Human papillomavirus type 16 (HPV-16) classes (E, AA, As, Af1, Af2) and their variants have different geographic distribution and different degrees of association with cervical lesions. This study was designed to examine HPV-16 variants among Italian women and their prevalence in case patients (affected by invasive cervical carcinoma or cervical intraepithelial neoplasia grade 2-3 and cervical intraepithelial neoplasia grade 1), versus control subjects with normal cervical epithelium (controls). A total of 90 HPV-16 positive cervical samples from women of Italian Caucasian descent have been tested, including 36 invasive cervical carcinomas, 21 with cervical intraepithelial neoplasias grade 2-3, 17 with cervical intraepithelial neoplasia grade 1 and 16 controls. HPV-16 was detected with an E6/E7 gene-specific polymerase chain reaction, and variant HPV-16 classes and subclasses were identified by direct nucleotide sequencing of the region coding for the E6 and the E7 oncoproteins, the MY09/11-amplified highly conserved L1 region, and the long control region (LCR). Among the 90 HPV-16 samples, nine viral variants have been identified belonging to the European (Ep-T350 and E-G350) and non-European (AA and Af-1) branches. The E-G350 is the prevalent variant in all analyzed different disease stages being present in 55.5% of ICC, 52.4% of cervical intraepithelial neoplasias 2-3, 47.1% of cervical intraepithelial neoplasia grade 1, and 50.0% of control samples. The non-European variants AA and Af1, rarely detected in control samples, represent 33.3% of all HPV-16 infections in invasive cervical carcinoma (with a peak of 19.4% and 13.9%, respectively), showing a statistically significant increase in frequency in more advanced lesions (chi(2) trend = 7.2; P < 0.05). The prevalence of HPV-16 Ep-T350, however, is higher in controls (43.7%) and in of cervical intraepithelial neoplasia grade 1 (41.2%) than in cervical intraepithelial neoplasia grade 2-3 (28.6%) and in invasive cervical carcinoma (11.1%) cases strongly suggesting lack of progression for pre-neoplastic lesions associated with such variant. The increased frequency of non-European variants in invasive lesions suggests that they are more oncogenic than European variants. This could have implications for future diagnostic and therapeutic strategies.
The causative role of human papillomaviruses (HPV) and HPV16 variants has been extensively studied in uterine cervix dysplastic lesions and invasive carcinoma; few such studies, however, have been performed in penile tumors. We have investigated HPV genotype and HPV16 variant distribution on 41 penile cancer biopsies from Italian patients. Cases were extracted from the respective pathology departments databases of National Cancer Institutes in Naples and Milan. HPV sequences were detected by PCR and characterized by direct sequence analysis. Infections with certain types of human papillomaviruses (HPV) have been strongly and consistently associated with the development of cervical intraepithelial neoplasia (CIN) and cervical cancer worldwide. 1-5 The more than 40 HPV genotypes infecting the genital mucosa can be divided into 3 groups: 'high-riskÕ or 'carcinogenicÕ types (16,18,31,33,35,39,45,51,52,56, 58, 59) associated with a high relative risk of cervical cancer; 'low riskÕ viruses (6,11,40,42,43,44,54, 61, 70, 72, 81, 89) associated with benign epithelial proliferations in the genital area, but not associated with invasive cervical cancer; and a group of 6 types (26,53, 66, 68, 73, 82) that is classified as 'probably carcinogenicÕ since there is limited data associating these HPV types with cervical cancer. 6,7 Additionally, carcinogenic HPVs are involved in the development of a subset of other carcinomas arising from mucosal squamous epithelial cells including penile carcinoma. 8 Penile cancer is a relatively rare disease in Europe and United States with incidence rates varying from 0.5 to 1.5 per 100,000 men. In other parts of the world and particularly in developing countries, however, it is a common male cancer with an incidence of 2 to 5 per 100,000 men, constituting for example, 12-22% of all male cancers in countries like Brazil, Uganda and Puerto Rico, which are also communities with high rates of cervical neoplasia. 9 Epidemiological studies have indicated that HPVs are sexually transmitted pathogens infecting the male and female squamous epithelium of the anogenital tract with similar prevalence rates (28%) in symptom-less university students. 10 Moreover, sub-clinical penile lesions (flat penile lesions) are frequently found in male sexual partners of women with CIN, with HPV infection rates of 73% and genotype concordance of 36% within the couples. 11 The prevalence of HPV-related high-grade penile intraepithelial neoplasia, however, is very low suggesting that penile tissue is less prone to maintain persistent infection and to undergo neoplastic transformation. As for the cervical cancer pathogenesis, several additional risk factors have been reported, in conjunction with HPV infection, for the development of invasive penile cancer: (i) exogenous cofactors (lack of circumcision in childhood, phimosis, smoking, trauma), 12,13 (ii) host cofactors (genetic factors, immune response) 14,15 and (iii) viral cofactors (infection by specific types, viral load, viral integration status).The frequency of ...
