title: 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.
authors: Department of Histopathology, Imperial College London, London, United Kingdom.|Department of Clinical Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
authors: Rania
authors: R
authors: Showeil
authors: Imperial Molecular Pathology Laboratory, Imperial College London, London, United Kingdom.
authors: Claudia
authors: C
authors: Romano
authors: Imperial Molecular Pathology Laboratory, Imperial College London, London, United Kingdom.
authors: Mikel
authors: M
authors: Valganon
authors: Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors: Maryou
authors: M
authors: Lambros
authors: Department of Histopathology, Imperial College London, London, United Kingdom.
authors: Pritesh
authors: P
authors: Trivedi
authors: Department of Histopathology, Imperial College London, London, United Kingdom.
authors: Susan
authors: S
authors: Van Noorden
authors: Epigenetics Group, International Agency for Research on Cancer, Lyon CEDEX 08, France.
authors: Ruethairat
authors: R
authors: Sriraksa
authors: Department of Clinical Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
authors: Dalal
authors: D
authors: El-Kaffash
authors: Obstetrics and Gynaecology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
authors: Nour
authors: N
authors: El-Etreby
authors: Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors: Rachael
authors: R
authors: Natrajan
authors: Imperial Molecular Pathology Laboratory, Imperial College London, London, United Kingdom.
authors: Letizia
authors: L
authors: Foroni
authors: Dorset Cancer Centre, Poole Hospital, Dorset, United Kingdom.
authors: Richard
authors: R
authors: Osborne
authors: Department of Histopathology, Imperial College London, London, United Kingdom.|Department of Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
authors: Mona
authors: M
authors: El-Bahrawy
mesh_terms: D001483:Base Sequence; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics; D060787:Neoplasm Grading; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D017434:Protein Structure, Tertiary / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C117307:KRAS protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras)
keywords: EGFR; borderline ovarian tumours