Heterochromatin and chromosome aberrations

The chromosome breaking effect of mitomycin C, methyl methanesulfonate, maleic hydrazide, 8-ethoxycaffeine and gamma rays on the primary root meristematic cells of Nigella damascena was studied. All the agents tested except 8-ethoxycaffeine, produced relatively fewer aberrations, when compared to Vicia faba cells, though both the species have nearly similar total chromosomal length. Test for the presence of heterochromatin in Nigella gave negative results and it is interpreted that the observed differences between Vicia and Nigella are due to the presence and absence of heterochromatin in their chromosome complements respectively. The role of heterochromatin in the production of chromosome aberrations and its significance in evolution are briefly discussed.     

Structural aberrations of chromosome 18

Summary 3 cases of the 18q — syndrome, 2 boys and 1 girl, are presented, and a comparison with data from the literature is given. The following features are typical of the syndrome: short stature, mental retardation, muscular hypotonia, a peculiar dysmorphia of the face and ears, cryptorchidism and small scrotum in males, proximally implanted thumbs, tapering fingers, excess of whorls on the fingertips, and dorsally implanted second toes. Midface hypoplasia with hypertelorism and cleft palate, as well as strabismus, were present in 2 of our patients, whereas all 3 showed nystagmus and prominence of anthelix and antitragus. In addition, 2 patients exhibited narrow ear canals and impaired hearing. One patient had coloboma of the iris and choroid, pale optic discs, and cleft lip; another had umbilical and inguinal hernias. Two cases represented de novo deletions of the long arm of chromosomes 18, whereas the karyotype of the father of the third case revealed a balanced translocation t(15;18)(q24;q21).

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Zusammenjassung 3 Patienten mit dem 18q — Syndrom, 2 Knaben und 1 Mädchen, werden vorgestellt und mit den Fällen der Literatur verglichen. Die folgenden typischen Merkmale des 18q — Syndroms fanden sich bei ihnen: Kleinwuchs, Schwachsinn, muskuläre Hypotonie, Gesichts- und Ohrdysmorphie, Kryptorchismus bei den Knaben sowie zurückversetzte Daumen, konisch zulaufende Finger, Häufung von Wirbelmustern auf den Fingerbeeren und nach dorsal versetzte 2. Zehen. 2 Patienten zeigten die für das 18q — Syndrom typische Mittelgesichtsdysplasie sowie Hypertelorismus und Strabismus, hingegen wiesen alle drei Nystagmus und eine charakteristische Ohrdysmorphie mit Vortreten von Anthelix und Antitragus auf. Je 2 Patienten waren schwerhörig bzw. hatten auffallend enge Gehörgänge. Bei einem Fall fanden sich noch ein Iris- und Chorioideakolobom, Opticusatrophie und eine Lippenspatle, bei einem anderen eine Nabel- und Leistenhernie. Bei 2 Patienten war die Deletion des langen Arms von Chromosome 18 neu entstanden, bei einem war der Vater Träger einer balancierten Translokation t(15;18)(q24;q21).

     

The fate of chromosome aberrations

Chromosomal aberrations rapidly disappear from populations of dividing cells, but little is known about the details of the process. One may ask, for example, whether a cell with an acentric fragment is virtually certain to die after the first mitosis or whether it has a high probability of surviving to the second. Some recent data on aberrations in cultured human lymphocytes lead to estimates that fragments (and presumably the cells containing them) survive to the next mitosis about 30% of the time and dicentric chromosomes about 50%. These estimates were made without regard for the proliferation of normal cells, however, and so must be somewhat in error. In fact, when cell proliferation is taken into account, the most likely value of survival of the fragment itself is about 80% (when both daughter cells are considered). Probable ranges of this value and of the other parameters considered are presented. It is hoped that this explicit formulation of a mathematical model will encourage further experimental examination of the effect of various aberrations upon cell populations.     

