Karyotypic evolution in patients with myelodysplastic syndromes

Serial cytogenetic studies were performed in 33 patients with myelodysplastic syndrome in order to establish the frequency of karyotypic evolution and to correlate the chromosome and clinical findings during the course of the disease. Fifteen of the 33 patients (45%) showed abnormalities in the first cytogenetic study and this percentage increased to 57% during the course of the disease. A stable karyotype (normal or abnormal) was found in 19 patients (58%), whereas the rest (42%) showed an unstable karyotype. Trisomy 8, monosomy 7, and del5q were the most frequent abnormalities, not only at presentation, but also during karyotypic evolution. Seven patients (23%) with a known evolution proceeded to leukemia; four of them had stable (22%) and three unstable (25%) karyotypes; however, 33% of patients with unstable karyotypes and only 5% with stable karyotypes died from complications of the disease. Our results suggest that karyotypic evolution is relatively frequent in these patients; this evolution could be related to a poor clinical prognosis, either evolving to leukemia or death.     

Cytogenetic findings in a human malignant melanoma metastatic to the brain

Cytogenetic analysis by G-banding of direct and preparations of a malignant melanoma metastatic to the brain in vitro showed a pseudodiploid modal chromosome number, including five marker chromosomes, one of which was an i(6p). These results agree with those recently reported about the preferential involvement of chromosome #6 in malignant melanoma.     

Serial cytogenetic study of a human glioma cell line

Chromosome studies were performed on a human glioma cell line. Nineteen passages were studied, and a heterogeneous chromosome complement with variable modal numbers was found. The main range varied from tetraploidy to triploidy. The presence of identical markers (9p?, 11p+, an increase in the copies of chromosome No. 7) in different passages suggests a clonal evolution.     

Chromosome studies in two human brain tumors

The cytogenetic findings based on G- and C-banding in two human brain tumors (a meningioma and an astrocytoma) are reported. Both tumors were characterized by hypodiploid modal numbers (45 and 40 chromosomes, respectively), chromosome 22 abnormalities, and the presence of several markers. This observation supports the hypothesis of the association of No. 22 chromosome abnormalities with tumors of the brain.     

Cytogenetic follow-up of patients with nonlymphocytic leukemia. II. Acute nonlymphocytic leukemia

Bone marrow (BM) karyotypes of 86 patients with acute nonlymphocytic leukemia (ANLL) were studied at the time of diagnosis; 39 of them (45%) were normally diploid and 47 (55%) showed acquired abnormalities. The median survival was no longer in the diploid group than in the aneuploid one. Nonrandom aberrations were often found: trisomy 8 (15 times), monosomy 7 (7 times), and t(8;21) (7 times). Two patients with acute promyelocytic leukemia presented with the t(15;17) in BM cells. Serial cytogenetic studies performed in 17 cases showed that karyotypic evolution closely followed the clinical evolution. Complete remission, obtained in 10 cases, was characterized by BM metaphases with a normal karyotype. Relapse after a period of complete remission was documented four times; the BM metaphases then showed the original abnormal karyotype with additional changes that, in three cases, were limited to a new structural aberration.     

Micronuclei in erythropoietic bone marrow cells: Relation to cytogenetic pattern and prognosis in acute nonlymphocytic leukemia

The bone marrow karyotype and the frequency of micronuclei in erythropoietic bone marrow cells (Howell-Jolly bodies) were determined in 25 adults with acute nonlymophocytic leukemia (ANLL). Ten patients had exclusively normal diploid bone marrow cells; 11 had a mixture of normal and abnormal cells, and 4 had abnormal bone marrow metaphases only. The frequency of micronuclei ranged from 3 to 28/2000 erythropoietic bone marrow cells (median 10). The number of micronuclei was significantly higher in patients with abnormal metaphases than in those with normal metaphases; in patients with a mixture of normal and abnormal bone marrow metaphases there was an association between the frequency of abnormal metaphases and the number of micronuclei. A striking difference in median survival time was found between patients with low and high numbers of micronuclei, irrespective of the cytogenetic bone marrow patterns. Patients with fewer than 10 micronuclei per 2000 erythropoietic bone marrow cells had a median survival of 148 days; those with more than 10/2000 had a median survival of only 34 days (0.002 < p < 0.02).     

