Clonal genomic alterations in glioma malignancy stages.

TLDR

Comparing constitutional and tumor genotypes at chromosomal loci using restriction fragment length alleles helps locate recessive mutations that predispose to cancer. The study genotypically tracks tumor progression by detecting stage‑specific somatic loss of heterozygosity with RFLP. Loss of chromosome 10 heterozygosity was found in 28 of 29 glioblastomas but not in lower‑grade gliomas, while nonrandom losses on chromosomes 13, 17, and 22 occurred across all grades, indicating that glioblastoma arises from earlier precursors through a common molecular pathway. Cancer Research 47:5518–5527 (1987).

Abstract

Comparison of constitutional and tumor genotypes at chromosomal loci defined by restriction fragment length alleles has proven useful in determining the genomic position and tissue specificity of recessive mutations that predispose to cancer (Hansen, M.F., and Cavenee, W.K. Cancer Res., 47:5518-5527, 1987). Here we have applied this approach to 53 unrelated patients with glial tumors of varying histological malignancy grade. Loss of constitutional heterozygosity for loci on chromosome 10 was observed in 28 of 29 tumors histologically classified as glioblastoma (malignancy grade IV) whereas no similar losses were observed in any of 22 gliomas of lower malignancy grade. Examination of restriction fragment length alleles on other chromosomes revealed that loss of sequences on chromosomes 13, 17, or 22 had occurred at nonrandom frequencies and in at least one instance of each malignancy grade of adult glioma. The tumors in which loss of constitutional heterozygosity was observed were composed of one or a mixture of glial cell subtypes displaying astrocytic, oligodendrocytic, and/or ependymal differentiation. These results demonstrate a close association of the loss of chromosome 10 sequences with the most malignant histological stage of glioma and that glioblastoma arises as the clonal expansion of an earlier staged precursor. Furthermore they suggest that glioblastoma is a common phenotypic and malignancy terminus for glial tumors of various cellular subtypes which is reached through a common molecular pathway. This approach which involves the identification of malignancy stage specific somatic losses of heterozygosity provides a genotypic, rather than phenotypic, analysis of tumor progression.