Analytical Review: Spontaneous Chromosomal Breakage and High Incidence of Leukemia in Inherited Disease

Abstract

Spontaneous chromosomal breakage has been found in six inherited diseases: ataxia telangiectasia, Bloom’s syndrome, Fanconi’s anemia, glutathione reductase deficiency, Kostmann’s agranulocytosis and pernicious anemia. These diseases are not equally well researched and the cytogenetic data are by no means uniform. However, in each disease, the incidence of leukemia is increased. Chromosomal breakage has been investigated primarily in vitro. In order to connect this phenomenon with each syndrome and with the development of malignancy, the relationship between in vitro results and in vivo events must be established. This relationship may be clarified through the use of direct chromosome preparations from the bone marrow and bone marrow smears. A few such investigations have been carried out. Any evaluation of the results must consider the complexity of the bone marrow in general, as well as in each disease and in each individual case. An understanding of in vivo events in turn would allow an evaluation of factors specific to the in vitro condition, and their ability to enhance, provoke or diminish breakage. It is our opinion that contradictory results from in vitro investigations are not yet confirmed. The kind of studies necessary for such confirmation is fairly clear and, until they have been carried out, it is premature to subgroup the various diseases. A complete understanding of these diseases is possible only when the primary metabolic defect is known. Pernicious anemia is well understood although the genetics remain to be clarified. Biochemical investigations of the other five diseases are still at a preliminary stage. However, a comparison of the cytogenetic data, the clinical picture, as well as the course of the diseases may lead to a conceptualization of the unknown metabolic defect. Although the primary causes for each disease differ they manifest themselves at the cellular level in vitro and/or in vivo as spontaneous chromosomal breakage. As a consequence of this phenomenon a change in the genetic material itself may create, by chance, primary yet unknown conditions for malignant growth. This may partially explain the correlation between spontaneous chromosomal breakage and leukemia. Methodical research in this field requires that blood cultures, bone marrow smears and direct chromosome preparations from bone marrow smears and direct chromosome preparations from bone marrow be included in the close following of the diseases. It is also imperative that the designation of types of chromosome aberrations be standardized and published in detail. This, together with continuing biochemical research will finally elucidate the primary defects involved.

Tissue cytogenetic studies in chronic ulcerative colitis and carcinoma of the colon

“…"7,15,2,3,26,30 Pre-invasive carcinomas are characterized by similar but possibly less complex chromosomal abnor-malities,l and certain karyotypic abnormalities are associated with an increased incidence of malignant neoplasms. 31 These observations indicate an important correlation between oncogenesis and chromosomes. In chronic ulcerative colitis there is an increased incidence of colon-rectal cancer, estimated as 5 to 30 times greater than in the general population.l4Sz2 Atypical epithelial changes are seen frequently, and are interpreted by some authors as carcinoma in situ or pre-malignant change~.l0J*>~5 Frequent observations in our gastrointestinal cytology laboratory have demonstrated atypical epithelial cells, closely resembling malignant cells, in patients with ulcerative colitis without known maIignancy.I2J"*2* These findings also have been noted by other investigat~rs,6,~~ emphasizing chronic ulcerative colitis as a potential precancerous condition.…”

Fanconi's anemia: terminal leukemia and “Forme fruste” in one family

“…Fanconi's anemia (FA), first described and characterized by Fanconi in 1927, has been thoroughly researched since 1964, when a new symptom was discovered: increased spontaneous chromosome instability (Schroeder et al 1964). The important implications of chromosomal breakage were soon noticed by several researchers investigating the close relationship between the chromosomal changes and the development of terminal leukemia in some FA-patients (Schroeder & Kurth 1971, German 1972, 1973, Schroeder 1972Meisner et al 1976).…”

Mitomycin C induced chromosome damage in fetal blood cultures and prenatal diagnosis of fanconi's anaemia

“…There is also a predisposition to cancer, particularly leukaemias (Swift, 1971). This disease is considered one of the chromosomal instability syndromes as it shows a high incidence of spontaneous chromosome damage (Schroeder e f al., 1964;Swift and Hirschhorn, 1966;Schuler et al, 1969;Schroeder and Kurth, 1971) and an abnormal sensitivity to polyfunctional alkylating clastogens (Sasaki and Tonomura, 1973 ;Auerbach and Wolman, 1976;Novotna et al, 1979;Cervenka et al, 1981). Such sensitivity has been used to diagnose the disease both pre-and post-natally.…”