Characterization of active mitogen-activated protein kinase in ovarian serous carcinomas.
OBJECTIVE
Mitogen-activated protein kinase (MAPK) plays a pivotal role in signal transduction. Activation of MAPK is regulated by upstream kinases including KRAS and BRAF, which are frequently mutated in low-grade ovarian serous carcinoma. This study evaluates the expression of active MAPK in ovarian serous carcinomas, with response to treatment and survival.


METHODS
Expression of active MAPK was assessed by immunohistochemistry in 207 cases of ovarian serous tumors. Immunoreactivity was correlated with tumor grade, mutational status of KRAS and BRAF, in vitro drug resistance, and clinical outcome.


RESULTS
There was a lower frequency of expression of active MAPK in high-grade ovarian serous carcinomas as compared with low-grade serous tumors, including borderline tumors and low-grade serous carcinoma (P < 0.001). Active MAPK was present in all of the 19 low-grade tumors with either KRAS or BRAF mutations as well as in 14 (41%) of 34 tumors with wild-type KRAS and BRAF in both low- and high-grade carcinomas. Expression of active MAPK alone served as a good survival indicator in the 2-year follow-up (P = 0.037) but not in the 5-year follow-up (P = 0.145). However, a combination of expression of active MAPK and in vitro sensitivity of paclitaxel significantly correlated with a better prognosis in 5-year survival rate (P = 0.048) in patients with advanced-stage high-grade serous carcinoma.


CONCLUSIONS
Active MAPK is more frequently expressed in low-grade than in high-grade ovarian serous carcinoma. Active MAPK serves as a good prognostic marker in patients with high-grade serous carcinomas.
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.
Chih-Yi
CY
Hsu
Robert
R
Bristow
Moon Seok
MS
Cha
Brant G
BG
Wang
Chung-Liang
CL
Ho
Robert J
RJ
Kurman
Tian-Li
TL
Wang
Ie-Ming
IeM
Shih
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D016190:Carboplatin / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D015689:Oncogene Protein p21(ras) / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016019:Survival Analysis; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D016190:Carboplatin; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases; D015689:Oncogene Protein p21(ras); D017239:Paclitaxel; D002945:Cisplatin