P53 MUTATIONS IN MATCHED PRIMARY AND METASTATIC HUMAN TUMORS

Mutations in the p53 tumor suppressor gene have been found to be the m ost frequent genetic alterations in human malignancies. To further exa mine the idea that neoplastic progression is associated with mutations in the p53 gene, we analyzed matched primary and metastatic tumor sam ples. The samples included 15 pairs of breast cancer and metastases to lymph nodes, four pairs of gastrointestinal adenocarcinomas and metas tases to liver, one colon adenocarcinoma and metastasis to a lymph nod e, and one lung carcinoma and metastasis in the pleura. Genomic DNA or cDNA from each tumor sample was amplified by the polymerase chain rea ction and labeled by using one biotinylated primer. The DNA strands we re separated with magnetic streptavidin beads and sequenced directly p 53 mutations were detected in 11 of 21 patients (52%) in either primar y tumors, metastases, or both. In six of these patients the primary tu mor and matched metastasis shared the same single mutation. In the oth er patients an additional mutation in the primary tumor only or a muta tion in the metastasis only was observed. Our data suggest that tumor development and progression toward metastasis involves structural alte rations in the p53 gene that occur early in carcinogenesis. In some ca ses, genetic changes in metastatic spreading may also include the appe arance of a mutation in a metastasis derived from a primary tumor expr essing wild-type p53, a selection of metastatic cells with a single mu tation from a primary tumor expressing two different mutations, or los s of heterozygosity. (C) 1995 Wiley-Liss, Inc.