title: Gene amplification and immunohistochemical expression of ERBB2 and EGFR in cervical carcinogenesis. Correlation with cell-cycle markers and HPV presence.
abstract: Although the members of the epidermal growth factor receptor family ERBB2 and EGFR are important therapeutic targets in the treatment of malignant neoplasias, little is known about their role in cervical carcinogenesis. Our objective was to evaluate the dysfunction of ERBB2 and EGFR at the gene copy number and protein expression level in neoplastic lesions of the uterine cervix with the aim of obtaining information about its role in cervical carcinogenesis and their possible use as therapeutic targets in these diseases. We studied gene amplification and protein expression of ERBB2 and EGFR and their relationship with Ki67, p16 and p53 and HPV presence in 22 normal/benign (N/B) cervices, 20 low-grade squamous intraepithelial lesions (LSILs), 70 high-grade SILs (HSILs) and 32 invasive squamous cervical carcinomas (ISCCs). No cases showed selective amplification of ERBB2 or EGFR but corresponding chromosome-specific probes displayed chromosome 17 and 7 polyploidy associated with the grade of the lesion (p<0.0001 and p=0.004, respectively) and with the positive expression of Ki67 and p16 (p<0.01). Concurrent polyploidy for both chromosomes was statistically related (p<0.0001). ERBB2 immunohistochemical expression was not observed in any of the study cases except for one ISCC but EGFR was associated with higher-grade lesions (N/B plus LSIL 21.4% vs. HSIL plus ISCC 45.5%; p=0.007). No association was observed between EGFR expression and that of cell-cycle markers or HPV presence. Increased copy number of EGFR and ERBB2 is due to polyploidy of 7 and 17 chromosomes, this being a phenomenon associated with lesion severity and with an increase in the expression of cell-cycle markers. EGFR, but not ERBB2, is expressed in precursor lesions of squamous cervical neoplasia and is related to the neoplastic progression but not to proliferation marker expression and therefore ERBB2 and this calls into question the usefulness of ERBB2 as a therapeutic target.
authors.affiliation: Molecular Pathology and Pharmacogenetic Group, Santa Lucía General University Hospital (HUGSL), 30202 Cartagena, Spain. Electronic address: pablo.conesa@carm.es.
authors.forename: Pablo
authors.initials: P
authors.lastname: Conesa-Zamora
authors.forename: Daniel
authors.initials: D
authors.lastname: Torres-Moreno
authors.forename: María A
authors.initials: MA
authors.lastname: Isaac
authors.forename: Miguel
authors.initials: M
authors.lastname: Pérez-Guillermo
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis; D002453:Cell Cycle / Q000235:genetics; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D018773:Genes, erbB-1; D018734:Genes, erbB-2; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D030361:Papillomavirus Infections / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics*; D046888:Tissue Array Analysis; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000235:genetics / Q000378:metabolism / Q000821:virology
chemical_list: D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human
keywords: CC; CIN; Cervical cancer; Cervical carcinogenesis; Cervical intraepithelial neoplasia; EGFR; ERBB2; Epidermal growth factor receptor; FISH; Fluorescence in situ hybridization; HER2; HPV; HPV16; HSIL; High-grade squamous intraepithelial lesion; Human epidermal growth factor receptor 2; Human papillomavirus; Human papillomavirus genotype 16; ICC; Invasive squamous cervical carcinoma; Ki67; LSIL; Low-grade squamous intraepithelial lesion; N/B; Normal/benign; SIL; Squamous intraepithelial lesion; p16; p53