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Accumulation of genetic defects during astrocytoma progression
Author(s) -
Cavenee Webster K.
Publication year - 1992
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/1097-0142(19920915)70:4+<1788::aid-cncr2820701621>3.0.co;2-l
Subject(s) - loss of heterozygosity , locus (genetics) , biology , genetics , chromothripsis , tumor progression , phenotype , cancer , chromosome , carcinogenesis , cancer research , telomere , gene , allele , genome instability , dna damage , dna
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.