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Base Transitions Are the Most Frequent Genetic Changes at P53 in Gastric Cancer¹

Department of Human Genetics, Sylvius Laboratory, Leiden University, Wassenaarseweg 72, 233 AL Leiden, the Netherlands (B. R., M. v. d. B., R. F., J. W., P. M. K.); Department of Genetics and Microbiology, Pavia University, Via Abbiategrasso 207, 27100 Pavia, Italy (B. R., N. S. P., G. N. R.); and Morgagni-Pierantoni Hospital and Istituto Oncologico Romagnolo, 47100 Forli, Italy (D.A.)

We searched for P53 mutations in gastric carcinoma by analyzing tumor DNAs from 29 patients. We detected 13 different somatic mutations in 15 patients (52%) and a biallelic polymorphism in exon 6 (5 heterozygous subjects). The somatic mutations were mainly localized in the sequences corresponding to the highly conserved domains of the protein. Twelve samples showed a single base change: 11 missense and 1 nonsense mutations. Three samples showed deletions leading to a frame shift, to the in-frame loss of 2 amino acids, and to the deletion of a splicing site. All point mutations, except one, were transitions, and 91% of them were G:CA:T changes.

We previously analyzed this panel of tumors for allelic loss at the 17p13 chromosomal region, where the P53 gene had previously been located: the results showed an increasing incidence of allelic loss in late-stage tumors. On the contrary, in the present study no trend between P53 mutations and tumor stages was found. This observation indicates that mutation events precede allelic loss in gastric cancer. Half (54%) of the mutations occurred in samples without allelic loss, suggesting that specific mutated alleles, acting in a dominant negative fashion, can alter in vivo the P53 protein function.

¹ This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro and from Praeventiefonds, the Dutch Cancer Society; B. R. was supported by an Erasmus fellowship during her stay at the Department of Human Genetics (Leiden University); the research of R. F. has been made possible by a fellowship of the Royal Netherlands Academy of Arts and Sciences.

² To whom requests for reprints should be addressed.

Received 11/10/92. Accepted 3/29/93.

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