Primary and Secondary Chromosome Aberrations in Cancer

We have proposed a hypothetical model to explain the role of chromosomal aberrations in malignant development. In this model we postulate two kinds of chromosomal changes: (1) primary, active changes caused by direct inter action between the oncogenic agent and the hereditary material of the host cello These changes are mainly somatic mutations, but mayaIso be associated with directed structural changes visible in the microscope; and (2) secondary, passive changes arising randomly by nondisjunction and structural rearrangements. They are followed by selection of cells with changes that amplify the primary change and thus appear as nonrandom chromosome patterns. This hypo thesis is discussed in the light of 1827 cases of human malignancy in which we have recently surveyed and systematized chromosomal aberrations. Special support for the idea of somatic mutations as the initiator of malignant development comes from work of Knudson and collaborators in human retinoblastoma. The Phl chromosome, predominant during the chronic phase of chronic myeloid leukemia (CML), is proposed as an instance of a primary change, whereas the chromosome changes during the blastic crisis of CML will illustrate the secondary changes. The most common of these secondary changes is actually the doubling of the Phl and thus an amplification of the primary change. The increase in number of copies of a specific chromosome reported by Green and collaborators demonstrates that this kind of amplification can result in direct response to the need for a specific gene located in that chromosome.