Accumulation of genetic defects during astrocytoma progression.
BACKGROUND
The development of human cancer generally is thought to entail a series of events that cause a progressively more malignant phenotype. This hypothesis predicts that tumor cells of the ultimate stage will carry each of the events; cells of the penultimate stage will carry each of the events minus the last one; and so on. Therefore, a dissection of the pathway from a normal cell to a fully malignant tumor may be viewed as the unraveling of a nested set of aberrations.


METHODS
In experiments designed to elucidate these events, genotypic combinations were compared at genomic loci defined by restriction endonuclease recognition-site variations in normal and tumor tissues from patients with various forms and stages of cancer.


RESULTS
The first step, inherited predisposition, is described best for retinoblastomas in which a recessive mutation of a locus residing in the 13q14 region of the genome is unmasked by aberrant, but specific, mitotic chromosomal segregation. A similar mechanism involving the distal short arm of chromosome 17 is apparent in astrocytic tumors, and the event is shared by cells in each malignant stage. This is distinct from a loss of heterozygosity for loci on chromosome 10, which is restricted to the ultimate stage, glioblastoma multiforme. In addition, this approach has been extended to include a wide variety of human cancers, and generally it is applicable.


CONCLUSIONS
These results identify a genetic approach to defining degrees of tumor progression and a means for determining the genomic locations of genes involved in the pathway as a prelude to their molecular isolation and characterization. They provide a molecular genetic-based oncology with clinical utility in differential pathologic findings, in disease groupings for therapeutic purposes, and in prenatal identification of latent disease carriers.
Cavenee
W K
WK
Ludwig Institute for Cancer Research, Royal Victoria Hospital, Montreal, Quebec, Canada.
D000483:Alleles; D001254:Astrocytoma / Q000235:genetics* / Q000473:pathology; D002869:Chromosome Aberrations; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008954:Models, Biological; D012516:Osteosarcoma / Q000235:genetics; D012175:Retinoblastoma / Q000235:genetics