The development of modern cancer cytogenetics is briefly reviewed. The observation around 1950 that ascites tumors were excellent materials for chromosome analysis acted as an incitement both of cancer cytogenetics and of mammalian cytogenetics in general.



The Philadelphia chromosome of chronic myelogenous leukemia (CML). discovered in 1960, was long unique in showing strict correlation between specific chromosomal deviation and malignant disease. Detailed chromosome analysis of large series of experimental tumors was needed to establish the distinction between significant and accidental chromosome deviations and to demonstrate that the former were nonrandom and formed predetermined patterns. These were correlated to the inducing factor rather than to the tissue type, from which the tumor developed.



Systematic analysis of chromosomal aberrations in more than 600 human neoplasms, studied by our group or taken from the literature, showed that in 12 different tumor types most chromosomes were unaffected, the significant deviations being clustered to 10 of the 24 human chromosome types. It was suggested that genes of special importance to malignant development were located in a few specific chromosomes.



The 2 obscure, cancer-associated phenomena of homogeneously staining chromosome regions and double minute chromosomes are briefly described and a tentative interpretation is proposed.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1601-5223.1977.tb01208.x

Chromosomes and cancer

Clustering of aberrations to specific chromosomes in human neoplasms. IV. A survey of 1,871 cases.

A growing body of evidence from human and animal cancer cytogenetics indicates that aneuploidy is an important chromosome change in carcinogenesis. Aneuploidy may be associated with a primary event of carcinogenesis in some cancers and a later change in other tumors. Evidence from in vitro cell transformation studies supports the idea that aneuploidy has a direct effect on the conversion of a normal cell to a preneoplastic or malignant cell. Induction of an aneuploid state in a preneoplastic or neoplastic cell could have any of the following four biological effects: a change in gene dosage, a change in gene balance, expression of a recessive mutation, or a change in genetic instability (which could secondarily lead to neoplasia). To understand the role of aneuploidy in carcinogenesis, cellular and molecular studies coupled with the cytogenetic studies will be required. There are a number of possible mechanisms by which chemicals might induce aneuploidy, including effects on microtubules, damage to essential elements for chromosome function (ie, centromeres, origins of replication, and telomeres), reduction in chromosome condensation or pairing, induction of chromosome interchanges, unresolved recombination structures, increased chromosome stickiness, damage to centrioles, impairment of chromosome alignment, ionic alterations during mitosis, damage to the nuclear membrane, and a physical disruption of chromosome segregation. Therefore, a number of different targets exist for chemically induced aneuploidy. Because the ability of certain chemicals to induce aneuploidy differs between mammalian cells and lower eukaryotic cells, it is important to study the mechanisms of aneuploidy induction in mammalian cells and to use mammalian cells in assays for potential aneuploidogens (chemicals that induce aneuploidy). Despite the wide use of mammalian cells for studying chemically induced mutagenesis and chromosome breakage, aneuploidy studies with mammalian cells are limited. The lack of a genetic assay with mammalian cells for aneuploidy is a serious limitation in these studies.

Chemically induced aneuploidy in mammalian cells: Mechanisms and biological significance in cancer

This survey of chromosomal aberrations in human neoplasms comprises 1,871 cases distributed on 15 groups of malignant disease, viz. 4 groups of myeloproliferative disorders with 1,328 cases, 5 groups of lymphoproliferative disorders with 369 cases and 6 groups of solid tumors with 174 cases. The material is presented in 17 tables, in which the variation of each chromosome is listed separately for each geographic region. In the discussion part a number of special problems are looked into. The difference in variation between the individual chromosomes was highly signifcant statistically. Within each tumor, all chromosomes which exceeded the average variation with more than 1 standard deviation were considered selectively involved. In all neoplasms taken together, the chromosomes selectively involved clustered to 15 of the 24 human chromosome types. Other topics taken up for discussion were the following: possible differences in chromosome variation between geographic regions; the specificity of certain marker chromosomes; the hypothesis of 2 essentially different kinds of chromosome aberration in cancer. The phenomena of genic amplification and recurrent translocation often found in cancer require the assumption of unorthodox cytogenetic mechanisms. One main conclusion of the paper is that the aberrations of the selectively involved chromosomes influence cancer development because of the genes they carry.

