Biomedical subjects
Publications and source records attributed to F Mitelman.
Sixteen patients with paroxysmal nocturnal hemoglobinuria (PNH) from five European centers have been submitted to chromosome analysis. All of them had a normal bone marrow karyotype. The associations between some chromosomally abnormal cases reported in the literature and "typical" PNH or PNH phenomenon during the course of other hematological disorders are discussed.
The pattern of heteromorphisms in the C-band-positive constitutive heterochromatin of human chromosomes No. 1, 9, and 16 was studied in peripheral lymphocytes of 45 patients with soft tissue sarcomas and 78 control individuals. The parameters of the heterochromatic regions analyzed were relative size, symmetry-asymmetry within homologous pairs, and incidence of inversions. No consistent differences were found in these parameters between controls and sarcoma patients.
The bone marrow karyotype was investigated in 98 patients with acute non-lymphocytic leukaemia (ANLL). The patients were divided into two groups according to age. (1) 47 patients were 20-54 (median 40) years old. 21 had a history of occupational exposure to chemical solvents, insecticides, or petrol products, and 26 were considered occupationally not having been exposed to such agents. In 4 exposed patients (19%) all bone marrow cells had clonal chromosomal aberrations (designated AA), while also 4 of the non-exposed patients (15%) were AA. Thus in young ANLL patients, there was no significant association between occupational exposure to potential mutagenic/carcinogenic agents and the AA constitution of the leukaemic cells. (2) 51 patients were 55 years of age or older (median 65 years). 16 were exposed and 8 of these (50%) had the AA constitution. 35 patients were non-exposed and only 4 (11%) were AA. It is known from previous studies that the survival of ANLL patients with AA is extraordinarily short. Accordingly the overrepresentation of AA in exposed patients 55 years or older, was associated with a shorter survival than that of the non-exposed elderly patients. The results suggest that etiologic factors may influence the clinical course of ANLL, especially in elderly patients.
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In 24 manual metal arc stainless steel welders (means: exposure time 19 years, 100 electrodes/d, air chromium level 81 micrograms/m3, urinary chromium 47 mumol/mol creatinine) and 24 matched referents, lymphocytes in peripheral blood were analyzed for cytogenetic effects. No statistically significant differences were observed as to frequency of cells with breaks and fragments (1.5% for the welders, 1.9% for the referents); gaps and isogaps (1.8 vs 2.0%); interchanges, dicentrics, rings and markers (0.8 vs 0.5%); total number of cells with structural aberrations (4.1 vs 4.4%); hyperdiploidy (0.3 vs 0.2%); or total number of cells with aberrations (4.4 vs 4.6%). Neither were there any differences in the frequencies of micronuclei (7.8 vs 7.9 per mille) or sister chromatid exchanges (11 vs 12 per cell) in lymphocytes of peripheral blood.
A new micronucleus method based on the analysis of lymphocytes with preserved cytoplasm revealed an increased frequency of micronuclei in 38 workers employed in a plant producing styrene-modified polyester resin as compared to the frequency in 20 referents (5.9 vs 3.6%). The time-weighted average of the styrene concentration in the workroom air varied between 1 and 36 ppm (mean 13 ppm) during the last year and correlated well to low urinary levels of mandelic acid, which ranged from 9 to 316 mg/g of creatinine (mean 65 mg/g of creatinine).
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Sister chromatid exchanges (SCE) and structural chromosome aberrations were analyzed in peripheral blood lymphocytes of 100 individuals, and correlated to age and sex. No correlation was found between the frequency of SCE and age, but older individuals had significantly more structural aberrations than younger. Females had significantly more SCE as well as structural chromosome aberrations than males. The positive correlations of SCE and structural aberrations to age and sex were also significant when these factors, as well as smoking habits, were taken into consideration in an analysis of covariance.
