Ovarian clear cell carcinomas: RHO GTPases may contribute to explain their singular biologic behavior

Abstract

Ovarian clear cell carcinoma is found more often confined to the ovary (stage I) than high-grade serous carcinoma. The RHO GTPase family of proteins is involved in tumor invasion and metastasis through regulation of the cytoskeleton. The expression of several RHO family genes, including RHOA, RHOC, CDC42, and 3 ARHGDIs (Rho GDP dissociation inhibitors), was studied by real-time polymerase chain reaction in 22 clear cell carcinomas and 31 high-grade serous carcinomas. Immunoreaction for p21-activated kinase 1 (a downstream effector of CDC42) was also investigated on 6 tissue microarrays containing 76 carcinomas (13 clear cell carcinomas and 63 high-grade serous carcinomas). Eight clear cell carcinomas (8/21; 38%) were at stage I, whereas only 3 high-grade serous carcinomas (3/31; 10%) were at stage I. Postoperatively, all patients were treated with taxane and cisplatinum or carboplatinum. ARHGDIA messenger RNA expression was higher in clear cell carcinomas than high-grade serous carcinomas (P = .07). In contrast, CDC42 messenger RNA levels were lower in clear cell carcinomas than high-grade serous carcinomas (P = .02). Immunoreaction for p21-activated kinase 1 was concordant with the results obtained by real-time polymerase chain reaction for CDC42. In clear cell carcinomas, RHOA and RHOC messenger RNA expression was lower in stage I than in advanced-stage tumors (P = .03 and P = .005, respectively). Furthermore, in high-grade serous carcinomas, RHOA expression was higher in patients who did not respond to chemotherapy (P = .04). ARHGDIA, CDC42, RHOA, and RHOC expression may contribute to explain the different stage at diagnosis of clear cell and high-grade serous carcinomas. RHOA may cause resistance of high-grade serous carcinoma to chemotherapy.