title: Growth factor receptor expression in anal squamous lesions: modifications associated with oncogenic human papillomavirus and human immunodeficiency virus.
abstract: High prevalence of squamous anal lesions is linked to oncogenic human papillomavirus (HPV). Human immunodeficiency virus (HIV) promotes anal carcinogenesis. Epidermal growth factor receptor (EGFR), HER2/neu, c-Met, and vascular endothelial growth factor receptor-1 (VEGFR1) (tyrosine kinase growth factor receptors) are implicated in tumor progression, but little is known about their role in anal lesions. We investigated their expression and distribution in normal, dysplastic, and carcinomatous anal epithelium and then tried to analyze the effects on these variables of HPV and the HIV-positive status. Seventy-one HIV-positive and 47 HIV-negative patients were selected. We studied growth factor receptors, p16 and Ki67 expression, by in situ hybridization, fluorescent in situ hybridization (FISH) and chromogen in situ hybridization (CISH), immunocytochemistry, and morphological quantification in 226 lesions, either infected by HPV6 and 11 (31 condylomas acuminata) or infected with oncogenic HPVs (48 invasive cancers, 147 anal intraepithelial neoplasias). No HER2/neu was detected. Strong EGFR immunolabeling was not accompanied by gene amplification. The number and intensity of EGFR- and c-Met-immunoreactive cells increased significantly during lesion progression, highlighting the effects of oncogenic HPVs. EGFR, c-Met, VEGFR1, and p16 were coexpressed in 96% of invasive cancers. HIV-modified c-Met expression in condyloma acuminata (P < .008) and invasive cancers (P < .02). Strong HIV-related immunodeficiency and an absence of antiretroviral therapy increased c-Met and/or EGFR expression. HIV-positive anal cancers showed correlated c-Met and VEGFR1 (P < .003), strong p16 labeling, and an increased Ki67 proliferation. The finding that EGFR, c-Met, and VEGFR1 involved in carcinogenesis are well-represented and coexpressed in anal cancers, especially in HIV-positive population, suggests possible novel targeted treatments for anal diseases.
authors.affiliation: Department of Pathology, Institut de la Santé et de la Recherche Médicale Unité773, Hôpital Bichat-Claude Bernard, 75018 Paris, France. francine.walker@bch.aphp.fr
authors.forename: Francine
authors.initials: F
authors.lastname: Walker
authors.forename: Laurent
authors.initials: L
authors.lastname: Abramowitz
authors.forename: Dalila
authors.initials: D
authors.lastname: Benabderrahmane
authors.forename: Xavier
authors.initials: X
authors.lastname: Duval
authors.forename: Véronique
authors.initials: V
authors.lastname: Descatoire
authors.forename: Dominique
authors.initials: D
authors.lastname: Hénin
authors.forename: Thérèse
authors.initials: T
authors.lastname: Lehy
authors.forename: Thomas
authors.initials: T
authors.lastname: Aparicio
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001005:Anus Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology*; D014408:Biomarkers, Tumor / Q000032:analysis*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology / Q000821:virology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000235:genetics; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D006678:HIV; D015658:HIV Infections / Q000150:complications; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D019394:Ki-67 Antigen / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000150:complications / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D017978:Receptors, Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D066246:ErbB Receptors; D019394:Ki-67 Antigen; D019859:Proto-Oncogene Proteins c-met; D018719:Erb-b2 Receptor Tyrosine Kinases; D017978:Receptors, Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1