Sister chromatid exchanges and chromosome aberrations induced by radiosensitizing agents in bone marrow cells of treated tumor-bearing mice

The frequency of sister chromatid exchanges (SCE) in vivo and chromosome aberrations and/or alterations were analyzed from the bone marrow cells of the treated dbrB tumor-bearing DBA/1J inbred mouse host. The results were compared with analogous data obtained from the bone marrow cells of untreated tumor-bearing mice for evaluation of the "indirect," i.e., somatic stress, effect on the normal host cells following triple-agent therapy intended for a mammary adenocarcinoma. Misonidazole (MIS), which is a known radiosensitizing drug, microwave hyperthermia (delta), and X-radiation (X) were used as therapeutic agents. Significant (P less than 0.05) numbers of SCE were induced in the bone marrow cells of the mice whose tumors received these triple-agent treatments (MIS + delta + X) simultaneously as compared with values of SCE per cell noted in bone marrow cells of untreated tumor-bearing control mice. The highest number of chromosome aberrations and alterations, including an increase in heteroploidy, was also noticed in the bone marrow cells of the mice whose tumors were treated simultaneously with MIS + delta + X. The triple-agent therapy on dbrB tumor also resulted in an unusually high polyploid metaphase plate in the bone marrow cell consisting of 320 chromosomes, indicating that this mode of therapy may act directly on the genetic material of the tumor-bearing host cells, inducing cytogenetic abnormalities as a side effect.     

Chromosomal abnormalities and their correlations with asbestos exposure and survival in patients with mesothelioma

Cytogenetic findings of our 30 previously reported and eight new patients with malignant pleural mesothelioma were summarised and correlated with asbestos fibre burden in lung tissue and survival. Successful cytogenetic analyses were performed on cells obtained from the tumours and/or pleural effusions of 34 of the 38 patients. Clonal chromosomal abnormalities were detected in 25 patients, 19 of them studied before treatment. Nine patients, seven of them studied before treatment, had normal karyotypes and/or non-clonal chromosomal abnormalities. Most of the karyotypic findings in the patients with clonal abnormalities were complex and heterogeneous, and no chromosome aberration specific to mesothelioma could be demonstrated. The following numerical abnormalities in decreasing order of frequency were preferentially present in karyotypic changes: -22, +7, -1, -3, -9, +11 and -14 (-/+ denoting partial or total loss or gain). Translocations and deletions involving a breakpoint at 1p11-p22 were the most frequent structural aberrations. Statistically significant correlations were found between high content of asbestos fibres in lung tissue and partial or total losses of chromosomes 1 and 4, and a breakpoint at 1p11-p22 (P = 0.0001, P = 0.003, P = 0.009, respectively). The number of copies of chromosome 7 short arms was inversely correlated with survival (P = 0.02). In this study no diagnostic cytogenetic markers of mesothelioma were found, instead the copy number of chromosome 7 short arms turned out to be a possible prognostic factor in malignant mesothelioma.     

Chromosomes and causation of human cancer and leukemia. XII. Banding analysis of abnormal chromosomes in polycythemia vera.

The chromosome constitution of bone marrow cells was determined in 13 patients with polycythemia vera (PV). In 5 of these patients definite karyotypic abnormalities were found: 3 with 46,XY,Fq-; 1 with 46,XY,11q-, 13q-; and 1 with missing Y. The latter cytogenetic finding is thought not to be related to the PV. The 4 patients with partial deletions of chromosomes had been treated with 32P, and 3 of them with chemotherapy also. Karyotypes from 2 of these patients, 1 with 46,XY,20q-, and another with 46,XY,11q-,13q- were examined with G and/or Q banding. From the results of the banding analysis, it appears that the abnormal chromosomes were due to simple deletions at specific sites on their arms, particularly in the cases with the F abnormality (20q11). The breaks occurred in the regions C11q and D12q. The portions missing from the original chromosomes could not be found on any chromosome. Most patients with PV do not develop chromosomal abnormalities through the course of their disease; when such abnormalities appear (20q- in particular), they seem to result exclusively from radiation (and possibly chemo-) therapy. Thus, cytogenetic changes do not appear to play a crucial role in the genesis of PV.     

