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1.  p53 codon 72 polymorphism and human papillomavirus associated skin cancer 
Journal of Clinical Pathology  2001;54(7):539-542.
Background/Aims—Non-melanoma skin cancers frequently harbour multiple human papillomavirus (HPV) types. A recent report suggests that a polymorphism of the p53 tumour suppressor gene that results in the substitution of a proline residue with an arginine residue at position 72 of the p53 protein might act as a risk factor in HPV associated malignancies. This study aimed to determine the following: (1) the relation between HPV infection and the development of cutaneous squamous cell carcinoma (SCC), and (2) whether there is a correlation between p53 codon 72 polymorphism and the development of SCC.
Methods—Blood samples were taken from 55 patients with skin cancer (both renal transplant recipients and immunocompetent patients with skin cancer) and 115 ethnically matched volunteers. A polymerase chain reaction based assay was used to determine p53 codon 72 genotypes. In addition, 49 benign and malignant lesions from 34 of the patients with skin cancer and 20 normal human skin samples from 20 of the control volunteers were examined for HPV.
Results—The proportions of p53 codon 72 genotypes found were 78% arginine homozygous, 2% proline homozygous, and 20% heterozygous among patients with skin cancer and 79% arginine homozygous, 3.5% proline homozygous, and 17.5% heterozygous among the control population. Statistical analysis showed no significant differences in the distribution of the two p53 isoforms between the patients with skin cancer and the control population. The predominant viral types detected in both the patients and the control group were EV associated HPVs, although the incidence was lower in normal skin samples than in malignant lesions or viral warts.
Conclusions—These results suggest that in a Celtic population there is no correlation between the presence of HPV, the p53 codon 72 arginine polymorphism, and the development of skin cancer.
Key Words: p53 codon 72 polymorphism • human papillomavirus • skin cancer
doi:10.1136/jcp.54.7.539
PMCID: PMC1731472  PMID: 11429426
2.  Human Papillomaviruses and Non-Melanoma Skin Cancer: Basic Virology and Clinical Manifestations 
Disease Markers  2007;23(4):247-259.
Human papillomaviruses (HPV) infect cutaneous and mucosal epithelia and induce benign and malignant lesions. Non-melanoma skin cancer (NMSC), encompassing basal cell carcinoma and squamous cell carcinoma (SCC), is the most frequent cancer in the Caucasian population, and the incidence has increased dramatically worldwide. Ultraviolet (UV) radiation is a major risk factor for NMSC, and cutaneous HPV is also considered to play an active role during the pathogenesis of these cancers. The first evidence for the involvement of HPV in NMSC was reported in patients with Epidermodysplasia verruciformis (EV). HPV types detected in skin tumours of these patients are referred to as EV/cutaneous HPV types belonging to the beta- and gamma-papillomaviruses (PV). Epidemiological studies have shown a higher risk of several EV/cutaneous HPV types for NMSC. Furthermore, in vitro and animal models show transforming properties of some PV types. The anti-apoptotic activities, and the delay of DNA repair mechanism caused by some EV/cutaneous HPV E6 proteins in response to UV-induced mutations, may lead to the persistence of DNA-damaged keratinocytes. Thus, specific EV/cutaneous HPV types as co-factors in association with UV-radiation and the immune system seem to be involved in the early pathogenesis of cutaneous SCC.
doi:10.1155/2007/942650
PMCID: PMC3851066  PMID: 17627060
3.  Pattern of HPV infection in basal cell carcinoma and in perilesional skin biopsies from immunocompetent patients 
Virology Journal  2012;9:309.
Background
The association between human papillomavirus (HPV) infection and non-melanoma skin cancers (NMSCs) such as squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) is not yet fully understood. We analysed the prevalence and spectrum of cutaneous beta-HPV types and mucosal/genital HPV types in paired biopsies (tumour and corresponding perilesional skin) obtained from 50 BCC immunocompetent patients. A small group of SCC patients (n=9) was also included. We also evaluated some previously postulated risk factors for HPV infection in NMSC patients.
