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.