The aim of the present investigation was to define the spectrum of mucosotropic human papillomaviruses among 414 Italian women with normal cervices (n = 183), low- and high-grade cervical squamous intraepithelial lesions (n = 101 and 65, respectively), and invasive squamous cervical carcinomas (n = 65). Human papillomaviruses were detected by broad spectrum consensus-primer-pairs MY09/MY11 and GP5+/GP6+-based polymerase chain reaction using three amplification methods and were characterized by nucleotide sequence analysis. The prevalence rates of HPV infections was 19.7%, 63.4%, 80%, and 81.5% in patients with normal cervices, low-grade, and high-grade squamous intraepithelial lesions, and cervical carcinomas, respectively. Among the 205 HPV-positive patients, a total of 31 mucosal HPV genotypes were identified of which 16 types, epidemiological classified as high-risk viruses (HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 66, 68, 73, and 82), have been found in 16.9%, 50.1%, 69.2%, and 78.5% of normal cervix, low-, and high-grade cervical squamous intraepithelial lesions, and cervical carcinoma groups, respectively. As expected, the HPV16 was the most represented viral type in all groups examined with frequency rates ranging from 8.7% in normal subjects to 58.5% in invasive carcinoma patients. Ten epidemiologically defined low-risk HPV types (HPV6, 11, 42, 54, 61, 70, 71, 72, 81, 83) were detected in 2.7%, 7.9%, and 6.1% of normal cervix, low-, and high-grade cervical squamous intraepithelial lesions, respectively, and in none of invasive carcinomas. Furthermore, five unknown risk viruses were detected in 3% of low-grade cervical squamous intraepithelial lesions (HPV30, 32, 67), in 3.1% of high-grade cervical squamous intraepithelial lesions (HPV62, 90), and in 1.5% of cervical carcinomas (HPV62). Larger epidemiological screening studies, with PCR amplification and followed by either hybridization-based procedures against sequence targets of all known HPV types or sequence analysis studies, are needed in order to assess the epidemiological risk of less represented HPV types, to identify unknown viruses, and to monitor the future eventual spread of unusual viral types related to vaccination programs and/or population mobility.
Mucosal, cutaneous and Epidermodysplasia verruciformis (EV)-related human papillomaviruses (HPVs) were searched by broadspectrum PCR in 86 conjunctival neoplasia biopsies and 63 conjunctival non-neoplastic control tissue from Ugandan subjects. Seven different EV-related HPV types, including a putative new HPV, and two mucosal HPVs were detected in 25% (14 out of 56) of HIVpositive, in 10% (three out of 30) of HIV-negative conjunctival neoplasia samples, and rarely (0 -1.6%) in control subjects. The absence of high-risk HPVs and the low detection frequency of EV-related HPV types in more advanced tumour stages (10%) raise doubts about their role in conjunctival carcinomas.
Human immunodeficiency virus (HIV)-positive women have high rates of cervical squamous intraepithelial lesions (SIL) and concurrent human papillomavirus (HPV) infections with a variety of genotypes whose oncogenic risk is poorly documented. The prevalence and persistence of HPV genotypes and HPV16 variants were analysed in 112 HIV-positive and 115 HIV-negative Italian women. HIV-positive women were more likely than HIV-negative women to be infected by HPV at the initial examination (39.3 vs 13.9 %, P,0.001) and to have a higher period prevalence of HPV infection over a 3-year follow-up (43.8 % vs 17.4 %, P,0.001), regardless of CD4 + cell counts and anti-retroviral therapy. 18, 31, 33, 35, 45, 52, 58 and 66), among the 20 different viral genotypes identified, were predominant in HIV-positive (33.9 %) compared with HIV-negative (13.9 %) women. Among HIV-infected women, with normal cytology as well as with SIL of any grade, the most common genotypes were HPV16 followed by HPV81, isolates from 18 HIV-positive and eight HIV-negative women were classified into variant lineages based on sequencing analysis of E6 and E7 genes and the long control region. Whilst the HPV16 G350 European variant was prevalent in both HIV-positive (10.7 %) and -negative women (3.5 %), HPV16 African 2 variant was only detected in HIV-positive women (3.6 %), suggesting different sexual mixing behaviours. The increased prevalence of uncommon viral genotypes and HPV16 variants in HIV-positive Italian women underscores the need to target a wide range of HPV types in cervical screening of high-risk women. INTRODUCTIONInfection with genital human papillomaviruses (HPVs) has been established as the primary cause of cervical squamous intraepithelial lesion (SIL) and invasive cervical cancer (zur Hausen, 1987;Bosch et al., 1995; IARC, 1995;Walboomers et al., 1999). To date, more than 40 HPV genotypes have been identified in the female genital tract and have been grouped as (i) 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59), associated with a high relative risk of cervical cancer; (ii) 11, 40, 42, 43, 44, 54, 61, 70, 72, 81 and 89), associated with benign epithelial proliferations; (iii) 'probable carcinogenic' viruses (HPV types 26, 53, 66, 68, 73 and 82), associated with cervical cancer in a few casecontrol studies; and (iv) 'undetermined risk' viruses (HPV types 2a, 3, 7, 10, 27, 28, 29, 30, 32, 34, 55, 57, 62, 67, 69, 71, 74, 77, 83, 84, 85, 86, 87, 90 and 91), whose oncogenicity has not yet been determined (Muñoz et al., 2003(Muñoz et al., , 2006Smith et al., 2007).Epidemiological studies, performed mainly on human immunodeficiency virus (HIV)-negative women, have shown that, despite the high prevalence and strong association with cervical neoplasia, the majority of HPV infections with high-and low-risk types are transient and only a fraction of persistent infections progress on to highgrade SIL and invasive cancer, underscoring the interplay of a number of environmental, viral and host factors in HPV-related tumour progression (Massa...
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