Results
All biopsies were negative for mucosal/genital HPV types. Overall, beta-HPV DNA was detected more often in SCC compared to BCC patients (78% vs 55% of total samples). The frequency of infection increased with the patient’s age [OR=4.88 (95% CI 1.29-18.39)]. There was no significant correlation between beta-HPV positivity and sex, skin type and UV exposure. The prevalence of beta-HPV species 1 types was significantly higher than those belonging to other beta-HPV species in biopsies from BCC (p=0.022) but not from SCC subjects (p=0.091). There was no significant difference in the overall prevalence of beta-HPV infection and the number of viral types between tumour lesions and perilesional skin. BCC samples were significantly more likely to be infected with beta-HPV species 1 types compared to perilesional skin (p=0.036) and showed a higher frequency of mixed infections (p=0.028).
Conclusions
These findings demonstrate that beta-HPV types belonging to species 1 are the most common HPV types detected in the skin of BCC patients. Moreover beta-1-HPV types and mixed infections are significantly more frequent in tumour samples than in healthy perilesional skin. Our results suggest that beta-1-HPVs as well as co-infection with more than one viral type could be important in NMSC and in particular in BCC.
Further studies aimed to compare the biological activity of viral types in tumours and in healthy skin (viral replication and expression, interference of infection with cellular functions) are necessary to understand the role of HPV infection in skin cancer.
doi:10.1186/1743-422X-9-309
PMCID: PMC3545977  PMID: 23244448
Human papillomavirus; Beta-HPV; Non-melanoma skin cancer; Basal cell carcinoma; Squamous cell carcinoma; Perilesional skin
4.  Cutaneous human papillomavirus infection, the EVER2 gene and incidence of squamous cell carcinoma: A case-control study 
The first evidence of an association between HPV and non-melanoma skin cancer comes from patients with epidermodysplasia verruciformis (EV). EV is a rare heritable disease characterized by cutaneous warts that display not only a high rate of progression to squamous cell carcinoma on sun-exposed sites, but also a strong predisposition to infection by β-HPVs, for which HPV 5 and 8 predominate. Two EV genes (EVER1 and EVER2) have been identified, and we tested the hypothesis that variation in the EVER2 gene (rs7208422) is related to seropositivity to HPV (of the genus β types) and risk of squamous cell carcinoma in a population-based case-control study of SCC (n = 239 cases and 432 controls). Among controls, variant genotype was associated with β-HPV seropositvity (OR = 2.3, 95%CI = 1.2–4.3), specifically HPV5 or 8 seropositivity (OR = 2.4, 95%CI = 1.1–5.1) and seropositivity for multiple β-HPV types (OR =2.7, 95%CI =1.1–6.6). Furthermore, variant genotype was also related to SCC risk [adjusted OR for homozygous variant versus homozygous wild type for the EVER2 polymorphism 1.7, 95% CI 1.1–2.7]. These data provide evidence for a role of genetic variation in the EVER2 gene in β-HPV infection and risk of SCC, shedding light on the link between HPVs and skin cancers.
doi:10.1002/ijc.23377
PMCID: PMC2705140  PMID: 18224692
human papillomavirus; skin cancer; EVER2
5.  The prevalence and pattern of HPV-16 immunostaining in uterine cervical carcinomas in Ethiopian women: a pilot study 
Introduction
Cancer of the cervix uteri is the second most common cancer among women worldwide. The association of human papillomavirus (HPV) infection with cervical carcinogenesis is well documented. This is a pilot study aiming to studying the prevalence and the pattern of Human Papilloma Virus Type 16 (HPV16) by immunostaining in the tissues of cervical carcinomas of Ethiopian women.
Methods
20 specimens of uterine cervical carcinomas were studied histopathologically and immunohistochemically for HPV16.
Results
Histologically the specimens were classified as: Ten cases were Non Keratinized Squamous cell carcinoma (NKSCC), six cases were Keratinized Squamous Cell Carcinoma (KSCC) and four cases were Adenocarcinoma (ADC). Immunohistochemistry study showed positivity in eleven cases (55%); seven cases (35%) were non-keratinized squamous cell carcinoma; three cases (15%) were keratinized squamous cell carcinoma and one case (5%) belonged to the adenocarcinomas.
Conclusion
This study reveals a significant detection of HPV in Ethiopian women by the use of advanced techniques such as Immunohistochemistry (IHC). The data of this study suggested that the marked expression of the HPV 16 was in the less differentiated uterine cervix carcinomas.
