The karyotypic pattern at different stages of tumor development may provide information on tumor progression but few data are available regarding human solid tumors. Cytogenetic analysis was performed on the primary tumor and four lung metastases of a synovial sarcoma, and the primary tumor, two consecutive local recurrences, and six pulmonary metastases, obtained at two different occasions, of a malignant fibrous histiocytoma (MFH). Simultaneous existence of more than one cytogenetically aberrant clone was also assessed through analysis of more than one sample from the same surgical specimen. Clonal chromosome aberrations were detected in all samples from the synovial sarcoma, and in both local recurrences and five of the metastases from the MFH. All clones in both tumors were cytogenetically related. The primary synovial sarcoma tumor contained two clones, one of which was also found in the lung metastases, together with a third clone that had acquired additional aberrations. Four clones with a near-tetraploid chromosome number and complex aberrations were identified in the MFH. Likely evolutionary pathways could be deduced in both cases. In the patient with synovial sarcoma one of the pulmonary metastases, rather than the primary tumor, might well have been the source of another of the pulmonary metastases. In the MFH the cytogenetic findings indicated the presence of two co-existing lineages in the primary tumor, one giving rise to the local recurrences and one to the pulmonary metastases. Our findings show that cytogenetic analysis can be used to establish the chronologic relationships between different clones in primary tumors, local recurrences and distant metastases, to determine what genetic changes are of importance for the metastatic capability of tumor cells, and to help establish the origin of the metastatic lesions.     

Cytogenetic characterization of tumors of the vulva and vagina

Neoplasms of the vulva and vagina account for less than 5% of all female genital tract cancers. Squamous cell carcinoma (SCC) represents more than 70% of the cases in both locales, followed by melanoma, basal cell carcinoma, Paget's disease, and other carcinoma subtypes. Until recently, only few cases had been analyzed by chromosome banding techniques and karyotyped, and also the number subjected to molecular cytogenetic analysis remains low. To understand better the genetic changes harbored by the neoplastic cells in cancer of the vulva and vagina, we analyzed cytogenetically 51 such tumors, finding karyotypic abnormalities in 37. All tumors were analyzed by G-banding, sometimes supplemented by multicolor fluorescence in situ hybridization, and a subset of tumors was also analyzed by comparative genomic hybridization. The two cytogenetically abnormal cases of Paget's disease both had two clones, one with gain of chromosome 7 as the sole change, the other with loss of the X chromosome among, in one case, other aberrations. The four cytogenetically abnormal malignant melanomas (three of the vulva, one of the vagina) presented complex karyotypes with aberrations involving different chromosomes but most often chromosome 1, specifically 1p12-q41. In the 31 cytogenetically abnormal SCCs, different clonal karyotypic abnormalities were seen. Intratumor heterogeneity with multiple clones was observed in 11 cases. The clones were cytogenetically unrelated in eight tumors but related in three, indicating that in the latter clonal evolution had taken place from a single malignantly transformed cell. The main chromosomal imbalances were gains of, or from, chromosome arms 3q, 5p, 8q, 9q, and 19q, and loss from 11q. Breakpoint clusters were seen in 11q13-23, 2q22-35, and 19q13, as well as in the centromeres and pericentromeric bands of chromosomes 3, 8, 9, 13, 14, and 22.     

Cytogenetic findings in phyllodes tumors of the breast: Karyotypic complexity differentiates between malignant and benign tumors

Clonal karyotypic abnormalities were detected in short-term cell cultures from six phyllodes tumors of the breast. Whereas all five benign tumors had simple chromosomal changes, the highly malignant one had a near-triploid stemline, indicating that karyotypic complexity is a marker of malignancy in phyllodes tumors. Interstitial deletions of the short arm of chromosome 3, del(3)(p12p14) and del(3) (p21p23), were the only aberrations in two benign tumors. Cytogenetic polyclonality was detected in three benign tumors: two had cytogenetically unrelated clones, whereas the third had three different, karyotypically related cell populations as evidence of clonal evolution. The finding of clonal chromosome abnormalities in both the epithelial and connective tissue components of the phyllodes tumors indicates that they are genuinely biphasic, that is, that both components are part of the neoplastic parenchyma.     

Do random (non-clonal) chromosome abnormalities in bone marrow predict a clone to come? Southwestern Oncology Group of Leukemia Cytogenetics Subcommittee

The biologic significance of clonal karyotypic abnormalities in human neoplasms is becoming better understood, but the significance of rare chromosomal aberrations is uncertain. Useful, yet arbitrary, cytogenetic definitions of a clone have been established and cases with a frequency of chromosome aberrations less than the accepted convention are explained by random loss, karyotypic instability/evolution, or other technical artifact. Are non-clonal chromosomal abnormalities that may predict future clinically significant clones being ignored? A brief case report is presented raising two such issues in the same myelodysplastic patient. This child had monosomy 7 and, later, trisomy 8, as well as increased numerical/structural aberrations seeming to predict relapse. Preliminary data from the Southwestern Oncology group is also presented. Non-clonal data should be included, when appropriate, in the clinical report.     

Cytogenetic changes in Wilms' tumors

Cytogenetic analysis of 20 Wilms' tumors using short-term culture techniques were undertaken. Chromosome abnormalities were detected in all tumors. In 19 of 20 cases only minor karyotypic changes were observed within cells with near-diploid chromosome numbers; only one tumor was predominantly hyperdiploid. Rearrangements involving chromosome 1 were the most frequently observed abnormality (in 25%) and often resulted in partial or complete trisomy for the long arm. In 20% of the tumors, abnormalities involving chromosomes 11 and 16 were present. The only other chromosomes frequently involved in structural or numerical changes were #12, and #18. Two discrete tumor foci within the same kidney differed cytogenetically, suggesting an independent origin for each focus. No correlation could be made between specific chromosome abnormalities and tumor stage or histologic subtype. Although constitutional deletion of chromosome region 11p13 has frequently been reported to predispose to Wilms' tumor formation, only two tumors with deletions involving this region were observed. Chromosomes from tumors treated with chemotherapy prior to surgical removal and culture yielded findings similar to those in untreated tumor cells.     

Cytogenetic and flow cytometric analysis of a clear cell chondrosarcoma

Cytogenetic analysis of a rare tumor, a clear cell chondrosarcoma of the spine, showed unusual karyotypic findings. The tumor had a predominant clone with a near-haploid chromosome complement of 30 chromosomes with loss of one homologue of each chromosome pair except chromosomes 5, 7, 12, and 19-22. A second clone with 58-60 chromosomes appeared to have originated by a doubling of the near-haploid clone. No structural changes were present. Comparison with other solid tumors and leukemias with near-haploid chromosome complements showed an interesting difference in the chromosomes which were preferentially disomic or monosomic in the two groups. Quantitative DNA analysis also showed aneuploid clones of cells corresponding to the near-haploid and hyperdiploid chromosome counts obtained cytogenetically.