title: Molecular genetics of human cancer predisposition and progression.
abstract: The development of human cancer is generally thought to entail a series of events that cause a progressively more malignant phenotype. Such a 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. A dissection of the pathway from a normal cell to a fully malignant tumor may thus 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. Similar mechanisms involving the distal short arm of chromosome 17 are apparent in astrocytic tumors and the events are shared by cells in each malignancy state. DNA sequencing indicates that these events accomplish the homozygosis of mutant alleles of the p53 gene. Copy number amplification of the epidermal growth factor receptor gene occurs in intermediate and late-stage tumors whereas loss of heterozygosity for loci on chromosome 10 is restricted to the ultimate stage, glioblastoma multiforme. These results suggest a genetic approach to defining degrees of tumor progression and the locations of genes involved in the pathway as a prelude to their molecular isolation and characterization.
authors.affiliation: Ludwig Institute for Cancer Research, Royal Victoria Hospital, Montreal, Canada.
authors.forename: W K
authors.initials: WK
authors.lastname: Cavenee
authors.forename: H J
authors.initials: HJ
authors.lastname: Scrable
authors.forename: C D
authors.initials: CD
authors.lastname: James
mesh_terms: D001254:Astrocytoma / Q000235:genetics; D002872:Chromosome Deletion; D016161:Genes, Retinoblastoma; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D009369:Neoplasms / Q000235:genetics*