PMCID: PMC3224022  PMID: 22121430
Cancer cervix; HPV 16; immunohistochemistry; Ethiopia
6.  Protective Vaccination against Papillomavirus-Induced Skin Tumors under Immunocompetent and Immunosuppressive Conditions: A Preclinical Study Using a Natural Outbred Animal Model 
PLoS Pathogens  2014;10(2):e1003924.
Certain cutaneous human papillomaviruses (HPVs), which are ubiquitous and acquired early during childhood, can cause a variety of skin tumors and are likely involved in the development of non-melanoma skin cancer, especially in immunosuppressed patients. Hence, the burden of these clinical manifestations demands for a prophylactic approach. To evaluate whether protective efficacy of a vaccine is potentially translatable to patients, we used the rodent Mastomys coucha that is naturally infected with Mastomys natalensis papillomavirus (MnPV). This skin type papillomavirus induces not only benign skin tumours, such as papillomas and keratoacanthomas, but also squamous cell carcinomas, thereby allowing a straightforward read-out for successful vaccination in a small immunocompetent laboratory animal. Here, we examined the efficacy of a virus-like particle (VLP)-based vaccine on either previously or newly established infections. VLPs raise a strong and long-lasting neutralizing antibody response that confers protection even under systemic long-term cyclosporine A treatment. Remarkably, the vaccine completely prevents the appearance of benign as well as malignant skin tumors. Protection involves the maintenance of a low viral load in the skin by an antibody-dependent prevention of virus spread. Our results provide first evidence that VLPs elicit an effective immune response in the skin under immunocompetent and immunosuppressed conditions in an outbred animal model, irrespective of the infection status at the time of vaccination. These findings provide the basis for the clinical development of potent vaccination strategies against cutaneous HPV infections and HPV-induced tumors, especially in patients awaiting organ transplantation.
Author Summary
Organ transplant recipients (OTR) frequently suffer from fulminant warts that are induced by cutaneous human papillomaviruses (HPV). Moreover, some skin HPV types may also be involved in the development of non-melanoma skin cancer. Mimicking the situation of immunosuppressed OTR who acquire cutaneous HPV infections already in childhood, we explored the efficacy of a vaccine in infected animals that additionally underwent immunosuppression. We demonstrate for the first time the success of a vaccine against a skin papillomavirus in a natural outbred animal system, which completely prevents both benign and malignant skin tumor formation even under immunosuppressed conditions. Hence, our study provides the basis for clinical development of a vaccine against cutaneous HPV infections, which may be particularly useful in transplant recipients.
doi:10.1371/journal.ppat.1003924
PMCID: PMC3930562  PMID: 24586150
7.  Cutaneous Human Papillomaviruses Found in Sun-Exposed Skin: Beta-papillomavirus Species 2 Predominates in Squamous Cell Carcinoma 
The Journal of infectious diseases  2007;196(6):876-883.
Background
A spectrum of cutaneous human papillomaviruses (HPVs) is detectable in nonmelanoma skin cancers, as well as in healthy skin, but the significance that the presence of these types of HPV DNA has for the pathogenesis of skin cancer remains unclear.
Methods
We studied 349 nonimmunosuppressed patients with skin lesions (82 with squamous cell carcinomas, 126 with basal cell carcinomas, 49 with actinic keratoses, and 92 with benign lesions). After superficial skin had been removed by tape, paired biopsy samples—from the lesion and from healthy skin from the same patient—were tested for HPV DNA. Risk factors for HPV DNA were analyzed in multivariate models.
Results
Overall, 12% of healthy skin samples were positive for HPV DNA, compared with 26% of benign lesions, 22% of actinic keratoses, 18% of basal cell carcinomas, and 26% of squamous cell carcinomas. HPV DNA was associated with sites extensively exposed to the sun, both for the lesions (odds ratio [OR], 4.45 [95% confidence interval {CI}, 2.44–8.11]) and for the healthy skin samples (OR, 3.65 [95% CI 1.79–7.44]). HPV types of Beta-papillomavirus species 2 predominate in squamous cell carcinomas (OR, 4.40 [95% CI, 1.92–10.06]), whereas HPV types of Beta-papillomavirus species 1 are primarily found in benign lesions (OR, 3.47 [95% CI, 1.72–6.99]).
