Abstract
To investigate the contribution of β‐catenin to the development of endometrial carcinoma, we searched for genetic alterations of the β‐catenin gene in primary endometrial carcinomas. Mutational analysis of exon 3 of the β‐catenin gene, encoding the serine/threonine residues for GSK‐3β phosphorylation, was performed for 35 tumors. Nucleotide sequencing analysis revealed that 5 tumors (5/35, 14%) contained mutations (S33C, S37C, S37F, T41A) that altered potential GSK‐3β phosphorylation sites. Each of the mutations resulted in the substitution of serine/threonine residues that have been implicated in the down‐regulation of β‐catenin through phosphorylation by GSK‐3β kinase. Furthermore, the incidence of β‐catenin mutations was significantly higher in early‐onset (3 of 5) than that in late‐onset tumors (2 of 30) (P=0.014, Fisher's exact test). Replication error (RER)‐positive phenotype was not detected in tumors with the β‐catenin gene mutation, although 10 of 35 tumors revealed RER. We performed immunohistochemistry of β‐catenin in 17 cases for which tissue samples were available. We confirmed accumulation of β‐catenin protein in both the nucleus and cytoplasm in 3 tumors, including two in which amino acid alterations had occurred at codon 33 and 37. The other case had no mutation in exon 3. Our results suggested that mutations at serine/threonine residues involved in phosphorylation by GSK‐3β affected the stability of β‐catenin. Accumulation of mutant β‐catenin could contribute to the development of a subset of endometrial carcinomas, particularly those of the early‐onset type.
Keywords: β‐Catenin, Human endometrial carcinoma, β‐Catenin‐Tcf pathway, Somatic mutations
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