Abstract 1314: Aberrant expression of beta-catenin and cyclin D1 in endometrial cancer

Abstract

Abstract Introduction: Wnt/beta-catenin/cyclin D1 pathway has been suggested to be involved in cell proliferation in endometrioid endometrial carcinomas (EEC), in addition to the activation of the PI3K pathway via PIK3CA and/or PTEN mutations. We previously reported that the mutations of cyclin D1 (CCND1 gene) promotes cell proliferation in EEC. However, the role of beta-catenin and its relationship with cyclin D1 is not yet well known. In this study, we focused on alterations of beta-catenin and cyclin D1 and their clinical impact in EEC. Methods: This study was conducted under approval of ethics committee of the institute and informed consent from each patient. Expressions of cyclin D1 and beta-catenin were examined by tissue microarray in formalin fixed 120 samples of EEC. The expression levels were evaluated by two pathologists, and the staining was classified as overexpressed when >50% of tumor cells showed strong staining in cytoplasm (for beta-catenin) and nucleus (for cyclin D1). Genomic DNA was isolated in 91 primary surgical specimens. Mutations of beta-catenin (exon 3 of CTNNB1 gene) and Cyclin D1 (exon 5 of CCND1 gene) were examined by PCR-direct sequencing. We constructed expression plasmid of various types of mutant beta-catenin and performed colony formation assay using these plasmids. Result: In 120 samples, beta catenin and cyclin D1 were overexpressed in 5 (4%) and 7 (6%) cases, respectively. Median follow-up period of these patients is 85 months. Interestingly, over-expression of these two proteins was not overlapped each other. In these 12 samples, 7 of 12 cases (58%) were stage III or IV. However, recurrence was only observed in one patient (5-year progression free survival rate is 92%). Mutations of CCND1 and CTNNB1 were detected in 2 (2%) and 9 (10%) cases, respectively. We confirmed that all these mutations are somatic. Mutations of CCND1 and CTNNB1 were also mutually exclusive. Although the two cases with CCND1 mutations died of disease, none of the nine cases with CTNNB1 mutations got recurrent (p=0.018 by Fisher's exact test). In colony formation assay, mutant beta-catenin at codon 32 and codon 37 did not increase the colony number, compared with wild-type beta-catenin (control), although mutants at codon 34 significantly augmented the colony formation. Conclusion: Aberrant expression of both beta-catenin and cyclin D1 are present in EEC, through mutations and/or overexpression, and alterations of beta-catenin might be associated with favorable prognosis. Our data suggest that function of mutant beta-catenin might be distinct among each mutation type. Further study is warranted to clarify the role of wnt/beta-catenin/cyclin D1 pathway in EEC. Citation Format: Yuji Ikeda, Katsutoshi Oda, Takahiro Koso, Daichi Maeda, Osamu Wada Hiraike, Tomoko Kashiyama, Aki Miyasaka, Kei Kawana, Tetsu Yano, Yoshihiro Kikuchi, Masashi Fukayama, Yutaka Osuga, Tomoyuki Fujii. Aberrant expression of beta-catenin and cyclin D1 in endometrial cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1314. doi:10.1158/1538-7445.AM2014-1314