Conclusions
Cutaneous HPV types are primarily detected at sites extensively exposed to the sun. HPV types of Beta-papillomavirus species 2, but not of species 1, are associated with squamous cell carcinoma.
doi:10.1086/521031
PMCID: PMC3795387  PMID: 17703418
8.  The sero-epidemiology of human papillomavirus among Caucasian transplant recipients in the UK 
Background
Despite intensive study of high-risk mucosal human papillomaviruses (HPV), little is known of the epidemiology of cutaneous HPV. As part of a study of cutaneous squamous cell carcinoma and HPV among organ transplant recipients (OTR) from London and Oxford, we investigated the seroprevalence and risk factors for 34 HPV types (detected using Luminex technology) among 425 Caucasian OTR without skin cancer.
Results
Overall, 86% of participants were seropositive to at least one HPV: 41% to mucosal alpha types, 33% to cutaneous alpha types, 57% to alpha types, 56% to beta, 47% to gamma types and 45% to other types (nu, mu, HPV101 and 103). In both centres, the most common types were HPV6 (33% and 26% for London and Oxford respectively), HPV8 (24% and 18%), HPV15 (26% and 29%), HPV17 (25% and 21%), HPV38 (23% and 21%), HPV49 (19% and 21%), HPV4 (27% and 23%), HPV65 (30% and 25%), HPV95 (22% and 20%), HPV1 (33% and 24%) and HPV63 (28% and 17%). The seroprevalence of 8 HPV types differed significantly (P < 0.05) between London and Oxford. Those individuals seropositive to multiple types of one genus were more likely to be seroreactive to multiple types of another genus. As expected, antibodies against mucosal alphaHPV types were more frequent in younger patients and among women. Sunbed use and sunbathing was associated with seropositivity to multiple gammaHPV (P-trend = 0.007) and self-history of abnormal smear was related to seroactivity to multiple betaHPV (P = 0.01). Skin type and other self reported markers of exposure to ultraviolet radiation were not consistently associated with any HPV types. No other distinguishing epidemiological features of transplant recipients with antibodies against single or multiple HPV types were identified.
Conclusion
Findings for mucosal HPV types were in line with results from previous studies. We observed differences in HPV seroprevalence between organ transplant recipients from two geographically close centres but no clear risk factor was found associated with cutaneous HPV seropositivity among organ transplant recipients. These findings have implications for interpretation of future seroepidemiology studies addressing the association between HPV and cutaneous SCC in OTR populations.
doi:10.1186/1750-9378-4-13
PMCID: PMC2749815  PMID: 19751499
9.  Human Papillomaviruses, p16INK4a and Akt expression in basal cell carcinoma 
Background
The pathogenic role of beta-HPVs in non melanoma skin cancer (NMSC), is not still completely understood, and literature data indicate that they might be at least cofactors in the development of certain cutaneous squamous cell carcinomas. However, only few reports contain data on basal cell carcinoma (BCC). The HPVs interact with many cellular proteins altering their function or the expression levels, like the p16INK4a and Akt. Our study aimed to determine the presence of different beta -HPV types and the expression of p16INK4a and Akt in BCC, the commonest NMSC, in the normal appearing perilesional skin and in forehead swab of 37 immunocompetent patients.
Methods
The expression of p16INK4a and Akt, by immunohistochemistry, and the HPV DNA, by nested PCR, were investigated in each sample.
Results
No correspondence of HPV types between BCC and swab samples was found, whereas a correspondence between perilesional skin and BCC was ascertained in the 16,7% of the patients. In BCC, 16 different types of beta HPV were found and the most frequent types were HPV107 (15,4%), HPV100 (11,5%) and HPV15 (11,5%) all belonging to the beta HPV species 2. Immunohistochemistry detected significant p16INK4a expression in almost all tumor samples (94,3%) with the highest percentages (> 30%) of positive cells detected in 8 cases. A statistically significant (p = 0,012) increase of beta HPV presence was detected in p16INK4a strongly positive samples, in particular of species 2. pAkt expression was detected in all tumor samples with only 2 cases showing rare positive cells, whereas Akt2 expression was found in 14 out of 35 BCC (40%); in particular in HPV positive samples over-expressing p16INK4a.
