Tumor progression stage: specific losses of heterozygosity.
The development of human cancer is generally 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 less the last one and so on. That is to say, a dissection of the pathway form a normal cell to a fully malignant tumor may be viewed as the unraveling of a nested set of aberrations. In experiments designed to elucidate these events, we have compared genotypic combinations at genomic loci defined by restriction endonuclease recognition site variation in normal and tumor tissues from patients with various forms and stages of cancer. The first step, inherited predisposition, is best described for retinoblastoma 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 malignancy stage. This is distinct from a loss of heterozygosity for loci on chromosome 10 which is restricted to the ultimate stage, glioblastoma multiforme. Further, this approach has has been extended to a wide variety of human cancers and shown to be generally applicable. The results suggest 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 have provided a molecular genetic-based oncology with clinical utility in differential pathology, 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; D001932:Brain Neoplasms / Q000235:genetics; D002869:Chromosome Aberrations; D004198:Disease Susceptibility; D016161:Genes, Retinoblastoma; D005910:Glioma / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D009378:Neoplasms, Multiple Primary / Q000235:genetics; D013120:Spinal Cord Neoplasms / Q000235:genetics