The status of epidermal growth factor receptor in borderline ovarian tumours

Abstract

The majority of borderline ovarian tumours (BOTs) behave in a benign fashion, but some may show aggressive behavior. The reason behind this has not been elucidated. The epidermal growth factor receptor (EGFR) is known to contribute to cell survival signals as well as metastatic potential of some tumours. EGFR expression and gene status have not been thoroughly investigated in BOTs as it has in ovarian carcinomas. In this study we explore protein expression as well as gene mutations and amplifications of EGFR in BOTs in comparison to a subset of other epithelial ovarian tumours.We studied 85 tumours, including 61 BOTs, 10 low grade serous carcinomas (LGSCs), 9 high grade serous carcinomas (HGSCs) and 5 benign epithelial tumours. EGFR protein expression was studied using immunohistochemistry. Mutations were investigated by Sanger sequencing exons 18-21 of the tyrosine kinase domain of EGFR. Cases with comparatively higher protein expression were examined for gene amplification by chromogenic in situ hybridization. We also studied the tumours for KRAS and BRAF mutations.Immunohistochemistry results revealed both cytoplasmic and nuclear EGFR expression with variable degrees between tumours. The level of nuclear localization was relatively higher in BOTs and LGSCs as compared to HGSCs or benign tumours. The degree of nuclear expression of BOTs showed no significant difference from that in LGSCs (mean ranks 36.48, 33.05, respectively, p=0.625), but was significantly higher than in HGSCs (mean ranks: 38.88, 12.61 respectively, p< 0.001) and benign tumours (mean ranks: 35.18, 13.00 respectively, p= 0.010). Cytoplasmic expression level was higher in LGSCs. No EGFR gene mutations or amplification were identified, yet different polymorphisms were detected. Five different types of point mutations in the KRAS gene and the V600E BRAF mutation were detected exclusively in BOTs and LGSCs.Our study reports for the first time nuclear localization of EGFR in BOTs. The nuclear localization similarities between BOTs and LGSCs and not HGSCs support the hypothesis suggesting evolution of LGSCs from BOTs. We also confirm that EGFR mutations and amplifications are not molecular events in the pathogenesis of BOTs.

HER-2 neu expression in surface epithelial ovarian tumors and its relationship with clinic-pathological parameters: a pilot study

“…8,9 Our study comprised of maximum number of cases of serous histotype (48.49%). This was similar to other studies conducted by Showeil et al, Asadinejad et al, Onwuka, Nielsen et al, Sapna Goel et al, and Cirstea et al [8][9][10][11][12][13] High grade tumors constituted maximum number of cases in the present study, comprising of 19 cases (57.57%). Our findings were similar to study conducted by Nielsen et al, in which 45% tumors were poorly differentiated followed by 30% well differentiated tumors and 25% moderately differentiated tumors with a significant p value of<0.001.…”

“…Other studies conducted by Asadinejad et al showed similar results (p value=0.567). 11 Contradicting results were found in studies conducted by Cirstea et al, Showeil et al, Goel et al and Nielsen et al [8][9][10]13 These studies demonstrated that there was significant association between different grades of ovarian epithelial tumors and HER-2 expression. This difference was due to larger study sample taken into account by them and differences in race, age and population of study.…”

Loss of 1p36.33 Frequent in Low-Grade Serous Ovarian Cancer

“…EGFR mutations are a rarity in SBTs and have not been previously reported in LGSOC. Showeil et al found a higher nuclear and cytoplasmic staining of EGFR in 61 SBTs and 10 LGSOC tumors compared to benign ovarian tumors or HGSOC tumors but could not detect any mutation [31]. Activating EGFR mutation can upregulate the PI3K pathway.…”

Evaluation of vitamin D biosynthesis and pathway target genes reveals UGT2A1/2 and EGFR polymorphisms associated with epithelial ovarian cancer in African American Women

“…The signaling pathway for EGFR is mediated by ligands including the epidermal growth factor in the regulation of cell proliferation, differentiation and apoptosis in normal cells. Research into the mechanisms of EGFR overexpression has focused on mutations and amplifications in the coding region of the gene containing the receptor tyrosine kinase domain . However, few studies on SNP variants in this region have been linked to EOC or other ovarian cancer histologic subtypes .…”

“…63 However, few studies on SNP variants in this region have been linked to EOC or other ovarian cancer histologic subtypes. 61,63 EGFR SNP rs114972508 is located in intron 1 of the EGFR gene. The location of the SNP is approximately 70 kb upstream of a VDR binding site also within EGFR intron 1 that has been shown experimentally to down regulate EGFR expression and proliferative function.…”