Conclusions
Our data show that p16INK4a and pAkt are over-expressed in BCC and that the high expression of p16INK4a and of Akt2 isoform is often associated with the presence of beta-HPV species 2 (i.e. HPV 15). The association of these viruses with the up-regulation of p16INK4a and Akt/PI3K pathway suggests that in a subtype of BCC these viruses may exert a role in the carcinogenesis or in other, still undefined, biological property of these tumors. If this particular type of BCC reflects a different biology it will remain undisclosed until further studies on a larger number of samples will be performed.
doi:10.1186/1756-9966-30-108
PMCID: PMC3271997  PMID: 22082146
HPVs; BCC; p16INK4a and Akt1/2; skin cancer
10.  Exposure Profiles and Human Papillomavirus Infection in Skin Cancer: An Analysis of 25 Genus β-Types in a Population-Based Study 
An increasing number of studies report that genus β human papillomaviruses (HPVs) are associated with skin cancer, with suggestions of specificity for squamous cell carcinoma (SCC) of the skin. We have conducted a systematic examination of HPV DNA in tumors from immunocompetent hosts, including SCC and basal cell carcinoma (BCC), using a highly sensitive methodology and population-based samples to test the hypothesis that a differential prevalence of β-HPVs exists between SCC (n = 101) and BCC (n = 101) tumors. When testing for all known β-HPV types, we found no significant difference in HPV prevalence between the two histologies. However, SCC lesions were significantly more likely to be infected with HPV genus β-species 1 (includes types 5 and 8), than BCC samples (P = 0.01); this difference was not observed for any other species. A histologic difference was also observed for those HPV types previously reported to be important in skin cancer (P = 0.003). SCC samples showed a higher rate of infectivity (that is, were positive for multiple types) than BCC tumors (P = 0.02). These data highlight the potential importance of various genus β-HPV types, in particular genus β-species 1 in SCC, and support the hypothesis of a behavioral difference of the virus within the two major histological skin cancers.
doi:10.1038/jid.2008.162
PMCID: PMC2705138  PMID: 18548109
11.  TERT Promoter Mutations Are Frequent in Cutaneous Basal Cell Carcinoma and Squamous Cell Carcinoma 
PLoS ONE  2013;8(11):e80354.
Activating mutations in the TERT promoter were recently identified in up to 71% of cutaneous melanoma. Subsequent studies found TERT promoter mutations in a wide array of other major human cancers. TERT promoter mutations lead to increased expression of telomerase, which maintains telomere length and genomic stability, thereby allowing cancer cells to continuously divide, avoiding senescence or apoptosis. TERT promoter mutations in cutaneous melanoma often show UV-signatures. Non-melanoma skin cancer, including basal cell carcinoma and squamous cell carcinoma, are very frequent malignancies in individuals of European descent. We investigated the presence of TERT promoter mutations in 32 basal cell carcinomas and 34 cutaneous squamous cell carcinomas using conventional Sanger sequencing. TERT promoter mutations were identified in 18 (56%) basal cell carcinomas and in 17 (50%) cutaneous squamous cell carcinomas. The recurrent mutations identified in our cohort were identical to those previously described in cutaneous melanoma, and showed a UV-signature (C>T or CC>TT) in line with a causative role for UV exposure in these common cutaneous malignancies. Our study shows that TERT promoter mutations with UV-signatures are frequent in non-melanoma skin cancer, being present in around 50% of basal and squamous cell carcinomas and suggests that increased expression of telomerase plays an important role in the pathogenesis of these tumors.
doi:10.1371/journal.pone.0080354
PMCID: PMC3832433  PMID: 24260374
12.  Cancer Associated Human Papillomaviruses 
Current opinion in virology  2012;2(4):459-466.
A small group of human papillomaviruses (HPVs) cause almost all cervical carcinoma and a significant percentage of other anogenital tract and oral carcinoma. Another group of HPVs causes non-melanoma skin cancers in genetically predisposed or immune suppressed patients upon UV exposure. HPV genome replication requires the host cell’s DNA synthesis machinery and HPVs encode proteins that maintain differentiated epithelial cells in a replication competent state. The resulting rewiring of cellular signal transduction circuits triggers several innate cellular tumor suppressor responses that HPVs need to inactivate in order to establish persistent and/or productive infections. This review emphasizes this interplay between virus and the infected host cells and points out biological similarities and differences between different groups of HPVs.
