Etiology and Pathogenesis > Tumor Progression  

Meeting Abstract

Genetic evidence for a precursor lesion to astrocytoma WHO grade II in a patient with a germline TP53 mutation and astrocytoma progression

Giulia Fulci, Nobuaki Ishii, Daniela Maurici, Kim M. Gernert, Pierre Hainaut and Erwin G. Van Meir

Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery and Winship Cancer Institute Emory University School of Medicine, Atlanta Georgia 30322, USA. Laboratory of Tumor Biology and Genetics, Lausanne, Switzerland. Mechanisms of the Carcinogenesis Unit, International Agency for Research on Cancer Lyon, France.

Little is known about the early events of human tumorigenesis. 
We used clonal analysis to determine the order of occurence of three p53 mutations during cell transformation in a p53 germline patient with recurrent astrocytoma (II-IV). 
The primary tumor contained two genetically distinct cell populations: the first showed R267W in the R283H germline allele and, the second, which clonally derived from the first, acquired E258D in the remaining WT allele. 
This provides the first genetic evidence for a precursor lesion to WHO grade II astrocytoma, not clinically detected to date. 
The germline p53R283H had partial loss of function since it could transactivate the CDKN1a(p21,WAF1,cip1) but not the BAX genes, whereas p53R267W+R283H and p53E258D were incapable of transactivating either promoter. 
Modeling of p53 interaction with DNA suggests that R283H mutation might weaken the interaction of K120 with the BAX p53 responsive element (p53RE). 
This indicates that tumor initiation and progression can result from monoclonal evolution of cell populations losing consecutively pro-apoptotic and growth arrest functions of p53 due to sequential accumulation of mutations in single TP53 alleles.