Medical genetics / edited by Victor A. McKusick and Robert Claiborne.

Date:
[1973]
Catalogue details

Licence: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

Credit: Medical genetics / edited by Victor A. McKusick and Robert Claiborne. Source: Wellcome Collection.

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    Oncogenic Implications of Chromosomal Instability JAMES GERMAN The New York Blood Center Cytogenetic analysis very often reveals abnormalities in the affected cells in human cancers. Abnormal mitotic fig¬ ures, abnormal numbers of chromosomes per cell, and abnormalities of chromosomal structure are to be found in most instances of human leukemia as well as in solid tumors. Most observers view these changes as a single phenomenon and but one expression of the uncontrolled cell growth that characterizes cancer, without assigning them an etiologic role. Others feel that a shifting chromo¬ somal complement could be of importance in the evolution of Ше tumor. Nonetheless, the possibility has not been ruled out that chromosomal change may be a primary event in some human malignant disease. Mutation involv¬ ing one or more genes could prove to be the essential cel¬ lular change that converts a normal cell to cancer or that permits emergence or progression of at least some forms of cancer. One possibility is that once a specific mutation has occurred, affected cells might be more susceptible to conversion to cancer by an unrelated oncogenic factor. Then again, perhaps the role of viruses in relation to chromosomal change is such that the latter permits a viral genome to combine linearly with a cell's ovra genome, initiating conversion to cancer. In considering the problem stated by the title of this paper, three observations deserve consideration: 1 ) Many human cancers appear to arise from a single cell; often this cell has one or more chromosomes differing in morphology from any in the complement of the affected individual's noncancerous cells. 2) Chromosomal instability, i.e., an increased number of disrupted and rearranged chromosomes, characterizes the cells of certain persons who are, because of some en¬ vironmental situation, at an increased risk of cancer. 3 ) Several rare genetic disorders, to be discussed here in some detail, which are characterized both by chromo¬ somal instability and an increased risk of cancer, share with well established causes of cancer — certain forms of radiation, certain chemicals, and certain viruses — the abil¬ ity to produce increased numbers of cells having de novo chromosomal rearrangements. Before documenting these three observations, however, a certain technical limitation should be mentioned. Only limited information is obtainable from the standard meth¬ ods of preparing cells for cytogenetic study. Subtle rear¬ rangements often go undetected, a situation that may be changed when technical advances, such as quinacrine fluorescent or Giemsa banding techniques (see Caspers- son and Zech, Chapter Three ), come into wider use in the study of cancer. Even taking this technical limitation into account, it would appear that chromosomal abnormalities are not invariably present, either in human or nonhuman cancers, including some of the most extensively studied experimental tumors. Conceivably, it may be that in some cancers no abnormalities will be detectable by any means because two separate classes of cancer exist, both exhibit¬ ing similar clinical manifestations and pathology but with alterations in the chromosome complement involved in only one class. Once this possibility is acknowledged, it be¬ comes possible to examine wdth greater objectivity the concept that chromosomal changes in a single cell may be associated with the development of a particular cancer. In part this concept rests on work by cytogeneticists establishing the presence of distinctive marker chromo¬ somes in many human cancers, that is, one or more chro¬ mosomes differing in morphology from any in the com¬ plement of the patient's unaffected cells, present from cell to cell in the cancer. Such marker chromosomes result from structural rearrangement, either intrachromosomal or in¬ terchromosomal. These are most often translocations, de¬ letions, or inversions (see Hirschhorn, Chapter One). The 39