Genetic alterations and protein expression of KIT and PDGFRA in serous ovarian carcinoma

Abstract

KIT and PDGFRA are receptor tyrosine kinases that can be specifically inactivated by small-molecule tyrosine kinase inhibitors, notably imatinib mesylate. In ovarian carcinoma, expression of KIT and PDGFRA protein has been documented, but the frequency and the molecular background of expression are poorly known. We analysed the expression of KIT and PDGFRA by immunohistochemistry in 522 serous ovarian carcinomas, and mutations of KIT and PDGFRA by denaturing high-performance liquid chromatographyin 125 and 187 serous ovarian carcinomas, respectively. No mutations of KIT or PDGFRA were detected. KIT expression was detected in 12% of carcinomas: low expression in 10% and high expression in 2% of cases. Using normal serous epithelium as a reference, decreased PDGFRA expression was detected in 12% and increased expression in 13% of carcinomas. Both KIT and PDGFRA expression were associated with high tumour grade, high proliferation index and poor patient outcome. By fluorescence in situ hybridisation, no KIT amplification was found in carcinomas with high KIT expression, but two cases showed a relative gain of chromosome 4. In conclusion, no mutations of KIT or PDGFRA were found, but a subset of serous ovarian carcinoma showed overexpression of the proteins, which was associated with aggressive tumour characteristics.

Expression of platelet-derived growth factors and their receptors in ovarian clear-cell carcinoma and its putative precursors

“…Although several reports have documented the frequent PDGF/PDGFR in ovarian clear-cell adenocarcinomas S Yamamoto et al expression of PDGFRs in ovarian carcinomas, the number of clear-cell adenocarcinoma cases included in those studies was generally small. [13][14][15]17 The largest series by Matei et al 16 demonstrated that 17 (90%) and 18 (95%) of 19 clear-cell adenocarcinomas were immunohistochemically positive for PDGFR-a and PDGF-AB, respectively, the former being almost concordant with our data.…”

“…Although such mutations and gene amplification have not been described previously in ovarian cancers, recent studies have demonstrated that PDGFR-a, PDGFR-b, and PDGF-AB are commonly expressed in ovarian cancers at frequencies as high as 87, 81, and 67%, respectively. [13][14][15][16] Moreover, Henriksen et al 17 have reported that PDGFRs or PDGFs were not detected in any of the benign ovarian tumors or normal ovarian epithelium they examined. Experiments in vivo have shown that PDGFRs activated by PDGFs modulate Akt and MAPK phosphorylation and significantly influence ovarian cancer cell proliferation and tumor expansion.…”

PDGF BB induces VEGF secretion in ovarian cancer

“…6,23,24 PDGFRa, but not PDGFRb, was found to be differentially expressed in ovarian carcinoma compared to normal ovarian epithelium and expression of PDGFRa was linked to poor prognosis 23 and aggressive tumor characteristics. 25,26 These preclinical findings supported the clinical investigation of PDGFR inhibitors, such as imatinib mesylate, in ovarian cancer.…”

Epithelial Ovarian Cancer

“…Further, a number of recent studies have indicated that EOC is linked to aberrant cell signaling, including Hedgehog (Hh) and platelet-derived growth factor (PDGF) signaling as well as over-expression of aurora A kinase (AURA) and deregulated expression of the novel tumor suppressor protein, checkpoint with forkhead-associated and ring finger domains (CHFR) [7][8][9][10][11][12][13][14][15][16][17][18][19]. Consequently, targeted agents against Hh pathway components, PDGFR and AURA have been explored recently in the management of ovarian cancer and recurrent disease [20].…”

“…Several reports document a change in the expression level of the alpha form of PDGFR (PDGFRα) compared to normal OSE cells and that this expression is associated with high tumor grade, high proliferation index, and poor survival rate [11][12][13][14].…”