The immunohistochemical expression pattern of beta-catenin has been correlated with beta-catenin gene mutations, clinicopathological features, and disease outcome in 69 stage I and II ovarian carcinomas. beta-Catenin expression was localized in the nuclei, in addition to the cytoplasm and membrane, in 11 tumors (16%): nine endometrioid carcinomas with widespread nuclear expression and two serous carcinomas with focal nuclear expression.
To summarize, the results of this study suggest that beta-catenin mutations and MI could represent two independent pathways in endometrioid ovarian carcinomas because they occur simultaneously very infrequently (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 localization.
Our study identifies activated Wnt signalling to be a marker for precursor lesions of OC and successfully develops a mouse model that mimics the earliest events in pathogenesis of OC by constitutively activating βcatenin.
These data are consistent with the hypothesis that BRCA1 mutations are involved in the etiology of hereditary ovarian carcinomas but occur rarely in sporadic tumors, and that the frequent allelic loss on chromosome 17q in this cancer type reflects the involvement of an additional tumor suppressor gene(s).
The used algorithm also allowed to identify healthy BRCA1 mutation carriers when compared to healthy wildtype women (sensitivity 88.4%, specificity 80.7%, AUC = 0.895; p = 6e-08), while this was less pronounced in patients with OC (sensitivity 66.7%, specificity 67.8%, AUC = 0.724; p = 0.00065).
These results suggest that germline mutations of the BRCA1 gene play an important role in the carcinogenesis of breast and/or ovarian cancer in a majority of breast-ovarian cancer families and in some site-specific ovarian cancer families.