doi:10.1016/j.coviro.2012.05.004
PMCID: PMC3422426  PMID: 22658985
13.  Detection of Human Papillomavirus DNA in Cutaneous Squamous Cell Carcinoma among Immunocompetent Individuals 
The presence of certain types of human papillomavirus (HPV) is a known risk factor for the development of anogenital squamous cell carcinomas (SCCs). A similar association has been hypothesized for cutaneous SCCs, although, to our knowledge, no studies to date have combined sensitive HPV DNA detection techniques with epidemiologic data controlling for known risk factors to explore the association. We designed a case–control study examining HPV prevalence using highly sensitive PCR-detection assays in tissue samples from 85 immunocompetent patients with histologically confirmed SCCs and 95 age-matched individuals without a prior history of skin cancer. A standardized interview was administered to all study subjects to collect information pertaining to potential confounding variables. The overall detection rate of HPV DNA was high in case lesions (54%) and perilesions (50%) and in both sun-exposed normal tissue (59%) and non-sun-exposed normal tissue (49%) from controls. In comparing case tissue to control tissue, there was no differential detection of HPV DNA across various HPV species. However, HPV DNA from β-papillomavirus species 2 was more likely to be identified in tumors than in adjacent healthy tissue among cases (paired analysis, odds ratio = 4.0, confidence interval = 1.3–12.0). The high prevalence of HPV DNA detected among controls suggests that HPV DNA is widely distributed among the general population. However, the differential detection of HPV β-papillomavirus species in tumors among cases suggests that certain HPV types may be involved in the progression of cutaneous SCCs.
doi:10.1038/sj.jid.5701227
PMCID: PMC3268673  PMID: 18185530
14.  Interferon Inducible IFI16 Expression in p16 Positive Squamous Cell Carcinoma of the Oropharynx 
ISRN Otolaryngology  2013;2013:263271.
Human-papillomavirus- (HPV-) positive oropharyngeal squamous cell carcinomas (OPSCC) are reported to be more responsive to treatment and to be related to a favorable prognosis compared with non-HPV carcinomas. However, the molecular basis of the responsiveness is unclear. Interferon inducible IFI16, which is implicated in the control of cell growth, apoptosis, angiogenesis, and immunomodulation in various types of cancers, is reported to be frequently expressed in the HPV-positive head and neck SCC and to correlate with a better prognosis. In this study, we hypothesized that HPV related OPSCC expresses IFI16 resulting in favorable prognosis. To clarify the relationship between the prognosis of HPV related OPSCC patients and IFI16 status, we examined immunohistologically the pretreatment specimens of OPSCC for the expression of p16 as a surrogate marker of HPV infection and IFI16. We could not show that the expression of IFI16 is associated with that of p16. There was no significant difference in the survival rate between IFI16 positive and negative groups. Patients with p16 negative tumor exhibited worse survival rate regardless of IFI16 status. In this limited case series, we could not conclude that IFI16 expression is altered in p16 positive OPSCC and that it would be a new predictive marker or a useful therapeutic tool.
doi:10.1155/2013/263271
PMCID: PMC3727209  PMID: 23956879
15.  Low frequency of human papillomavirus infection in conjunctival squamous cell carcinoma of Mexican patients 
Background
The relationship between Human Papillomavirus (HPV) infection and conjunctiva cancer is controversial. HPV detection will provide more information about the role of this infectious agent in the biology of conjunctiva cancer. In the present study, DNA extracted and purified from 36 Conjunctival Squamous Cell Carcinomas (CSCC) was evaluated by PCR for HPV DNA sequences. The results were correlated with the clinical and histopathological variables.
Results
The results showed that HPV DNA was present in 8 CSCC samples (22%); HPV16 was the sole type detected. Significant association was found between HPV detection and the limbus tumor subtype (p = 0.03). All the samples were non-metastatic squamous cell carcinoma.
Conclusions
The HPV presence in CSCC from Mexican patients is not a common event.
doi:10.1186/1750-9378-6-24
PMCID: PMC3226560  PMID: 22099431
conjunctiva; carcinoma; HPV
16.  Oral HPV infection in a clinic-based sample of Hispanic men 
BMC Oral Health  2014;14:7.
Background
Human papillomavirus (HPV) is associated to the pathogenesis of various cancers, such as oropharyngeal squamous cell carcinoma, which has a high incidence in Puerto Rican men. Despite the burden of oral cancer in Puerto Rico, little is known about the epidemiology of oral HPV infection, particularly in high-risk men. Therefore, this study is aimed at determining the prevalence of oral HPV infection, the genotype distribution and correlates associated with oral HPV infection in men of at least 16 years of age attending a sexually transmitted infection (STI) clinic in Puerto Rico.