Chromosomes and causation of human cancer and leukemia. XIII. An evaluation of karyotypic findings in erythroleukemia.

This study was an attempt at defining the cytogenetic features of erythroleukemia (EL), particularly as related to the group of AML patients with MAKA (major karyotypic abnormalities), which generally were caused by three or more cellular events of translocation or nondisjunction. Eight of the 17 patients with MAKA had a diagnosis of EL or possible EL. In most cases, MAKA was featured by hypodiploidy, karyotypic instability, and polyploidy in the leukemic cells. The most common abnormalities were loss of B or G group chromosomes and gain of a no. 16 or one or more marker chromosomes. Each of the markers of 2q+, Dq+, mar(A2, st), mar(C12, M), r(?F) and minute metacentric and acentric markers was observed in two or more patients. The extent of polyploidy seemed to be correlated with the proportion of erythroid precursor cells in the marrow and with the karyotypic instability. Since the patients exhibited the same chromosomal features, whether or not they had a diagnosis of EL or possible EL, and since patients without such a diagnosis also had cytologic suggestions of EL, a close relation of MAKA to EL is assumed. It is believed that patients with MAKA constitute one of the three chromosomally classifiable groups of EL.     

Nonrandom chromosome changes in malignant melanoma

Chromosome aberrations were analyzed in 4 cases of malignant melanoma (MM) after disaggregation of the tumors with collagenase and short-term culture. In all cell cultures, the MM cells displayed a typical triangular spindle form. The chromosome number was near-diploid in one case and near-triploid in three cases. A total of 27 abnormal chromosomes were identified with the Giemsa banding technique. By far, the most common types of abnormalities were translocations, followed by deletions and isochromosomes. Chromosomes 1, 6, and 7 were found to be most frequently involved in structural aberrations. Markers originating from chromosomes 1 and 6 were found in all four cases, and abnormalities of chromosome 7 were found in three. Each marker chromosome was unique for a given case; no common markers for two or more cases were found. Based on the present results and an analysis of reports on the chromosomal constitution of MM cells in the literature, we suggest that abnormalities involving chromosomes 6 and 7 may be a characteristic feature of MM. Aberrations of chromosome 1, although common in MM, may be part of a general cytogenetic feature in human neoplasia.     

Cytogenetic findings in 14 benign cartilaginous neoplasms

Benign cartilaginous tumors represent a spectrum of neoplastic processes with variable clinical and pathologic presentations. These tumors are histologically characterized by the presence of chondrocytes surrounded by a cartilaginous matrix. Few studies describe karyotypic abnormalities in these benign lesions. We report a series of 14 chondromas from a single institution. Conventional cytogenetics was performed on short term cultures from all cases. Clonal chromosome aberrations were found in nine tumors. One soft tissue chondroma contained three clones with t(6;12)(q12;p11.2), t(3;7)(q13;p12), and der(2)t(2;18)(p11.2;q11.2). Three periosteal chondromas displayed random structural aberrations of chromosomes 2, 3, 6, 7, and 11 and loss of chromosome 13. Among the enchondromas, three tumors displayed chromosome losses, one contained a complex translocation involving chromosomes 12, 15, and 21 as well as an inv(2)(p21q31),t(12;15;21)(q13;q14;q22) and a separate enchondroma showed a translocation involving chromosomes 12 and 22. Our data suggest that considerable cytogenetic heterogeneity exists among benign chondromatous tumors.     

Chromosomes and causation of human cancer and leukemia. XXVI. Binding studies in acute lymphoblastic leukemia (ALL).

