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Aneuploidy Predicts Outcome in Patients with Endometrial Carcinoma and Is Related to Lack of CDH13 Hypermethylation

Authors' Affiliations: Departments of ¹ Laboratory Medicine, ² Pathology, and ³ Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine; ⁴ Department of Obstetrics and Gynecology, Tokuyama Central Hospital, Yamaguchi, Japan; and ⁵ Department of Gynecology, National Kyushu Cancer Center, Fukuoka, Japan

Requests for reprints: Yutaka Suehiro, Department of Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan. Phone: 81-836-22-2337; Fax: 81-836-22-2338; E-mail: ysuehiro{at}yamaguchi-u.ac.jp.

Purpose: Many investigators have reported that aneuploidy detected by flow cytometry is a useful prognostic marker in patients with endometrial cancer. Laser scanning cytometry (LSC) is a technology similar to flow cytometry but is more feasible for clinical laboratory use. We evaluated the usefulness of DNA ploidy detected by LSC as a prognostic marker in patients with endometrial cancer and investigated genetic and epigenetic factors related to aneuploidy.

Experimental Design: Endometrial cancer specimens from 106 patients were evaluated. The methylation status of CDH13, Rassf1, SFRP1, SFRP2, SFRP4, SFRP5, p16, hMLH1, MGMT, APC, ATM, and WIF1 and mutations in the p53 and CDC4 genes were investigated. LSC was carried out to determine DNA ploidy. Fluorescence in situ hybridization was done with chromosome-specific centromeric probes to assess chromosomal instability.

Results: Univariate and multivariate analyses revealed that p53 mutation and lack of CDH13 hypermethylation associated positively with aneuploidy. Univariate analysis showed that aneuploidy, chromosomal instability, and lack of CDH13 hypermethylation as well as surgical stage were significantly predictive of death from endometrial cancer. Furthermore, multivariate analysis revealed that stage in combination with either DNA aneuploidy or lack of CDH13 hypermethylation was an independent prognostic factor.

Conclusion: These results suggest that analysis of DNA ploidy and methylation status of CDH13 may help predict clinical outcome in patients with endometrial cancer. Prospective randomized trials are needed to confirm the validity of an individualized approach, including determination of tumor ploidy and methylation status of CDH13, to management of endometrial cancer patients.