title: Validation of Serological Antibody Profiles Against Human Papillomavirus Type 16 Antigens as Markers for Early Detection of Cervical Cancer.
abstract: Cervical cancer (CC) is the second most frequent neoplasia among women worldwide. Cancer prevention programs around the world have used the Papanicolaou (Pap) smear as the primary diagnostic test to reduce the burden of CC. Nevertheless, such programs have not been effective in developing countries, thus leading to research on alternative tests for CC screening. During the virus life cycle and in the process toward malignancy, different human papillomavirus (HPV) proteins are expressed, and they induce a host humoral immune response that can be used as a potential marker for different stages of the disease. We present a new Slot blot assay to detect serum antibodies against HPV16 E4, E7, and VLPs-L1 antigens. The system was validated with sera from a female population (n = 485) aged 18 to 64 years referred to the dysplasia clinic at the General Hospital in Cuautla, Morelos, Mexico. To evaluate the clinical performance of the serological markers, the sensitivity, specificity, positive, and negative predictive values and receiver-operating characteristic curves (for antibodies alone or in combination) were calculated in groups of lesions of increasing severity. The results showed high prevalence of anti-E4 (73%) and anti-E7 (80%) antibodies in the CC group. Seropositivity to 1, 2, or 3 antigens showed associations of increasing magnitude with CC (odds ratio [OR] = 12.6, 19.9, and 58.5, respectively). The highest association with CC was observed when the analysis was restricted to only anti-E4+E7 antibodies (OR = 187.7). The best clinical performance to discriminate CC from cervical intraepithelial neoplasia 2 to 3 was the one for the combination of anti-E4 and/or anti-E7 antibodies, which displayed high sensitivity (93.3%) and moderate specificity (64.1%), followed by anti-E4 and anti-E7 antibodies (73.3% and 80%; 89.6% and 66%, respectively). In addition, the sensitivity of anti-E4 and/or anti-E7 antibodies is high at any time of sexual activity (TSA), which suggests they can be biomarkers for the early detection of CC. The sensitivity of anti-E4 antibodies was low (<10%) when the TSA was <10 years, and it increased up to 100% in relation to the TSA, suggesting that anti-E4 antibodies can be useful as HPV exposure markers at early stages of the disease.
authors.affiliation: From the Center for Research on Infectious Diseases (DAS-P, AP-S, MM-G, LC-A, LG-X), National Institute of Public Health, Cuernavaca, Morelos; Center for Research in Population Health (AC-V, EO-P), National Institute of Public Health, Cuernavaca, Morelos; Academic Unit of Chemical Biology and Pharmaceutical Sciences (ANR-O), Autonomous University of Nayarit, Tepic Nayarit; Dysplasia Clinic "Dr. Mauro Belauzaran Tapia" General Hospital in Cuautla (EO-F), Cuautla Morelos; and Faculty of Medicine (FE-G), Autonomous University of Morelos State (UAEM), Cuernavaca, Morelos, Mexico.
authors.forename: Dolores Azucena
authors.initials: DA
authors.lastname: Salazar-Piña
authors.forename: Adolfo
authors.initials: A
authors.lastname: Pedroza-Saavedra
authors.forename: Aurelio
authors.initials: A
authors.lastname: Cruz-Valdez
authors.forename: Eduardo
authors.initials: E
authors.lastname: Ortiz-Panozo
authors.forename: Minerva
authors.initials: M
authors.lastname: Maldonado-Gama
authors.forename: Lilia
authors.initials: L
authors.lastname: Chihu-Amparan
authors.forename: Angelica Nallelhy
authors.initials: AN
authors.lastname: Rodriguez-Ocampo
authors.forename: Emilia
authors.initials: E
authors.lastname: Orozco-Fararoni
authors.forename: Fernando
authors.initials: F
authors.lastname: Esquivel-Guadarrama
authors.forename: Lourdes
authors.initials: L
authors.lastname: Gutierrez-Xicotencatl
mesh_terms: D000328:Adult; D000914:Antibodies, Viral / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D055088:Early Detection of Cancer / Q000379:methods*; D005260:Female; D052162:Human papillomavirus 16 / Q000276:immunology*; D006801:Humans; D008875:Middle Aged; D011446:Prospective Studies; D012698:Serologic Tests; D002583:Uterine Cervical Neoplasms / Q000097:blood* / Q000821:virology*
chemical_list: D000914:Antibodies, Viral; D015415:Biomarkers