Chromosomes were studied in the bone marrow cells of 101 patients with acute lymphoblastic leukemia (ALL) hospitalized at or attending the clinics of Roswell Park Memorial Institute (RPMI) between January, 1968, and December, 1976. Aneuploidy was observed in about 50% (54/101) of the cases. Two cases were hypodiploid and the remaining were either pseudo or hyperdiploid. The frequency of abnormalities and the chromosomal numbers were similar to those of 106 cases studied in our laboratory prior to 1968. Of 50 recently unselected cases of ALL in whom Q- and G-banded karyotypes were attempted, 31 were successfully analyzed with these techniques. The banding patterns revealed 16 cases to have chromosome abnormalities and four of these to have a similar abnormality, i.e., partial deletion of the long arm of chromosome no. 6: two cases had a 6q- with additional abnormalities and two had 6q- as the sole karyotypic abnormality. The breakpoint in chromosome no. 6 seemed to involve a segment from q21 to q25. An isochromosome of the long arm of no. 7, i(7q), was observed in two cases, two additional no. 21 chromosomes were observed in five cases and, except for the Y, all other chromosomes participated in the karyotypic changes encountered in the 16 cases in which banding analyses were performed. Banding analysis has afforded the first reliable approach towards ascertaining karyotypic evolution in ALL, which was achieved in eight cases of the present study. The chromosomes contributing to this karyotypic evolution were distributed widely. Thus, all chromosomes except the Y participated in numerical and/or structural karyotypic changes. Even though nonrandom chromosome changes may occur early in ALL, the pristine prototypic picture of the karyotypes in ALL is often obfuscated by successive chromosomal changes and hyperdiploidy by the time the karyotypes are analyzed in this condition. Further cytogenetic studies are required, with special attention to karyotypic evolution, in order to uncover the significance of chromosomal changes in early and late ALL.     

Karyotypic characterization of bronchial large cell carcinomas

Cytogenetic analysis of short-term cultures from 26 primary bronchial large cell carcinomas and 1 metastasis from a primary large cell carcinoma revealed clonal chromosome abnormalities in 20 tumors and a normal karyotype in 6. No outgrowth was obtained in 1 case. Simple aberrations were present in 3 tumors; in 1, the only change was a reciprocal translocation between chromosomes 1 and 6, in another the sole anomaly was a supernumerary marker ring chromosome and in a third loss of the Y chromosome was the only clonal change. The remaining 17 tumors had complex karyotypes. The chromosomes most frequently involved in structural rearrangements were chromosomes 1, 2, 3, 5, 6, 7, 6, 10, 11, 13, 14 and 17. The bands most frequently affected were 1q11-12, 1p13. 7q11, and 17p11-13. The rearrangements led to repeated losses of 1p, 1q, 3p, 6q, 7q and 17p and gains of 5q and 7p. The emerging karyotypic picture of large cell lung carcinomas indicates more similarities with adenocarcinomas than with other pathologic subgroups of lung cancer. © 1994 Wiley-Liss, Inc.     

Cytogenetic study in therapy-related myelodysplastic syndromes (t-MDS) and acute non-lymphocytic leukaemia (t-ANLL)

A cytogenetic study was performed in 27 patients suspected of t-MDS or t-ANLL. In 12 patients the diagnosis of t-MDS or t-ANLL was confirmed by morphological, cytochemical and immunophenotypical analysis. The cases were classified as RA (one), RAEB (four), CMML (two), ANLL (five). They had received chemotherapy and/or RT for Hodgkin's disease (eight cases), solid tumours (three cases) and multiple myeloma (one case). Clonal chromosome abnormalities were found in bone marrow or peripheral blood cells in all the 12 cases. Five patients had a clonal abnormality of chromosome no. 5 (monosomy, deletions, translocation and inversion of 5q). The critical region on chromosome no. 5 comprised bands q12-q34. Monosomy and deletion of chromosome 7q was observed in the other two patients. In the six remaining patients various karyotypic patterns were observed including a t(4;11) (q21;q23) in one case, monosomies (four cases) and trisomies (one case) of different chromosomes. In the other 15 cases, the presence of a normal karyotype together with the morphological and immunophenotypical characterisation was consistent with a diagnosis of non-neoplastic specimens.     

Cytogenetic and clinical assessment of six patients with erythroleukemia

We report the detailed karyotypic analysis and clinical features of six patients with erythroleukemia (EL). Five of six patients studied displayed substantial numeric and structural chromosome abnormalities. The most common alterations in these patients were monosomy for chromosome 7 and 16. All five patients displaying chromosomal abnormalities presented with 100 percent abnormal metaphases in their bone marrow at the time of initial diagnosis. The remaining patient was studied only during remission and had a normal diploid karyotype in all marrow cells analyzed. No patient in this study had either a Ph1 -chromosome (characteristic of CML), or translocations of chromosome #8-#21 (characteristic of AML-M2). Clinically, all but one patient had a brief history; the exception having had polycythemia rubra vera for 18 years prior to the onset of EL. All patients were treated with current Southwest Oncology Group (SWOG) protocols using cytosine arabinoside and anthracycline combinations. Three of five patients entered complete remission. However, remission durations were short (approximately six months) and median survival just over one year. Cytogenetic analysis of three patients in hematologic remission revealed persistence of chromosomal alterations. It is suggested that such remissions be reclassified as partial rather than complete based upon the cytogenetic information.     