Methods
A cross-sectional study consisting of 205 men was conducted. Participants provided a 30-second oral rinse and gargle with mouthwash. Following DNA extraction, HPV genotyping was performed in all samples using Innogenetics Line Price Assay (INNO-LiPA). A questionnaire was administered, which included a demographic, behavioral and a clinical assessment. Descriptive statistics and bivariate analysis were used to characterize the study sample. Variables that achieved statistical significance in the bivariate analysis (p < 0.05) were assessed in multivariate logistic regression models.
Results
The mean age of the study sample was 38.5 ± 14.2 years. Oral HPV prevalence among men was 20.0% (95.0%CI = 14.8%-26.1%) and of HPV type 16 was 2.4% (95.0%CI = 0.8%-5.6%). Oral HPV prevalence significantly increased over increasing age categories (p-trend = 0.001). Multivariate analysis showed that oral HPV was independently associated with number of sexual partners (adjusted OR = 1.02; 95%CI = 1.01-1.03) and lifetime use of cigarettes (adjusted OR = 3.00; 95%CI = 0.98-9.16).
Conclusions
Oral HPV among the sampled men in the STI clinic was high, regardless of the HIV status or sexual behavior. Interventions in STI clinics should include screening for HPV in the oral cavity for the early detection and reduction of long-term consequences of oral HPV infection, such as oropharyngeal cancer.
doi:10.1186/1472-6831-14-7
PMCID: PMC3906756  PMID: 24460642
Oral HPV infection; Epidemiology; High-risk men; STI/STD clinic; Puerto Rico
17.  Serological relationship between cutaneous human papillomavirus types 5, 8 and 92 
The Journal of general virology  2009;90(0 1):136-143.
Evidence of a possible association of cutaneous human papillomavirus (HPV) types, especially members of the genus Betapapillomavirus, and the development of non-melanoma skin cancer (NMSC) is accumulating. Vaccination with virus-like particles (VLPs) consisting of self-assembled L1, the major capsid protein, has been introduced to control anogenital HPV infection. This study examined the serological relationship between betapapillomavirus (β-PV) types 5 and 8 and the new type HPV-92, which has recently been isolated from a basal cell carcinoma containing a high number of viral genomes. Following expression by recombinant baculoviruses, the L1 protein of HPV-92 self-assembled into VLPs that elicited high-titre antibodies after immunization, similar to VLPs from HPV-5 and -8. Haemagglutination inhibition (HAI) assays were used as a surrogate method for the detection of virion-neutralizing antibodies, which correlates with protection from infection. Antisera raised against HPV-5 and -8 VLPs displayed HAI activity not only against the homologous type, but also against heterologous HPV types 5, 8 and 92, whereas HAI activity of antisera against HPV-92 VLP was restricted to the homologous type. The results of neutralization assays using HPV-5 pseudovirions were consistent with those from HAI assays. Cross-neutralizing immune responses by VLP vaccination against heterologous HPV types may provide broader protection against the multiplicity of HPV types detected in NMSC. If a close link to HPV infection can be conclusively established, these results may provide a basis for further evaluation of VLPs of β-PVs as candidates for a prophylactic skin-type HPV vaccine, aimed at reducing the incidence of NMSC.
doi:10.1099/vir.0.006189-0
PMCID: PMC3795330  PMID: 19088282
18.  Interplay between human papilloma virus infection and p53 gene alterations in head and neck squamous cell carcinoma of an Indian patient population 
Journal of Clinical Pathology  2006;60(9):1040-1047.
Aim
To investigate the complex interplay between human papilloma virus (HPV) infection and p53 gene alteration in 92 head and neck squamous cell carcinoma (HNSCC) and 28 leukoplakia samples from eastern India.
Methods
DNA isolated from the patient samples was subjected to HPV detection, loss of heterozygosity (LOH) analysis of the chromosome 17p region harbouring p53, genotyping at the p53 codon 72 locus and sequencing of the entire p53 gene to identify somatic mutations. Codon 72 heterozygotes carrying the p53 mutation were further cloned and resequenced to identify the allele harbouring the mutation.