The karyotypic pattern in 69 patients with Ph1-positive chronic myeloid leukaemia (CML) was investigated during the blastic phase (BC) and correlated with survival and certain parameters of potential prognostic significance, including blast morphology, basophilia and thrombocytopenia. There was no difference in median survival in BC between patients with and without aberrations in addition to the Ph1. Nor were there any differences in this respect among patients with the specific aberrations +Ph1, +8, iso(17q), or other abnormalities. There was no correlation between the incidence of thrombocytopenia and any particular karyotypic change. However, the incidence of basophilia was a characteristic feature for patients with an iso(17q). The survival time in BC was considerably longer in patients with a lymphoid morphology of the blastic cells compared to the myeloid varieties, and within the myeloid varieties the survival in BC was longer in patients with granular differentiated blasts than in those with granular atypical blast cells. No obvious correlation was apparent between blast morphology and karyotypic pattern. However, a pattern was discernible regarding survival and certain chromosomal changes within some morphologic groups: in patients with granular differentiated and lymphoid morphology, the median survival in BC was considerably longer when the bone marrow cells had a Ph1 as the sle abnormality compared to patients who had additional aberrations.
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The study of chromosomal aberrations in tumour cells by means of modern banding techniques has become a rapidly expanding branch of cancer research. Large amounts of information about cancer-associated chromosomal aberrations have accumulated, and new data continue to appear at a rapid rate. The systematic evaluation of these data has disclosed a number of correlations between chromosomal change and neoplastic disease in experimental animals and man: (1) Chromosomal aberrations are strictly non-random, and in several instances the aberrations are highly consistent and show a remarkable degree of specificity. (2) Chromosomes selectively involved in different types of neoplasia cluster to certain specific chromosome types, and evidence has been presented indicating that certain chromosomal regions may be affected selectively. (3) Suggestive results from work with experimental tumours indicate a direct interaction between the tumour-inducing factor and the chromosomes of the host cell. A hypothetical model, originally proposed by Levan and Mitelman (1977) and elaborated in detail by Mitelman and Levan (1981) to explain the role of chromosomal aberrations in malignant development, is presented. According to this idea, the chromosomal aberrations associated with malignancy may be of essentially two distinct kinds, with different modes of origin. One kind of aberration, the primary or active, arises from direct interaction between the inducing agent and the genetic material of the target cell. Primary aberrations are therefore located in specific chromosomal regions. The other kind of aberration, the secondary or passive, arises by chance disturbances of mitosis. Since, however, only those secondary changes that happen to enhance the effect of the primary change have selective value and will thus accumulate in a population, the passive changes exhibit distinct nonrandom patterns that reflect the primary changes. Conversely, it should be possible to deduce from the distribution of aberrations which chromosomes were originally affected by a primary change; and close observation of those chromosomes involved in nonrandom changes should therefore give indications as to the location in the genome of the original lesions induced by the oncogenic agent.
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We have proposed a hypothetical model to explain the role of chromosomal aberrations in malignant development. In this model we postulate two kinds of chromosomal changes: (1) primary, active changes caused by direct interaction between the oncogenic agent and the hereditary material of the host cell. These changes are mainly somatic mutations, but may also be associated with directed structural changes visible in the microscope; and (2) secondary, passive changes arising randomly by nondisjunction and structural rearrangements. They are followed by selection of cells with changes that amplify the primary change and thus appear as nonrandom chromosome patterns. This hypothesis is discussed in the light of 1827 cases of human malignancy in which we have recently surveyed and systematized chromosomal aberrations. Special support for the idea of somatic mutations as the initiator of malignant development comes from work of Knudson and collaborators in human retinoblastoma. The Ph1 chromosome, predominant during the chronic phase of chronic myeloid leukemia (CML), is proposed as an instance of a primary change, whereas the chromosome changes during the blastic crisis of CML will illustrate the secondary changes. The most common of these secondary changes is actually the doubling of the Ph1 and thus an amplification of the primary change. The increase in number of copies of a specific chromosome reported by Green and collaborators demonstrates that this kind of amplification can result in direct response to the need for a specific gene located in that chromosome.
A terminal deletion of the long arm of one chromosome 21 at band q21 was found in two patients with acute leukemia and a low platelet count: one case of acute myelomonocytic leukemia and one case of acute lymphocytic leukemia. The segment deleted from chromosome 21 could not be found translocated to any other chromosome of the complement. The results indicate that the 21q- marker chromosome may be due to a true deletion and that the marker is no specific for primary thrombocythemia or other myeloproliferative disorders associated with thrombocytosis.