Karyotope and survival in human acute leukemia.

Of 111 patients presenting with acute forms of leukemia, 44% had a chromosomally abnormal cell line in the bone marrow at diagnosis. In each of the acute leukemia forms (myeloid, lymphatic, stem-cell), patients with karyotypic abnormalities showed mean and median survival times like those with normal chromosomes. Both groups showed a wide range of survival times. The mean and median survival times of patients with mixed populations of chromosomally normal and abnormal cells did not differ from those of patients with exclusively abnormal cells in the bone marrow. The karyotypic abnormalities associated with acute leukemia, as well as having no etiologic significance, probably do not determine the subsequent course of the leukemia.     

Molecular cytogenetic characterization of primary cultures and established cell lines from non-medullary thyroid tumors

To further delineate the role of chromosomal aberrations in non-medullary thyroid tumors, we performed cytogenetic analyses of established thyroid cancer cell lines and primary tumors using spectral karyotyping (SKY), G-banding and comparative genomic hybridization (CGH). Five of the primary thyroid tumors revealed an abnormal karyotype. In a follicular thyroid carcinoma, we observed two translocations t(2;10), t(2;5) and losses of chromosomes 10p and 22. In a papillary thyroid carcinoma (PTC), a balanced translocation t(3;15) was revealed, while a case of metastatic PTC carried several clonal translocations involving ten different chromosomes. Numerical aberrations were observed in two of the five follicular adenomas analyzed, both leading to gain of chromosome 7 material. Furthermore, we cytogenetically characterized the three established thyroid cancer cell lines CGTH W-1, ARO and DRO. SKY, in combination with G-banding, revealed structural and numerical karyotypic abnormalities in all three cell lines and the breakpoint regions partly overlapped those of the primary tumors. The copy number changes detected by CGH correlated well with the karyotypic findings and demonstrated high-level amplifications in chromosomes 1, 5, 7, 8, 9, 11 and 19. The results provide evidence of chromosomal regions involved in non-medullary thyroid tumorigenesis, while further characterization of the observed translocations may lead to the identification of novel fusion oncogenes for thyroid cancer.     

DNA-fingerprint changes compared to karyotypes in acute leukemia

Chromosomal analysis is routinely used in follow-up studies of acute leukemia, but it cannot be used in patients who do not have karyotypic abnormalities in blastic phase (10-46% of all cases). Recently we have demonstrated that unspecific DNA-fingerprint (DNA-F) changes can be detected in blastic phase of leukemia by DNA-F analysis. These changes can be used as molecular markers of the disease and in the follow-up studies of acute leukemia karyotyping and DNA-F analysis are complementary. The comparative analyses of leukemia samples with both these methods could help to localize minisatellite loci in chromosomes and reveal new DNA areas related to leukemia. New, more specific probes targeted to specific chromosomes could consequently be developed. We compared the DNA-F to the karyotypes of 50 acute leukemia patients. In blastic phase, 19 patients had DNA-F alterations and 31 patients abnormal karyotypes, 12 patients had both DNA-F alterations and karyotypic abnormalities. DNA-F changes were detected in six of the 16 patients with normal karyotypes and 19 patients with normal DNA-F had abnormal karyotypes at the time of diagnosis. Eleven patients showed neither DNA-F changes nor abnormal karyotypes in blastic phase. Three acute myeloid leukemia (AML) patients with DNA-F changes in blastic phase had trisomy eight as a sole abnormality or combined with balanced translocation, which suggests that there might be AML associated minisatellite locus in chromosome 8. In other cases the karyotypes were complicated and no clear evidence of the relationship of DNA-F changes with other chromosomes could be found.     

