KRAS and MAPK1 Gene Amplification in Type II Ovarian Carcinomas

Mohammed Rahman,Hiroshi Katagiri,Kohji Miyazaki,Naomi Nakayama,Noriyuki Ishikawa,Emi Sato,Tomoka Ishibashi,Kouji Iida,Masako Ishikawa,Kentaro Nakayama,Atsuko Katagiri,Munmun Rahman

doi:10.3390/ijms140713748

Mohammed Rahman, Hiroshi Katagiri + Show 10 more

Open Access

https://doi.org/10.3390/ijms140713748

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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.

Highlights

Ovarian carcinoma is the most lethal gynecological malignancy in American [1] and Japanese women
The other cell lines (KF28, A2780, and OVCA18) showed weak expression of ERK1/2. These results suggested that activation of ERK1/2 may not depend on KRAS/MAPK1 amplification or KRAS mutations in type II ovarian carcinoma cell lines
We reported earlier that KRAS or BRAF mutations were quite common in low-grade serous ovarian carcinomas with prototypic histology of type I ovarian carcinoma but rare in high-grade serous ovarian carcinomas [8,10]

Summary

Introduction

Ovarian carcinoma is the most lethal gynecological malignancy in American [1] and Japanese women. Standard treatment involves aggressive cytoreductive surgery followed by platinum- and taxane-based chemotherapy [2,3]. Initial response rates to platinum-based chemotherapy exceed 75%, most tumors will eventually recur and become refractory to treatment, with a median survival of less than five years [2,4]. There are well-established surgical and chemotherapeutic treatments for ovarian cancer, there is significant opportunity to develop drugs targeting specific molecular pathways and to reduce rates of metastasis or relapse. Drugs of this type would be useful for recurrent disease that shows chemoresistance. There is an initial, preclinical need to improve our understanding of the molecular pathways underlying ovarian carcinogenesis

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