Clustering of aberrations to specific chromosomes in human neoplasms

Diethylstilbestrol (DES) has been demonstrated previously to induce morphological and neoplastic transformation of Syrian hamster embryo cells in the absence of any measurable induction of gene mutation. To determine if DES induces cell transformation by a genetic mechanism at the chromosomal level, the effect of DES on structural aberrations and numerical chromosome changes was examined in asynchronous and synchronized cells. Over the concentration range which is optimal for cell transformation, DES failed to induce any increase in chromosome aberrations in the cells. In contrast, significant numerical chromosome changes were observed in DES-treated cultures. The percentage of metaphases with a near diploid chromosome number increased to 19% at 48 hr after treatment. By comparison, cells from control cultures contained only 1 to 2% aneuploid metaphases with a near diploid chromosome number. No significant increase in the number of metaphases with a near tetraploid number (>70) of chromosomes was observed in the DES-treated cultures. DES induced both chromosome loss and gain, and no significant difference was detected between the number of hyperdiploid and hypodiploid cells. Chromosome loss or gain was observed for chromosomes in each karyotype group. These findings suggest that DES induces chromosome nondisjunction. Synchronized cell cultures were obtained by first growing the cells in 1% serum and then in 10% serum with hydroxyurea which blocked the cells at the G1-S border. Upon release of the hydroxyurea block, the cells entered into S phase in a very synchronous manner. The cells were treated for 3 hr during one of four time periods after hydroxyurea release. During the first period, the cells were primarily in early S phase, while the second period included cells in late S phase. During the third period most of the cells were undergoing mitosis, while in the fourth period most of the cells were in G1 phase, although some mitotic cells were observed. Treatment of the synchronized cells with DES during early or late S phase resulted in little morphological transformation. However, treatment during the third period, when the majority of the cells were in mitosis, resulted in a peak of transformation which was 15 times the level observed in cultures treated in early or late S phase. Treatment during the fourth time period resulted in a reduced level of cell transformation. Treatment of synchronized cultures with DES resulted also in a cell cycle-dependent induction of aneuploid cells which paralleled the induction of cell transformation, with the greatest level observed following treatment during mitosis. No increase in the percentage of polyploid metaphases or chromosome aberrations was observed in the DES-treated synchronized cells. Parallel dose-response curves for cell transformation and aneuploidy induction by DES were observed when the synchronized cultures were treated during the mitotic phase of the cell cycle. Possible mechanisms for DES-induced aneuploidy and the evidence supporting a role for nonrandom numerical chromosome changes in neoplastic development, as well as significance of aneuploidy in cancer, are discussed.

https://cancerres.aacrjournals.org/content/canres/43/8/3814.full.pdf

Aneuploidy induction and cell transformation by diethylstilbestrol: a possible chromosomal mechanism in carcinogenesis.

The chromosomes of 13 sarcomas induced in the rat by 7,12-dimethylbenz(α)anthracene (DMBA) were studied in direct preparations and in early cultures, using conventional and G-banding techniques. In 12 of the 13 tumors additional material of chromosome A2 was involved in the stemline karyotypes, either as complete extra chromosomes A2 or as marker chromosomes containing segments of A2. These observations strengthen the earlier conclusion that increase in the proportion of A2 material in the karyotype favors the development of DMBA tumors. Several of the markers were apparently identical to markers reported in DMBA leukemias by other workers. By detailed structural analysis of the A2-containing marker chromosomes the segment of critical significance was tentatively located to certain bands in the middle region of A2.

The specificity of chromosome A2 involvement in DMBA-induced rat sarcomas.

The chromosomes were studied in direct preparations of 10 primary carcinomas, induced in rats by the application of 7,12-dimethylbenz(a)anthracene (DMBA) to the auricular skin. The chromosome variation accompanying the malignant growth was definitely non-random and involved preferentially 2 chromosome types, A2 and members of the D group. This chromosome pattern was of the same type as reported earlier in DMBA-induced leukemias and sarcomas of the rat. The present results support the conclusion that the inducing factor—not the tissue origin of the tumour—determines the karyotypic evolution.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1601-5223.1974.tb01444.x

Ulf Ahlström

Papers

The specificity of chromosome A2 involvement in DMBA-induced rat sarcomas.

Chromosomes of primary carcinomas induced by 7,12‐dimethylbenz(a)anthracene in the rat