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(HPV) Induced Cervical Dysplasia

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(HPV) Induced Cervical Dysplasia Cent. Eur. J. Biol.• 5(5) • 2010 • 554-571 DOI: 10.2478/s11535-010-0051-z Central European Journal of Biology Diagnostic role of p16/INK4A protein in Human Papillomavirus (HPV) induced cervical dysplasia Review Article Július Rajčáni1,2,*, Marián Adamkov1,3, Jana Hybenova1, Jaroslav Jackuliak1, Marian Benčat1 1Alpha Medical a.s., 03601 Martin, Slovak Republic 2Institute of Virology, Slovak Academy of Sciences, 84505 Bratislava, Slovak Republic 3Institute of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University, 03601 Martin, Slovak Republic Received 15 October 2009; Accepted 13 April 2010 Abstract: The p16/INK4A protein is a cellular regulatory polypeptide over-expressed in the presence of high levels of the Human Papillomavirus (HPV) coded E7 protein. This review outlines the use of p16 antigen staining in cervical biopsies as well as in PAP smears summarizing the corresponding literature and commenting the authors’ own experience. The p16 antigen is a reliable marker for dysplastic cells in CINII/CINIII (HSIL) lesions as viewed in cervical biopsies. When PAP smears were examined at large scale screening for p16 antigen- reactive and atypical cells, considerable variations could be found especially in ASCUS graded lesions. Therefore, the presence of p16-reactive atypical cells in PAP smears should be interpreted together with the cytological signs of dysplasia, such as the altered N/C ratio. In addition, women revealing p16-positive ASCUS/LSIL specimens should be examined for the presence of HPV DNA. Detection of HPV DNA alone, i.e. in the absence of cytological screening has a low predictive value, since the clearance of HPV may occur even in the absence of morphological alterations. Combined cytological as well as molecular follow up contributes to the efficiency of diagnostic and increases the probability of correct interpretation of the pre-cancerous lesions by non-invasive techniques. Keywords: Staining for p16/INK4 antigen • Human papillomavirus (HPV) DNA testing • Screening of pre-cancerous lesions • Cervical intraepithelial neoplasia (CIN) • Squamous intraepithelial lesion (SIL) © Versita Sp. z o.o. Abbreviations HSIL - High grade SIL; ASC - Atypical squamous cell; L - Late (expressed) proteins; ASCUS - Atypical squamous cells of undetermined LCR - Long control region; significance; LR-HPV - Low risk HPV; CIN - Cervical intraepithelial neoplasia; LSIL - Low grade SIL; CPE - Cytopathic effect; NIL - No intraepithelial lesion; vDNA - Viral DNA; N/C ratio - Nuclear to cytoplasm ratio; E - Early (expressed) proteins; nt - Nucleotide; EGF - Epidermal growth factor; ORF - Open reading frame; GP - General primer; PAP - Papanicolaou (staining); H.E. - Haematoxylin eosin (staining); PDGF - Platelet derived growth factor; HPV - Human papillomavirus; PCR - Polymerase chain reaction; HC - Hybrid capture; SIL - Squamous intraepithelial lesion; HR-HPV - High risk HPV; SSC - Squamous cell carcinoma. * E-mail: [email protected] 554 Diagnostic role of p16/INK4A protein in Human Papillomavirus (HPV) induced cervical dysplasia 1. Host cell transformation by human and/or with severe dysplastic changes, were designated as high risk (HR-HPV). In contrast, genotypes causing papillomaviruses benign lesions and only exceptionally related to cancer Human papillomaviruses (HPV) infecting the female were designated as low risk. genital tract represent the main cause of cervical The HPV virions are small (55 nm in size) non- dysplasias [1,2] and subsequently developing enveloped capsids. As result of productive replication, squamous cell carcinomas (SSC). In addition to HPV, they form aggregates within nuclei of squamous the Papillomaviridae family encompasses viruses epithelium cells that show koilocytosis [6]. HPV does infecting cattle (BPV), monkeys (RhPV), horses (EcPV) not grow outside of squamous epithelium cells, i.e. it and other mammals. The human (HPV) isolates were is extremely difficult to isolate the virus in conventional grouped into 118 genotypes based on the similarity human cell cultures [7]. The purified virions reveal and/or variations of their genomes. The genotype was icosaedral symmetry, being composed of 72 subunits defined by at least 10% dissimilarity of the capsid formed by 2 structural proteins (L1 and L2), which are polypeptide (L1) sequence. Based on the comparison expressed at late intervals of the productive replication of L1 sequences of all genotypes, 96 of them fulfilling cycle. The viral double stranded DNA (vDNA) has the above mentioned criterion were included into the about 8 kilobase pairs (kbp) and encodes 7 or 8 non- novel classification, while the rest are regarded either structural polypeptides, designated E1-E8 (E=early). for candidate genotypes and/or for subtypes (2-10% The transcription of viral mRNA is under control of nucleotide dissimilarity). According to novel classification a 1.1 kbp vDNA region, which is rich in promoters [3,4], the Papillomaviridae family has 13 genera. The (LCR=long control region). The oncogenic virus coded clinically important genotypes that cause lesions at polypeptides E5, E6 and E7 induce cell proliferation and/ mucosal membranes and/or on the skin belong to or may drive cells into permanent division by different 12 out of 15 species within the Alphapapillomavirus mechanisms. Their open reading frames (ORF) are genus (Table 1). Noteworthy, the recently accepted L1 located close to LCR, which has a great impact for host phylogenetic tree-based classification may not reflect cell transformation resulting from the integration of HPV the serological relationships among the L1 proteins. genome in the course of latency [8-11]. Because the No Alphapapillomavirus common or species-specific HPV genome does not encode its own DNA polymerase, epitopes could be determined in cross ELISA tests its productive replication depends on the division of host against recombinant L1 fusion proteins from 15 HPV epithelium cells. The vDNA molecules are copied by the genotypes representing 6 species [5]. In clinical practice, help of E1 and E2 proteins within dividing cells of the the genotypes most probably associated with cancer basal and/or suprabasal layers of squamous epithelium. Disease Frequent association Rare association Skin infection: Deep plantar warts 1, 2 4, 63 Common warts 2, 1 4, 26, 27, 29, 41, 57, 65 and 77 Butcher’s warts 7, 2 1, 3, 4, 10 and 28 Epidermodysplasia verruciformis (ER)* 2, 3, 5, 8, 9, 10, 12, 14, 15 and 17 19, 20, 21, 22, 23, 24, 25, 36, 37, 38, 47 and 70 Skin carcinoma associated with ER 5 and 8 Anogenital infection: Condyloma acuminatum 6, 11 30, 42, 43, 44, 45, 51, 54, 55, 70 Intraepitelal dysplasia (16, 18, 74, 86) 6, 11, 26, 31, 33, 35, 39, 42, 43, 44, 45, 51, 6**, 11**, 16, 18 (CIN I a CIN II/III) 52, 53, 56, 58, 66, 73 and 82 Carcinoma in situ; invasive carcinoma 16, 18, 31, 45 33, 35, 39, 51, 52, 56, 58, 59, 66, 67, 68, 73 and 82 Recurrent laryngeal papilloma 6, 11 Conjuctival papilloma 6, 11 and 16 Table 1. High risk (in bold) and low risk HPV genotypes according to their frequency. * congenital skin lesion with high sensitivity to HPV **(CIN I/LSIL, CIN II or non-invasive CINIII/HSIL) 555 J. Rajčáni et al. During differentiation of the stratified epithelium, in a proportion of ASCUS graded smears (sometimes productive (vegetative) virus replication continues within characterized by ASC-H cells) and in LSIL smears, the spinous and/or surface epithelium cells, in which but later on becomes clearly prevalent in HSIL grade the L1/L2 and E4 proteins are abundantly expressed smears and, of course, in cervical cancer. Women (Table 2). The E4 protein causes dramatic changes showing the prevalence of integrated HPV DNA were in the cytokeratin network altering the cytoplasmic almost 10 years older than those with a predominating environment of spinous cells, which contributes to the episomal HPV DNA pattern, which points to a higher risk HPV induced cytopathic effect and koilocytosis [12-14]. of HPV infection in women aged over 35 years [20]. These changes accelerate the release of virions Three non-structural HPV coded oncoproteins are assembled due to self-aggregation of the L1/L2 protein involved in host cell proliferation and immortalization complexes. In contrast, the few vDNA copies harbored (E5, E6 and E7) causing continuous host cell division in suprabasal and transitory cells during latency get rather than direct malignant transformation (Table 3). distributed into dividing daughter cells by means of E2 The E5 protein enhances the sensitivity of HPV carrier protein [15,16]. In such a way, the latent HPV genome cells to external proliferative stimuli, such as the is continuously maintained in the basal and suprabasal epidermal growth factor [21]. It also binds to growth squamous epithelium layer despite the absence of factor receptors, for example the platelet growth productive virus formation. It should be mentioned factor receptor (PDGFR), and activates the signal that during long-term latency, the integration of HPV transmission in a ligand independent manner [22,23]. DNA may associate with linearization of the persisting Because the integrated vDNA always encompasses vDNA molecule. At integration, the circular HPV DNA is the ORFs of E6 and E7 oncoproteins as well as the interrupted, usually within the E2 gene ORF [17]. Thus, closely positioned LCR sequence, the continuing the HPV genome persists within transformed host cells and increased expression of E6/E7 proteins seriously in two different forms: as non-integrated (episomal)
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