P53 GENE MUTATION SPECTRUM IN HUMAN UNKNOWN PRIMARY TUMORS

Mutations affecting the p53 gene are associated with many human malign acies, but little is known about changes in p53 in unknown primary tum ors (UPTs), which are characterized as tumors with advanced stages of malignancy. We therefore investigated the frequency of p53 mutations i n a series of 15 unknown primary tumor biopsies and eight cell lines e stablished from UPTs. Mutations in the conserved regions of the p53 ge ne were verified by single - strand conformation polymorphism analysis of exons 5 - 9 and were verified hy direct DNA sequencing of polymera se chain reaction products. A point mutation leading to an amino acid change in the p53 protein was found in six cases, and a mutation causi ng a change to termination was found in one case. A frameshift mutatio n was observed in one cell line. In one patient and one cell line we o bserved more than one mutation in the p53 coding sequence. Overall, th e frequency of mutations that changed the p53 coding sequence in the U PTs we studied was 26% (6/23). Mutations were distributed in eight cod ons of the p53 gene. Seven of these tumors showed a reduction to homoz ygosity at the p53 allele. but one tumor apparently retained heterozyg osity. We conclude that although UPTs represent highly metastatic adva nced tumors that are expected to have a high incidence of p53 mutation s, the frequency of p53 mutations is relatively low, suggesting that p 53 mutations may not play a major role in the development and progress ion of this unique tumor type.