PRIMITIVE NEUROECTODERMAL TUMORS OF THE CEREBRAL HEMISPHERES IN 2 SIBLINGS WITH TP53 GERMLINE MUTATION

We report on two siblings (brother and sister) who developed cerebral PNETs at the age of 5 years and 6 months, respectively. Both children were treated by operation followed by polychemotherapy. The brother al so received cranio-spinal irradiation. Nevertheless, the children died about 12 months and 24 months post-operatively due to extensive cereb ral tumor recurrences. Shortly after having lost both of her children, the mother developed an intra-abdominal tumor, which was resected and histologically diagnosed as ovarian carcinoma. Because of this unusua l familial clustering of tumors and a positive history of brain tumors and other cancers in several maternal relatives, we analyzed DNA isol ated from both PNETs and the ovarian carcinoma as well as constitution al (leukocyte) DNA from the whole family for mutation of the TP53 tumo r suppressor gene. This analysis revealed that all tumors were homozyg ous for a missense mutation at codon 213 (CGA double right arrow, TGG) resulting in an amino acid exchange from arginine to tryptophane. The same mutation was present in one TP53 allele in the constitutional DN A of the mother and the children, indicating that the mother had trans mitted a TP53 germline mutation to both of her children. Analysis of l oss of heterozygosity at microsatellite markers from 17p confirmed del etion of the paternal (wild-type) allele in both PNETs. Further invest igation of the PNETs by comparative genomic hybridization revealed mul tiple chromosomal abnormalities. Interestingly, some genomic changes w ere common to both PNETs, while many others were not, a finding sugges ting substantial genomic instability, probably as a consequence of p53 inactivation.