beta-catenin mutations and aberrant nuclear expression during endometrial tumorigenesis

To clarify the possible role of aberrant beta -catenin expression during en dometrial tumorigenesis, a total of 199 cases of endometrial carcinomas (en dometrioid type), as well as 37 cases of simple/complex and 32 of atypical hyperplasias, was consecutively investigated for immunohistochemistry, alon g with 141 normal endometrial samples distant from carcinomas. Of 199 carci noma cases, 73 tumours as well as 44 normal samples were also analysed usin g a combination of RT-PCR and Southern blot hybridization, Western blot, an d mutation gene assays. Cell membrane beta -catenin immunoreactivity showed a stepwise decrease from normal, through atypical hyperplasia, to grade 3 carcinomas. In contrast, the nuclear accumulation in atypical hyperplasias and grade 1 or 2 tumours was higher than in simple/complex hyperplasias. Mu tations in exon 3 of the beta -catenin gene involving codons 33, 34, 37, 41 , and 45 were observed in 16 (22.9%) of 70 endometrial carcinomas, as well as 3 (12.5%) of 24 atypical hyperplasias, the results being significantly r elated to low membrane and high nuclear immunoreactivity but not relative m RNA expression levels, suggesting that the gene mutations may be closely as sociated with changes in subcellular distribution. In addition to significa nt association between beta -catenin mutation and low grade histological ma lignancy (P = 0.048), the mutations were detected in none of 15 and 13 (26% ) of 50 rumours with or without lymph node metastasis, the difference being significant (P = 0.027). These findings suggest that beta -catenin abnorma lities may play an important role in a relatively early event during the en dometrial hyperplasia-carcinoma sequence. (C) 2001 Cancer Research Campaign .