Model for the genetic evolution of human solid tumors.

A conceptual model is proposed for the genetic evolution of many human solid tumors that is based on the observations that cancer cells may spontaneously double their chromosome number; that cells with excessive chromosome numbers may be cytogenetically unstable, both losing chromosomes randomly during subsequent cell divisions, and often developing structural abnormalities in the chromosomes that are retained; and that some structural chromosome abnormalities may activate growth-promoting genes. The sequence of tetraploidization with chromosome loss can occur repeatedly in a given tumor. The available evidence supporting the model is reviewed. A computer simulation system that embodies these concepts is described and the model is used to generate distributions of chromosome number/cell under various simulated conditions and in a variety of simulated biological settings. A simulation of the time course of changes in chromosome number per cell that accompany the spontaneous neoplastic transformation of mouse fibroblasts in vitro is described. The best fit to the data was obtained when provision was made for the activation of at least two growth-promoting genes. The conditions for generating discrete aneuploid peaks in cytogenetic and flow cytometric studies were explored; our modeling studies suggest that the activation of a growth promoting gene is required in order to produce a discrete aneuploid peak. Our modeling studies suggest that the overrepresentation of individual oncogene-bearing chromosomes in aneuploid cell lines may require the activation of gene dose-dependent growth-promoting genes and is not likely to occur in cell lines in which at least two copies of each normal chromosome are required for cell survival. Overall, the results obtained using the model are consistent with a wide variety of flow cytometric and cytogenetic studies in human solid tumors.

Karyotypic evolution of a human undifferentiated large cell carcinoma of the lung in tissue culture.

Serial cytogenetic studies were performed on a cell line derived from a pleural effusion from a patient with undifferentiated large cell carcinoma of the lung. The initial sample had a broad range of chromosome numbers per cell, with a hypodiploid/pseudodiploid stem line and a hypotetraploid sideline. A sequence consisting of a doubling of chromosome number per cell followed by chromosome loss was observed repeatedly during 40 culture passages. The presence of metaphase spreads showing evidence of endoreduplication suggested this as a likely mechanism for the doubling of chromosome number per cell. Eleven marker chromosomes were observed in the cells of the primary sample; these markers persisted through all subsequent passages. Chromosomes 1, 2, 6, 7, 8, 11, and 16 were consistently overrepresented; each of these chromosomes was involved in marker formation. Chromosomes 4, 5, 9, 10, 19, 21, and 22 were consistently underrepresented. Every chromosome, either in its normal form and/or as part of a marker, was represented on the average by at least one copy per diploid cell. Eighteen new marker chromosomes were observed during the course of cell cultivation; one of these evolved into a clonal marker over the course of six cell passages. Of the new marker chromosomes that were formed during the observation period, the majority were found in hypotetraploid cells.

Pallister-Killian and Fryns syndromes: nosology.

Fryns syndrome is a lethal autosomal recessive multiple congenital anomaly syndrome characteristic "coarse" facies, cleft palate, diaphragmatic hernia, and distal digital hypoplasia. The appearance of the face and digits is very similar to that observed in Pallister-Killian syndrome (mosaic isochromosome 12p), although the incidence of cleft palate, diaphragmatic hernia, and neonatal death is much lower in the latter condition. We report on an infant with many manifestations of Fryns syndrome ("coarse" face, cleft palate, cloudy corneae, diaphragmatic hernia, distal digital hypoplasia, and neonatal death) who was found to be mosaic for i(12p). Her diagnosis was changed to Pallister-Killian syndrome and the family was counselled accordingly. The clinical overlap between Fryns and Pallister-Killian syndromes is discussed. Because the chromosome abnormality in Pallister-Killian syndrome is often limited to fibroblasts and may be selectively eliminated both in vivo and in vitro, some Pallister-Killian patients may be misdiagnosed with Fryns syndrome and given an erroneously high recurrence risk. Newborn infants with the Fryns or Pallister-Killian phenotypes should have chromosome studies involving multiple tissues so that the correct diagnosis can be made. This will contribute to the understanding of both disorders and facilitate appropriate genetic counselling.