Chromosome patterns in 26 South African children with acute nonlymphocytic leukemia (ANLL)

Of 46 black leukemic children 52% had acute nonlymphocytic leukemia (ANLL), whereas only 11% of 62 white leukemic children had the disease. An abnormal karyotype was found in 73% of the 26 children with ANLL, and the majority of abnormal karyotypes were pseudodiploid. "Balanced" translocations were noted in 10 children, of whom four had t(8;21) associated with M2 ANLL, two had t(15;17) and M3 ANLL, two had a t(9;22), one child with M5 ANLL had t(10p;11q), and an infant with congenital M5 ANLL had t(8;16). Monosomy #7 was detected in two preleukemic children who subsequently developed M4 ANLL. Hyperdiploidy was present in only three cases. These patterns were compared with those of other published series, confirming the increased frequency of chromosome abnormalities in children with ANLL. The differing ratio of ANLL:ALL, some of the distinctive clinical features, and the high frequency of detectable chromosome abnormalities in black children may be reflections of a particular oncogenic agent(s) within their environmental background that could be responsible for the initiation of the leukemic process.     

Cytogenetic follow-up of patients with nonlymphocytic leukemia I. Philadelphia chromosome-positive chronic myeloid leukemia

Chromosomes of blood and bone marrow cells were studied in 53 patients with Philadelphia chromosome (Ph¹)-positive chronic myeloid leukemia (CML). Fifty patients presented with t(9;22) and three with variant translocations: t(17p+;22q?); t(17q+;22q?), and t(1;9;22). Serial studies were carried out in 27 patients during both the chronic and the blastic phase of the disease. Five patients in the chronic phase developed cytogenetic changes in addition to the Ph¹. In two of these cases the changes preceded a transformation into acute leukemia, but in three cases no acceleration of the disease has occurred 1 to 4 years after the emergence of the subclones. Blastic transformation occurred in 15 instances; 11 of these patients acquired additional nonrandom chromosomal changes: trisomy 8 (9 times), i(17q) (4 times), trisomy 17 (2 times), trisomy 19 (7 times), and duplication of the 22q? (6 times). Clonal evolution was found in eight cases, either at the onset of blastic transformation or later in follow-up cultures. The differences between karyotypic evolution during the chronic and blastic phases of CML are discussed, together with their prognostic significance.     

Clinical implications of monosomy 7 in acute nonlymphocytic leukemia

A group of 18 patients with acute nonlymphocytic leukemia and the chromosomal aberration monosomy 7 in their bone marrow cells was compared to a group of control patients with the same disease but normal bone marrow chromosomes. The monosomy 7 group of patients had a higher incidence of fever and infections, and a higher white blood cell and granulocyte count compared to the control group at the time of diagnosis. The clinical difference between the groups continued over the first month of hospitalization. Complete remission was obtained in 12% of the monosomy 7 group and in 59% of the control group. Survival was clearly longer in the control group of patients. Monosomy 7 of the bone marrow in acute nonlymphocytic leukemia is therefore to be considered a bad prognostic sign.     

Acute nonlymphoblastic leukemia with bone marrow eosinophilia and structural anomaly of chromosome 16

A patient with acute myelocytic leukemia in relapse presented with t(16;21) (p12;q22). Hematologic studies revealed a large number of abnormal eosinophils in the bone marrow. The complexity of chromosome #16 rearrangements associated with acute nonlymphocytic leukemia and the possible significance of chromosomes #16 and #21 in relation to the concomitant eosinophilia are briefly discussed.     

Secondary chromosome changes in chronic myeloid leukemia: Relation to treatment

Thirty four patients with Philadelphia (Ph¹) chromosome positive chronic myeloid leukemia with clonal bone marrow chromosome aberrations in addition to the Ph¹, were divided into two groups: 1) 23 patients treated with busulfan only during the chronic phase, and 2) 11 patients treated with intensive chemotherapeutic schedules during the chronic phase. In all the material studied, about 85% of the patients showed at least one of three particular changes: +8, iso(17q), and/or +Ph¹. The frequency of each of these three aberrations was similar in the two groups. Additional structural changes of a clonal nature were, however, seen in only 3 of the 23 patients treated with busulfan only, but were present in 5 of the 11 patients treated with intensive chemotherapy. The results indicate that intensive chemotherapy may produce new stable abnormal clones in patients with leukemia. Furthermore, chromosome 1 was involved in aberrations in all 5 patients with structural changes undergoing intensive chemotherapy, but in no patient treated with busulfan only. The 11 patients treated with intensive chemotherapy were studied in Italy, whereas 20 of the 23 patients treated with busulfan only were studied in Sweden. The possibility that the differences recorded between the two groups may be geographical in nature rather than induced by treatment cannot be excluded.     

