Genetic aberrations in gliomatosis cerebri support monoclonal tumorigenesis.

Gliomatosis cerebri is a rare condition in which the brain is infiltrated by an exceptionally diffusely growing glial cell population involving at least 2 lobes, though often more extensive, sometimes even affecting infratentorial regions. The neoplastic proliferation may have a monoclonal origin, or alternatively, reflect progressive neoplastic change of an entire tissue field ("field cancerization"). The presence of an identical set of genetic aberrations throughout the lesion would point to monoclonality of the proliferation. In contrast, the finding of non-identical genetic changes in widely separated regions within the neoplasm would support the concept of field cancerization. In the present study, a unique autopsy case of gliomatosis was available to verify either one of these hypotheses. Tissue samples were randomly taken from 24 locations throughout the brain and used for genetic investigation. In all samples the histology showed an identical picture of slightly elongated astrocytic cells, typical for gliomatosis. TP53 exon 5-8 mutation analysis was performed on all samples. Genome-wide screening for chromosomal aberrations was accomplished by comparative genomic hybridization (CGH). In addition, loss of heterozygosity analysis for polymorphic markers on chromosomal regions of the 2 most frequently observed DNA deletions was carried out. The most widespread genetic aberration was mutation of exon 7 of TP53, which was detected in 20 of 24 samples. Bidirectional sequencing revealed a mutation in codon 234 (TAC234TGC), resulting in an amino acid substitution Tyr-Cys. CGH analysis revealed losses on 2q11-q31 in 13 of 24 samples and losses on 19q13-qter in 10 of 24 samples from both left and right hemispheres. Allelic imbalances for markers on 2q (2q14.3 and 2q22.1) and 19q (both 19q13.2) were demonstrated in 10 of 24 and 18 of 24 samples, respectively. Other widespread chromosomal aberrations included losses on 3q13-qter and 16q22-qter and gains on 7q22-qter. The wide distribution of a particular set of genetic aberrations in this case supports the concept of monoclonal tumor proliferation. The results point to involvement of TP53 mutation in the tumorigenesis of gliomatosis cerebri.