Abstract: In this study, we examined the clinical significance of KRAS and MAPK1 amplification and assessed whether these amplified genes were potential therapeutic targets in type II ovarian carcinoma. Using fluorescence in situ hybridization, immunohistochemistry, and retrospectively collected clinical data, KRAS and MAPK1 amplifications were identified in 9 (13.2%) and 5 (7.4%) of 68 type II ovarian carcinoma tissue samples, respectively. Interestingly, co-amplification of KRAS and MAPK1 seemed to be absent in the type II ovarian carcinomas tested, except one case. Active phospho-ERK1/2 was identified in 26 (38.2%) out of 68 type II ovarian carcinomas and did not correlate with KRAS or MAPK1 amplification. There was no significant relationship between KRAS amplification and overall or progression-free survival in patients with type II ovarian carcinoma. However, patients with MAPK1 amplification had significantly poorer progression-free survival than patients without MAPK1 amplification. Moreover, type II ovarian carcinoma cells with concomitant KRAS amplification and mutation exhibited dramatic growth reduction following treatment with the MEK inhibitor PD0325901. These findings indicate that KRAS/MAPK1 amplification is critical for the growth of a subset of type II ovarian carcinomas. Additionally, RAS/RAF/MEK/ERK pathway-targeted therapy may benefit selected patients with type II ovarian carcinoma harboring KRAS/MAPK1 amplifications.
Keywords: type II ovarian carcinoma; KRAS; MAPK1; gene amplification; survival; MEK inhibitor
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Rahman, M.T.; Nakayama, K.; Rahman, M.; Katagiri, H.; Katagiri, A.; Ishibashi, T.; Ishikawa, M.; Sato, E.; Iida, K.; Nakayama, N.; Ishikawa, N.; Miyazaki, K. KRAS and MAPK1 Gene Amplification in Type II Ovarian Carcinomas. Int. J. Mol. Sci. 2013, 14, 13748-13762.
Rahman MT, Nakayama K, Rahman M, Katagiri H, Katagiri A, Ishibashi T, Ishikawa M, Sato E, Iida K, Nakayama N, Ishikawa N, Miyazaki K. KRAS and MAPK1 Gene Amplification in Type II Ovarian Carcinomas. International Journal of Molecular Sciences. 2013; 14(7):13748-13762.
Rahman, Mohammed T.; Nakayama, Kentaro; Rahman, Munmun; Katagiri, Hiroshi; Katagiri, Atsuko; Ishibashi, Tomoka; Ishikawa, Masako; Sato, Emi; Iida, Kouji; Nakayama, Naomi; Ishikawa, Noriyuki; Miyazaki, Kohji. 2013. "KRAS and MAPK1 Gene Amplification in Type II Ovarian Carcinomas." Int. J. Mol. Sci. 14, no. 7: 13748-13762.