WILD-TYPE P53 PROTEIN UNDERGOES CYTOPLASMIC SEQUESTRATION IN UNDIFFERENTIATED NEUROBLASTOMAS BUT NOT IN DIFFERENTIATED TUMORS

Neuroblastoma (NB), a tumor arising from the sympathetic nervous syste m, is one of the most common malignancies in childhood, Several recent reports on the p53 genotype found virtually exclusive wild-type statu s in primary tumors, and it was postulated that p53 plays no role in t he development of NE. Here, however, we report that the vast majority of undifferentiated NBs exhibit abnormal cytoplasmic sequestration of wild-type p53. This inability of p53 to translocate to the nucleus pre sumably prevents the protein from functioning as a suppressor. Thirty of 31 cases (96%) of undifferentiated NE showed elevated levels of wil d-type p53 in the cytoplasm of all tumor cells concomittant with a lac k of nuclear staining. p53 immunoprecipitation from tumor tissues show ed a 4.5- to 8-fold increase over normal protein levels. All of 10 tum ors analyzed harbored wild-type p53 by direct sequencing of full-lengt h cDNA and Southern blot. In addition, no MDM-2 gene amplification was seen in all 11 tumors analyzed. In contrast, no p53 abnormality was d etected in 14 differentiated ganglioneuroblastomas and 1 benign gangli oneuroma. We conclude that loss of p53 function seems to play a major role in the tumorigenesis of undifferentiated NE. This tumor might abr ogate the transactivating function of p53 by inhibiting its access to the nucleus, rather than by gene mutation. Importantly, our results su ggest that (i) this could be a general mechanism for p53 inactivation not limited to breast cancer (where we first described it) and that (i i) it is found in a tumor previously not thought to be affected by p53 alteration.