Chromosome pattern,occupation, and clinical features in patients with acute nonlymphocytic leukemia

Chromosome banding pattern of bone marrow cells, cell morphology according to the FAB classification, and clinical findings were compared in two groups of adult patients with acute nonlymphocytic leukemia (ANLL): 52 patients occupationally exposed to chemical solvents, insecticides, or petrol products, and 110 patients with no history of occupational exposure to potential mutagenic/carcinogenic agents. Striking differences were found between the two groups: (1) Clonal chromosomal aberrations were present in 75% of exposed patients compared with only 32% in the nonexposed group. (2) Of the patients exposed to solvents and insecticides 92% had abnormal chromosomes, whereas only 29% of patients exposed to petrol products showed abnormalities; in the total material $\text{10}\text{13}$ exposed patients with normal chromosomes were exposed to petrol products. (3) The relationship between chromosomal abnormality and exposure was evident in both females and males. However, only 29% of women with an abnormal karyotype were exposed, whereas 70% of males with an abnormal karyotype were exposed. (4) The incidence of certain characteristic karyotypic abnormalities, i.e., $\text{?5}\text{5}\text{q}\text{?}$, $\text{?7}\text{7}\text{q}\text{?}$, +8, +21, t(8;21), and t(9;22), were decidedly more common in exposed than in nonexposed patients. At least one of these changes were present in 92% of exposed patients with aberrations, whereas in the nonexposed group the incidence was only 60%. (5) The monocytic varieties of ANLL (M4 + M5) were more common in the nonexposed patients, whereas erythroleukemia (M6) was more common in the exposed group. The predominance of abnormal karyotypes in the exposed compared to the nonexposed patients was similar in leukemia types M1 + M2 and in M4 + M5. (6) There was no difference in survival time between the two groups and the same correlation was obvious in both exposed and nonexposed patients: patients who had only abnormal metaphases had poorer prognosis than those with normal bone marrow metaphases only (6 vs 1.5 months). This correlation was obvious in patients classified as acute myeloid leukemia (AML) as well as in the monocytic varieties of ANLL.     

Anomalies of the long arm of chromosome 11 in human myelo- and lymphoproliferative disorders. I. Acute nonlymphocytic leukemia

In a series of 365 consecutive ANLL cases of which 45.1% had abnormal karyotypes, 13 cases were detected with a structural abnormality of the long arm of chromosome 11. Besides one isochromosome 11q, there were six deletions and six translocations. Of these 12 patients, seven had acute monocytic leukemia (FAB-type M5), two had an M4, two had an M2, and one case of secondary leukemia had an M3-like disorder. Similar results with regard to the type of leukemia were obtained upon analysis of 41 cases of ANLL with an 11q anomaly described in the literature. This study confirms that a high proportion of acute monocytic leukemias and a lesser proportion of acute myelomonocytic leukemias are characterized by an 11q anomaly, mostly involving bands q22 and/or q23. Acute monocytic leukemia with an 11q structural anomaly appears to have a poor prognosis.     

Diagnostic and prognostic significance of chromosome abnormalities in acute nonlymphocytic leukemia

Chromosome abnormalities in acute nonlymphocytic leukemia (ANLL) are of diagnostic and prognostic importance. The presence of an abnormality in ANLL patients predicts an unfavorable course; the prediction is particularly significant for acute myelocytic leukemia. The occurrence of a t(15;17) assists in the diagnosis of “microgranular” acute promyelocytic leukemia; transmission electron microscopy can aid in confirming this diagnosis. The presence of a chromosome abnormality in previously treated malignant lymphoma patients with undiagnosed cytopenia supports a diagnosis of preleukemia. The presence of a chromosome abnormality in patients with the hypereosinophilic syndrome might identify the subset of patients who have a neoplastic disease.     

Patient with chronic myelogenous leukemia and late appearing Philadelphia chromosome

The sixth example of a late appearing Ph¹ chromosome in a patient with typical chronic myelogenous leukemia is the subject of the present report. Knowledge of the true frequency of this apparently rare event awaits systematic longitudinal cytogenetic studies of patients with Ph¹-negative CML.     

Critical chromosome rearrangement in acute promyelocytic leukemia

We report here a patient with acute promyelocytic leukemia (APL) who has two normal chromosomes #15 but a structurally abnormal chromosome #17. This case indicates that the critical point of rearrangement in APL is not necessarily in chromosome #15 but may, alternatively, be in chromosome #17.     