Chromosome abnormalities of leukemia cells in adult patients with T-cell leukemia

Chromosomes of 30 patients with adult T-cell leukemia were analyzed. Chromosome abnormalities were found in all the patients examined. The modal chromosome number of abnormal cells was hypodiploid in 2 patients, diploid in 14, and hyperdiploid in 9. The remaining 5 patients had bimodal chromosome numbers (diploid and hyperdiploid modes). Although all the patients showed various numerical or structural chromosome abnormalities, they also had common chromosome abnormalities. Aberrations of chromosome 1 were noted in 20 of the 30 patients, aberrations of chromosome 3 were seen in 20, trisomy 6 or 6q- was found in 17, aberrations of chromosome 10 were noted in 16, aberrations of the long arm of chromosome 14 were seen in 9, and trisomy 18 was seen in 7. There was no particular relationship between the difference in clinical symptoms and disparity in chromosome abnormalities.     

Chromosome studies in preleukemic states. V. Prognostic significance of single versus multiple abnormalities

The prognostic value of marrow chromosome findings was examined in 242 patients with preleukemic myelodysplastic syndromes (MDS) or myeloproliferative disorders (MPD), with emphasis on the significance of single versus multiple karyotypic changes. In both groups, the results showed that patients with multiple chromosome abnormalities in a marrow clone had a very high probability of early death, from progression to leukemia or from other complications of hematopoietic dysfunction. Conversely, in patients with a hemic clone having only one karyotypic alteration (involving a single chromosome or single translocation), survival over 2 years was only slightly reduced as compared to those without chromosome abnormality. The only single karyotypic alteration perhaps associated with a markedly shortened survival was monosomy 7. These findings suggest that the conclusions of previous studies concerning the grave consequences of chromosome alterations in preleukemia largely reflect the clinical significance of clones with multiple cytogenetic changes. Prior knowledge of the karyotypic status of preleukemic patients should be helpful in evaluating current attempts to find effective treatment for these difficult disorders.     

Chromosomes and causation of human cancer and leukemia. X. Banding patterns in cancerous effusions.

Cells from five cancer effusions (two ovarian carcinomas, two lung cancers, and one carcinoma of the breast) were analyzed by G-, C-, and Q-banding techniques. The following observations were made: 1) The origin of some marker chromosomes could be traced accurately by these banding techniques. 2) Several chromosomes, which appeared normal with conventional staining techniques, were found to be re-arranged ones and, hence, abnormal. 3) Chromosomes No. 1, No. 3 and No. 11 were the most frequently involved in aberrations, whereas No. 12, No. 13, No. 17-20, and No. 22 Were least frequently involved. Only in one case each was the X chromosome or the Y chromosome involved in aberrations. The Y chromosome was found to be missing in all cancer cells of one lung cancer. 4) Each effusion had characteristic markers, invariably present in each cell, whether the cells were near diploid, or polyploid. 5) No common markers were observed in the two ovarian carcinomas studied, whereas the two lung cancers had a few common markers.     

Population-based demographic study of karyotypes in 1709 patients with adult acute myeloid leukemia.

Few large demographic studies of acute myeloid leukemia (AML) are derived from population-based registries. Demographic and karyotypic data were provided for AML cases from two regional leukemia registry databases in Scotland and the Northern Region of England. A population-based dataset was compiled, comprising 1709 patients aged >16 years (1235 North England/474 Scotland patients). The most common cytogenetic abnormalities involved chromosomes 5 and/or 7 (17%). Patients with the following abnormal chromosome 5/7 combinations: -5, del(5q), -5/-7 and del(5q)/-7 represented a significantly older population (P < 0.01, ANOVA). t(8;21) was the only 'favourable' karyotype found in older age. Karyotypic complexity varied within chromosome 5/7 combination groups; those containing -5, -5/-7, -5/del(7q), del(5q)/-7 or del(5q)/del(7q) combinations were significantly more frequently complex than those containing -7 and del(7q) (P < 0.01, chi2 test). Additional recurring cytogenetic abnormalities within complex karyotypes containing chromosome 5/7 combinations included (in order of frequency), abnormalities of chromosomes 17, 12, 3 and 18. Complex karyotypes not involving chromosomes 5 or 7 represented 30% of all complex karyotypes, occurred in younger patients than those involving chromosomes 5 and 7, and frequently included additional trisomy 8 (26%). In conclusion, we describe subgroups within adverse karyotypes, with different demographics, degree of complexity and additional chromosome abnormalities.     

