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Chromosomes and malignancy
Abstract
Nature is the international weekly journal of science: a magazine style journal that publishes full-length research papers in all disciplines of science, as well as News and Views, reviews, news, features, commentaries, web focuses and more, covering all branches of science and how science impacts upon all aspects of society and life.
The treatment of rat embryo secondary cultures with DMBA or DMBA-3H for 5,9, or 24 h resulted in chromosome damage consisting mainly of chromatid type aberrations. There was an increase in the percentage of labelled nuclei and metaphases with increasing length of exposure. In terms of incidence of chromatid lesions, the largest telocentric chromosome (No. 2) was the most susceptible of the autosomes. Banding pattern analysis demonstrated that the region associated with negative band 2q24 of the No. 2 chromosome had the highest number of lesions. An increased accumulation of DMBA-3H label occurred in approximately the same chromatid area of a small fraction of cells exposed for either 5 or 9 h prior to mitosis. The complete loss of DMBA-3H chromosomal labelling after DNAse treatment suggests that the visible grains represent carcinogen-bound DNA. After DMBA and BrdUrd, there was an increase in the number of sister chromatid exchanges compared to controls treated with BrdUrd only; the location of the exchange points on chromosome No. 2 was similar in samples treated with either DMBA and BrdUrd or BrdUrd alone. Additional experiments with thymidine-3H showed that the non-random chromatid lesions on chromosome No. 2 may result from endogenous radiation from the incorporated tritium. These studies demonstrate that a specific chromosome may be affected by diverse agents and that chromatid lesions frequently occur at the site of sister chromatid exchanges.
If, as has been proposed, the factor which controls the malignant nature of a cell behaves as a recessive genetic character, a somatic mutation in the normal dominant homologous gene of a diploid cell, which carries the malignant factor, may allow the expression of the recessive malignant character. Using this proposal together with the molecular theory of cell survival, a mathematical equation is derived to provide a general description of the dose response for radiation-induced malignancy which is non-linear and peaked. The equation is based on the assumption that a radiation-induced DNA double-strand break can cause a somatic mutation or a chromosome aberration which may leave the cell in a precancerous state. The equation is used to analyse data on the radiation-induced transformation of diploid cells and extended logically to analyse data on the transformation of tetraploid cells.
If the fundamental lesions responsible for malignancy are indeed some form of genetic or epigenetic loss, then one would expect that in hybrids between malignant and non-malignant cells recessive inheritance of malignancy would be the rule. But our evidence on the nature of the genetic lesions is at best suggestive; and it may well be that a detailed examination of a wider range of experimental material will reveal cases in which malignancy is inherited as a dominant character. I do not believe that any such cases have yet been established; but their existence would not detract from the interest of the observations that I have described. That malignancy can be suppressed, and suppressed by the activity of a normal body cell is, it seems to me, no small thing; and perhaps I may be forgiven for hoping that the further exploration of this phenomenon may contribute in some small way to our understanding of what remains one of the most distressing of human maladies.
In human meningiomas one G group chromosome is regularly missing. Using a fluorescence staining (Atebrine-acetic acid) in 5 meningiomas it could be shown that always one chromosome No. 22 was missing. In one meningioma we found an accessory stemline bearing a Ph1-like chromosome, which could be identified to be a deleted No. 22. — The similarities of the chromosomal findings in meningiomas and the chronic myeloic leukemia are discussed.Als regelmiger Befund ist beim menschlichen Meningeom der Verlust eines G-Chromosoms nachzuweisen. Wir untersuchten mit Hilfe einer Fluorescenzfrbung (Atebrin-Essigsure) 5 Meningeome und konnten zeigen, da immer ein Chromosom Nr. 22 fehlt. In einem Meningeom, das eine zustzliche Stammlinie mit einem Ph1-hnlichen Chromosom aufweist, wurde das Fragment als deletiertes Chromosom Nr. 22 identifiziert. — Die hnlichkeit der chromosomen-morphologischen Befunde beim Meningeom und bei der chromischen myeloischen Leukmie werden diskutiert.
KNOWLEDGE of the detailed pattern of fluorescence of the normal human karyotype, showing more than 200 bands per haploid chromosome set1, has enabled us to recognize, both in biopsies and in cell cultures from several Burkitt lymphomas, an extra band in one homologue of D group chromosome pair No. 14. The deviation was seen in all analysable cells of five out of six tumour biopsies and of seven out of nine tumour cell lines examined, representing twelve different tumours from nine male and three female patients. In three tumours both biopsies and cultures were examined, and it was found that all gave results consistent in the two types of samples. Thus, two of them had the marker band in both the biopsy and culture, the third revealed the marker band absent in both cases. The remaining tumours were investigated only in biopsies or only in culture. They were positive in eight cases, negative in one. Of the twelve tumours examined altogether, ten were positive and two negative.
CELLS from nine consecutive patients with chronic myelogenous leukaemia (CML) have been analysed with quinacrine fluorescence and various Giemsa staining techniques. The Philadelphia (Ph1) chromosome in all nine patients represents a deletion of the long arm of chromosome 22 (22q-)1,2. An unsuspected abnormality in all cells from the nine patients has been detected with these new staining techniques. It consists of the addition of dully fluorescing material to the end of the long arm of one chromosome 9 (9q+). In Giemsa-stained preparations, this material appears as an additional faint terminal band in one chromosome 9. The amount of additional material is approximately equal to the amount missing from the Ph1 (22q-) chromosome, suggesting that there may be a hitherto undetected translocation between the long arm of 22 and the long arm of 9, producing the 9q+ chromosome.