Silver bands in chronic granulocytic leukemia: I. Increased banding associated with blastic transformation

We have tested the proposal that the level of silver banding in leukemic cells of Ph1 + chronic granulocytic leukemia (CGL) patients increases as the disease progresses. Blood and/or bone marrow cells from 14 patients were cultured for 24 hr before banding. In all but one case, there were two populations of mitoses, those with silver bands on their nucleolar organizing regions (NORs) and those without. The percentage of cells that banded was higher, on average, in cultures from 7 patients in blastic transformation (80%) than in 8 chronic cases (36%) or in one accelerated phase (49%). Also, the mean number of NORs stained in banded cells was higher in blastic phase (6.9) compared with chronic phase cells (4.4). Hyperdiploid cell lines were present in four cases of myeloblastic transformation. All such cells were silver banded, and the mean fraction of NORs banded in them was relatively high. An increase in silver banding with time was shown in two of the patients. It seems that silver banding does increase in CGL cells as the disease progresses. This may arise either through an increase in the rate of ribosomal RNA synthesis in leukemic cells present in the blastic phase or possibly by a decrease in the rate of degradation (or processing) of newly synthesized rRNA.     

Increased levels of spontaneous and mutagen-induced chromosome aberrations in skin fibroblasts from patients with adenomatosis of the colon and rectum

Fibroblast cell strains were established from skin biopsies taken from patients with adenomatosis of the colon and rectum (ACR) and their relatives. A total of 57 different strains (33 from patients and 24 from healthy members of ACR families not at an increased risk for colon polyposis) were tested for their frequencies of spontaneous structural chromosome aberrations, i.e., chromatid and isochromatid gaps, breaks, and interchanges. In 47 strains (27 from patients, 20 from controls), the frequencies of structural chromosome aberrations were also determined after exposing the cells to N-methyl-N'-nitro-N-nitroso-guanidine (MNNG). Both spontaneously and after mutagen treatment, the group of patient strains exhibited, on average, approximately twice the number of chromosome aberrations found in the control group. This increase was highly significant (p less than 0.001), even though there was a considerable overlap between patient and control strains. Treatment with MNNG led to a marked increase in chromosome aberrations in both patients and controls. The small differences in aberration frequencies seen between Gardner and other patient strains were clearly insignificant.     

Chromosomal banding patterns in patients with acute nonlymphocytic leukemia

Approximately 50% of acute nonlymphocytic leukemia (ANLL) patients studied with banding techniques have detectable clonal karyotypic abnormalities. Although there is considerable variability, certain nonrandom abnormalities are observed, including trisomy 8, monosomy 7, and the 8;21 translocation (frequently accompanied by loss of an X or Y). The 15; 17 translocation is highly specific for acute promyelocytic leukemia. Clonal evolution of the karyotype can be observed in a significant number of ANLL patients for whom serial cytogenetic analyses are obtained. Gain of a No. 8 is the most frequently observed evolutionary change. Bone marrow cells from patients who develop ANLL following treatment of a previous malignancy often have hypodiploid modal numbers and frequently show loss of all or part of a chromosome No. 5 or No. 7.     

Variant Ph translocations in chronic myeloid leukemia

Variant translocations were found in eight of 142 consecutive patients with Ph-positive, chronic myeloid leukemia encountered in our laboratory during the last decade. Two patients had simple, two-way variant translocations: t(17;22)(p13;q11) and t(16;22)(q24;q11). Both of these patients had an additional translocation involving chromosomes #9: t(7;9)(q22;q34) and t(9;17)(q34;q21), respectively. Complex variant translocations were found in four cases: t(2;9;22)(p23q12;q34;q11), t(3;9;22)(p21;q34;q11), t(9;12;22)(q34;q13;q11q13), and t(13;17;22)(p11;p11q21;q11). In two cases, the only discernable cytogenetic aberration was del(22)(q11). A review of the chromosomal breakpoints involved in this series and in 185 cases of variant Ph translocations previously reported in the literature reveals that a disproportionately large number of breakpoints are located in light-staining regions of G-banded chromosomes. Furthermore, the breakpoints in simple variant translocations are more often located in terminal chromosomal regions, whereas, the breakpoints in complex translocations typically affect nonterminal bands. No obvious correlation was detected between variant Ph translocation breakpoints and either fragile sites, oncogene locations, or consistent chromosome breakpoints in other malignancies.