Chromosomal aberrations of multiple myeloma in Chinese patients at diagnosis: a study by combined G-banding and multicolor spectral karyotyping

Cytogenetic investigation of multiple myeloma (MM) has been difficult by conventional methods and most of the data have been derived from western population where incidence of MM is much higher as compared to that of Asians. The current study represents the first report of chromosomal aberrations of multiple myeloma in Chinese. We investigated 25 consecutive Chinese patients with MM for chromosomal aberrations at diagnosis using G-banding and multicolor spectral karyotyping (SKY). Of the 21 patients successfully analyzed by G-banding, 11 patients revealed cytogenetic abnormalities showing complex numerical and structural aberrations, which were further characterized with SKY. An abnormal karyotype significantly associated with blastic MM was observed. Consistent with the western literature, structural rearrangements involving chromosomes 1, 6, 8, 19, numerical abnormalities of gains in chromosomes 9, 3, and 5, and losses in chromosomes 13 and 14 were observed. However, there were notably higher incidences of -22/22q- (4/11) and structural aberrations of chromosome X but a lower incidence of -X. The biological implications of these findings, if confirmed, deserve further evaluation.     

Karyotypic Evolution: Cytogenetics Follow-Up Study In Childhood Acute Lymphoblastic Leukemia

Forty seven children affected with acute lymphoblastic leukemia (ALL) were cytogenetically investigated ‍at diagnosis and all through different stages of the disease (remission and relapse). A clonal karyotypic abnormality ‍was found in 32% at diagnosis (mainly comprised of cALLa+). A hyperdiploid mode with chromosome counts ‍ranging from 47-58, was found to be most prominent among cALLa+ patients. The most common numerical ‍aberrations were gain of chromosomes 2, 5, and 21. The structural aberrations at diagnosis were found to be ‍del(9)(p22), inv(9)(p11q13) and del(19)(p12). None of the children showed ph+ chromosome. A good prognosis ‍was found in cALLa+ children with an abnormal karyotype at diagnosis and of these children, those who ‍showed karyotypic instability , had a significantly longer first remission time. The karyotypic evolution ‍through remission(s) and relapse(s) revealed the occurrence of structural alterations , including changes in ‍chromosomes 3, 6, 9, 21 and 22. However, irrespective of the karyotypic clonal nature at diagnosis, ‍chromosome 9 was the most commonly involved chromosome through the course of disease. ‍     

Clinical and cytogenetic correlations in 63 patients with therapy-related myelodysplastic syndromes and acute nonlymphocytic leukemia: further evidence for characteristic abnormalities of chromosomes no. 5 and 7

Clinical, histologic, and cytogenetic features in 63 patients with a therapy-related myelodysplastic syndrome (t-MDS) or acute nonlymphocytic leukemia (t-ANLL) following cytotoxic chemotherapy or radiotherapy for a previous disease were analyzed. Eleven patients had received only radiotherapy for the primary disorder. In most cases, high doses had been administered to treatment ports that included the pelvic or spinal bone marrow. Twenty-one patients had received only chemotherapy for their primary disease, all for more than 1 year and all but one with an alkylating agent, either alone or in combination with other drugs. Thirty-one patients had received both radiotherapy and chemotherapy, either concurrently or sequentially. A clonal chromosomal abnormality was observed in marrow or blood cells from 61 of the 63 patients (97%). Fifty-five patients (87%) had a clonal abnormality of chromosomes no. 5 and/or 7 consisting of loss of all or part of the long arm of the chromosome. The critical chromosome region that was consistently deleted in all 17 patients with del(5q) comprised bands q23 to q32. In addition to nos. 5 and 7, five other chromosomes (no. 1, 4, 12, 14, and 18) were found to be nonrandomly involved. Both t-MDS and t-ANLL are late complications of cytotoxic therapies that have distinctive clinical and histologic features and are associated with characteristic aberrations of chromosomes no. 5 and 7. It seems likely that these two chromosomes contain genes involved in the pathogenesis of these hematopoietic neoplasms.