KRAS and MAPK1 Gene Amplification in Type II Ovarian Carcinomas

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.

Erdheim–Chester disease: A systematic review

“…In spite of the small size and the short follow-up of the case series described, dramatic responses were recorded after a few weeks of treatment, emphasizing the pivotal role of BRAF mutation in this disease. Mutations of BRAF result in a conformational change of a serine/threonine-protein kinase that leads to a chronic activation of RAS-RAF-MEK-ERK pathway and, therefore, to accelerated proliferation and survival of cells [33]. The oncogenic activity of BRAF mutations has been extensively documented in several neoplasms, traditionally including melanoma [34] and hematologic malignancies such as extra-osseous multiple myeloma [35] as well as the oncogene-induced senescence (OIS), a protective physiological process based on the activation of both p16 and p21 against the oncogenic transformation due to a cell cycle derangement [36,37].…”

MicroRNA-320 targets mitogen-activated protein kinase 1 to inhibit cell proliferation and invasion in epithelial ovarian cancer

“…MAPK1, additionally termed, extracellular regulated kinase 2, has been reported to be abnormally expressed in various human cancers, including cervical (45), myeloma (46), sacral chordoma (47), non-small cell lung cancer (48) and gastric cancer (49). Rahman et al (29) reported that MAPK1 is highly expressed in ovarian cancer tissues and cell lines (28,29). Functional assays have demon-Functional assays have demonstrated that MAPK1 underexpression suppresses growth and metastasis in ovarian cancer SKOV3 cells (28).…”

“…3A, the seed sequence of miR-320 was complementary to the 3'UTR of MAPK1. MAPK1 is overexpressed in EOC tissues and cell lines (28,29), and contributes to the tumorigenesis and tumor development in EOC (28), which led to the hypothesis that MAPK1 may be a direct target of miR-320 in EOC. To determine whether MAPK1 is a direct target gene of miR-320, a luciferase reporter assay was performed in CAOV3 and OVCAR3 cells co-transfected with miR-320 mimics or miR-NC, and luciferase reporter vector containing the wild type or mutant 3'UTR of MAPK1.…”

KRAS mutation coupled with p53 loss is sufficient to induce ovarian carcinosarcomas in mice

“…Early studies suggested that endogenous K‐ras G12D alleles initiate ovarian peritoneal endometriosis and endometriotic‐like lesions in transgenic mice, and the G12D mutation of K‐ras has been identified as the main mutation in human epithelial malignancies . Previous studies found that the mutations of Kras (∼5.8%) are also be detected in Type II ovarian tumors . Type II tumors include high‐grade serous, malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinomas, with high proliferative activity and a 5‐year patient survival rate of ∼ 30%.…”

“…6 Previous studies found that the mutations of Kras (5.8%) are also be detected in Type II ovarian tumors. 10 Type II tumors include high-grade serous, malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinomas, with high proliferative activity and a 5-year patient survival rate of 30%. Mutations in p53 (37% of all tumours) are frequently detected in Type II tumors.…”