beta-catenin expression pattern, beta-catenin gene mutations, and microsatellite instability in endometrioid ovarian carcinomas and synchronous endometrial carcinomas

beta -Catenin gene mutations and microsatellite instability (MI) have been reported in endometrioid ovarian carcinomas. In colon but not endometrial c ancer, beta -catenin gene mutations are associated with a replication error phenotype and MT. In this study the authors investigate whether beta -cate nin mutations and MI are two independent oncogenic pathways in endometrioid ovarian carcinomas. They also evaluate the usefulness of these molecular m arkers in determining the primary origin of simultaneous tumors in the ovar y and endometrium. This study was performed on 26 patients diagnosed with p rimary endometrioid ovarian carcinoma, five of whom also had pathologically diagnosed primary synchronous endometrioid endometrial carcinoma. Immunohi stochemical and molecular analyses indicated that there were 25 primary ova rian tumors with four primary synchronous endometrial cancers and one ovari an metastasis of a primary endometrial carcinoma. All studies were performe d on formalin-fixed, paraffin-embedded tissue samples. The beta -catenin ex pression pattern (nuclear vs. membranous) was analyzed immunohistochemicall y. Mutations in exon 3 of the beta -catenin gene were studied by polymerase chain reaction, single-strand conformational polymorphism, and direct sequ encing. MI status was established by studying BAT-26 and BAT-25 mononucleot ide repeats. In the group with 21 single ovarian tumors, is (85%) had beta -catenin nuclear expression, eight (38%) had beta -catenin gene mutations ( always associated with beta -catenin nuclear expression), and four (19%) ha d MI. Only one case (5%) had both beta -catenin gene mutations and MI. The mutations affected one of the serine/threonine residues targeted for phosph orylation by glycogen synthase kinase-3 beta or adjacent residues. At codon 32, a GAC-to-TAC (D32Y) change was found; at codon 33, two TOT-to-TOT (S33 C) changes were found; at codon 37, three TCT-to-TTT (S37F) changes and one TCT-to-TGT (S37C) change were found; and, lastly, one ACC-to-GCC change at codon 41 (T41A) was detected. Four of the 25 endometrioid ovarian carcinom as (16%) had an associated synchronous endometrial carcinoma. There was a h igher percentage of beta -catenin mutations (n = 3, 75%) in synchronous ova rian carcinomas than in single ones, although with a similar percentage of MI (n = 1, 25%). beta -catenin mutations were S37C in two cases and D32G in one. One of the four endometrial carcinomas showed an S33C beta -catenin m utation, and two carcinomas had MI. None of the four tumors had both beta - catenin gene mutation and MI. beta -catenin gene mutations were always asso ciated with a nuclear beta -catenin expression pattern, whereas MI was asso ciated with a membranous pattern. In one patient both the ovarian and the e ndometrial carcinomas had beta -catenin gene mutations, in another patient both tumors showed MI, whereas in the remaining two patients the ovarian ca rcinomas showed beta -catenin gene mutations and the endometrial carcinomas showed MI. To summarize, the results of this study suggest that beta -cate nin mutations and MI could represent two independent pathways in endometrio id ovarian carcinomas because they occur simultaneously very infrequently t in 5% of these cases). beta -catenin mutations are always associated with a nuclear beta -catenin expression pattern, whereas cases with a replication error -plus phenotype showed no abnormal beta -catenin subcellular localiz ation. The study of the beta -catenin expression pattern, beta -catenin mut ations, and MI, together with conventional clinicopathologic findings, coul d aid in distinguishing between the metastatic or independent origin of sim ultaneous endometrioid ovarian and endometrial carcinomas. Tumors with identical immunohistochemical and molecular features should the refore be considered to have a common origin.