Molecular characterization of EGFR, PDGFRA and VEGFR2 in cervical adenosquamous carcinoma

Abstract

BackgroundAdenosquamous carcinoma of the uterine cervix is an infrequent but aggressive subtype of cervical cancer. A better understanding of its biological behaviour is warranted to define more accurate prognosis and therapeutic targets. Currently, the blockage of receptor tyrosine kinase (RTKs) activity is an efficient therapeutic strategy for many different cancers. The objective of this study was to investigate EGFR, PDGFRA and VEGFR2 RTKs overexpression and activating gene mutations in a cohort of 30 adenosquamous carcinomas of the uterine cervix.MethodsEGFR, PDGFRA and VEGFR2 immunohistochemistry was performed in all samples, followed by DNA isolation from the gross macroscopically dissection of the neoplastic area. Screening for EGFR (exons 18–21) and PDGFRA (exons 12, 14 and 18) mutations was done by PCR – single-strand conformational polymorphism (PCR-SSCP).ResultsDespite the presence of EGFR immunohistochemical positive reactions in 43% (13/30) of the samples, no EGFR activating mutations in the hotspot region (exons 18–21) were identified. A silent base substitution (CAG>CAA) in EGFR exon 20 at codon 787 (Q787Q) was found in 17 cases (56%). All PDGFRA immunohistochemical reactions were positive and consistently observed in the stromal component, staining fibroblasts and endothelial cells, as well as in the cytoplasm of malignant cells. No activating PDGFRA mutations were found, yet, several silent mutations were observed, such as a base substitution in exon 12 (CCA>CCG) at codon 567 (P567P) in 9 cases and in exon 18 (GTC>GTT) at codon 824 (V824V) in 4 cases. We also observed the presence of base substitutions in intron 14 (IVS14+3G>A and IVS14+49G>A) in two different cases, and in intron 18 (IVS18-50insA) in 4 cases. VEGFR2 positivity was observed in 22 of 30 cases (73.3%), and was significantly associated with lack of metastasis (p = 0.038).ConclusionThis is the most extensive analysis of EGFR, PDGFRA and VEGFR2 in cervical adenosquamous carcinomas. Despite the absence of EGFR and PDGFRA activating mutations, the presence of overexpression of these three important therapeutic targets in a subset of cases may be important in predicting the sensitivity of adenosquamous carcinoma to specific anti-RTKs drugs.

High VEGFR1/2 expression levels are predictors of poor survival in patients with cervical cancer

“…VEGFR2 overexpression has been reported in various types of cancer, including cancers of the head and neck, lungs, colon, uterus, ovaries, and breast. [8,9] Among esophageal adenocarcinoma and squamous cell carcinoma specimens, 100.0% of the assessed tumors were VEGFR2-positive. [10] …”

Regulation of Angiogenesis in Human Cancer via Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2)

“…In a study, VEGFR-2 positivity was observed in 22 of 30 cases (73.3%) cervical adenosquamous carcinoma but was significantly associated with lack of metastasis (p=0.038) (Longatto-Filho et al 2009). In contrast, Kuemmel et al found that VEGFR-2 levels were increased in positive lymph node patients (p = 0.024) and in metastatic disease (p = 0.003).…”

“…Tissue Subtype Positive rate Reference Bladder Carcinoma 50% (Xia et al 2006) Brain Glioma 71.4% (Steiner et al 2004b) Breast Adenocarcinoma 64.5% (Nakopoulou et al 2002) Cervix Adenosquamous carcinoma 73.3% (Longatto-Filho et al 2009) Colon Carcinoma 71.4% (Cheng et al 2004) Esophagus Carcinoma 100% (Gockel et al 2008) Kidney Clear cell cancer 35% (Badalian et al 2007 Table 1. VEGFR-2 expression in human tumors and malignant cell lines.…”

EGFR Promoter Methylation Detection in Cervical Cancer by a Hybridization-Fluorescence Polarization Assay

“…[1][2][3] EGFR is overexpressed in the majority of cervical cancers. 4,5 Strategies toward EGFR inhibition in cervical cancers by either anti-EGFR antibodies (cetuximab) or by tyrosine kinase inhibitors (gefitinib and erlotinib) are ongoing but have not yet been conclusive. [6][7][8] The methylation of EGFR promoter could be a mechanism of transcriptional silencing of this gene in cervical cancer.…”