Recurrent chromosome aberrations in cancer

Cytogenetic investigations of neoplastic cells during the past 25 years have revealed more than 600 acquired, recurrent, balanced chromosome rearrangements, and it has been established that every tumor type, studied in a sufficient number to permit conclusions, may be subdivided on the basis of specific, and even pathognomonic, abnormalities. At the molecular level, the balanced rearrangements exert their action through one of two alternative mechanisms: Deregulation of one gene by relocation to an immunoglobulin or T-cell receptor gene, or the creation of a hybrid gene by the fusion of parts of two genes. At present, nearly 100 genes have been found to be involved in neoplasia-associated chromosomal rearrangements, the great majority in hematological disorders. At the same time, the clinical usefulness of various cytogenetic abnormalities as diagnostic and prognostic aids has been increasingly appreciated. The identification of a recurring chromosome abnormality can assist in the diagnosis and subclassification of a malignant disease and, hence, in the selection of the appropriate treatment. The karyotype is also an independent prognostic factor. In hematological neoplasms, where the knowledge of chromosome abnormalities still is much more complete than is the case with solid tumors, cytogenetic analysis now plays an integral part in the diagnostic work-up of individual patients. Data obtained during recent years strongly suggest that corresponding breakthroughs will be achieved in solid tumors within a not-too-distant future.     

Radiation-produced chromosome aberrations: colourful clues

Ionizing radiation produces many chromosome aberrations. A rich variety of aberration types can now be seen with the technique of chromosome painting. Apart from being important in medicine and public health, radiation-produced aberrations act as colorful molecular clues to damage-processing mechanisms and, because juxtaposition of different parts of the genome is involved, to interphase nuclear organization. Recent studies using chromosome painting have helped to identify DNA double-strand-break repair and misrepair pathways, to determine the extent of chromosome territories and motions, and to characterize different aberration patterns left behind by different kinds of radiation.     

Cancer progression by non-clonal chromosome aberrations

The establishment of the correct conceptual framework is vital to any scientific discipline including cancer research. Influenced by hematologic cancer studies, the current cancer concept focuses on the stepwise patterns of progression as defined by specific recurrent genetic aberrations. This concept has faced a tough challenge as the majority of cancer cases follow non-linear patterns and display stochastic progression. In light of the recent discovery that genomic instability is directly linked to stochastic non-clonal chromosome aberrations (NCCAs), and that cancer progression can be characterized as a dynamic relationship between NCCAs and recurrent clonal chromosome aberrations (CCAs), we propose that the dynamics of NCCAs is a key element for karyotypic evolution in solid tumors. To support this viewpoint, we briefly discuss various basic elements responsible for cancer initiation and progression within an evolutionary context. We argue that even though stochastic changes can be detected at various levels of genetic organization, such as at the gene level and epigenetic level, it is primarily detected at the chromosomal or genome level. Thus, NCCA-mediated genomic variation plays a dominant role in cancer progression. To further illustrate the involvement of NCCA/CCA cycles in the pattern of cancer evolution, four cancer evolutionary models have been proposed based on the comparative analysis of karyotype patterns of various types of cancer.     

Screening human populations for chromosome aberrations

In order to determine the usefulness of micronuclear counts (MNC) for identifying people with relatively high frequencies of chromosome aberrations we have examined factors that influence the MNC in a learning set of blood samples obtained from 28 adults. The presence of cells with chromosome aberrations among approximately 170 metaphase cells per sample was the most important factor. Controlling for the effect of chromosome aberrations we found that age had a significant effect on MNC, but that donor sex, the mitotic index, the per cent of metaphase cells in the second or third division or the frequency of abnormal anaphase cells did not. Using logistic regression analysis we found that MNC was an excellent predictor of the presence of cells with chromosome aberrations among both the learning set and a test set of 17 additional blood samples.     

Balanced and unbalanced pericentric inversion of a chromosome 14

Summary Three males with a 46,XX karyotype are described. In two of them, evidence of a Y-containing line was found. In the first case, 1 of 500 lymphocyte metaphases was 47,XXY. In the second, 1 of 400 oral mucosa cells contained a Y body. The proportion of low-grade XX/XXY mosaics found among XX males now stands at about 17%.     

Significance of structural chromosome aberrations in human sperm: analysis of induced aberrations

Summary A significant increase in the incidence of structural chromosome anomalies has been observed in the sperm of patients treated with radio and/or chemotherapy for different types of cancer when analyzed by the interspecific fertilization of hamster eggs. The analysis of these aberrations shows that while in controls only 9.4% of structural abnormalities are of the stable type, in treated patients this figure increases to 39.3%, thus indicating that the anomalies have not been produced during the fertilization of the hamster egg. However, it is possible that part, or even most, of the breaks appear as a result of a reduced repair capacity of sperm chromosomes in the cytoplasm of the hamster egg.