Results
HPV positivity in the HNSCC samples was 69%; 21% of the HNSCC were found to harbour p53 mutations in the coding region of the gene. The absence of the p53 mutation in HPV positive tumours was statistically significant compared to the HPV negative tumours (p = 0.01), but the same did not hold true for p53 LOH (p = 1.0). Among the germline p53 codon 72 heterozygotes, the Pro allele was preferentially lost (p = 0.02) while the Arg allele was mutated in the majority of cases. The risk of HPV mediated tumourigenesis increased with the increase in number of Arg alleles at the codon 72 locus.
Conclusion
It is proposed that genetic and epigenetic alteration of p53 follow distinct pathways during the development of HNSCC from normal epithelium via dysplasia. The p53 mutation and HPV mediated p53 inactivation possibly constitute two independent pathways of tumourigenesis.
doi:10.1136/jcp.2005.034835
PMCID: PMC1972436  PMID: 17079356
HNSCC; HPV;  p53 mutation;  p53 LOH;  p53 polymorphism
19.  In situ hybridization study on human papillomavirus DNA expression in benign and malignant squamous lesions of the esophagus. 
Journal of Korean Medical Science  1996;11(6):467-473.
Histologic changes suggesting HPV infection are occasionally found adjacent to squamous cell carcinoma or in squamous papilloma of the esophagus, but the relationship between HPV infection and benign and malignant squamous lesions of the esophagus is not yet dear. The aim of this study was to examine the role of HPV in squamous lesions of the esophagus. Microscopic examination with emphasis on HPV infection was done on 15 cases of squamous cell carcinoma and 26 cases of squamous papilloma. In situ hybridization technique for wide-spectrum HPV probe was performed on 35 endoscopically biopsied esophageal tissues. Among the histologic parameters suggesting HPV infection, acanthosis was the most frequent finding: 100.0% in benign and malignant esophageal lesions, and koilocytosis and intraepithelial capillary loops were the second (92.7%).: Dyskeratosis, basal cell hyperplasia and bi- or multinucleation were 52.3%, 44.0% and 34.1% in frequency, respectively. On in situ hybridization study, the HPV DNA expression rates of 10 squamous cell carcinomas with evidence of HPV infection and 15 carcinomas without evidence of HPV infection were 60.0% and 33.3%, respectively. In contrast to the carcinoma cases, only one (10.0%) of 10 squamous papillomas revealed positive signal. In conclusion, HPV infection is strongly associated with squamous cell carcinoma, but the causal relation of HPV to squamous papilloma is inconspicous.
PMCID: PMC3054261  PMID: 9008094
20.  The Immune Response to Papillomavirus During Infection Persistence and Regression 
The Open Virology Journal  2012;6:241-248.
Human papillomavirus (HPV) infections cause a significant global health burden, predominantly due to HPV-associated cancers. HPV infects only the epidermal cells of cutaneous and mucosal skin, without penetration into the dermal tissues. Infections may persist for months or years, contributed by an array of viral immune evasion mechanisms. However in the majority of cases immunity-based regression of HPV lesions does eventually occur. The role of the innate immune response to HPV in persistence and regression of HPV infection is not well understood. Although an initial inflammatory infiltrate may contribute to disease regression, sustained inflammation at the HPV-induced lesions, characterized by macrophage and neutrophil infiltration, has been observed in persistence. Pathogen-associated molecular patterns (PAMPs) are important in innate recognition. The double stranded DNA and an L1 and L2 capsid components of the HPV virion are potential PAMPs that can trigger signaling through cellular pattern recognition receptors, including toll-like receptors (TLR). TLR expression is increased in regressing HPV disease but is reduced in persistent lesions, suggesting a role for TLR in HPV regression. With regard to the adaptive immune response, a key indicator of regression in humans is infiltration of the lesion with both CD4 and CD8 T cells. In individuals with persistent lesions, CD8 T cell and immune suppressive regulatory T cells (Tregs) infiltrate the infection site. There is no association between persistence or regression and the presence of serum antibodies to the viral capsid antigens of HPV. There is still much to be learned about the immunological events that trigger regression of HPV disease. Understanding the viral and host factors that influence persistence and regression is important for the development of better immunotherapeutic treatments for HPV-associated disease.
doi:10.2174/1874357901206010241
PMCID: PMC3547310  PMID: 23341859
Adaptive immunity; epidermis; immune evasion; innate immunity; papillomavirus; persistence; regression.
21.  Human Papillomavirus as an Independent Predictor in Oral Squamous Cell Cancer 
Aim
There is an increasing evidence for the role of high risk human papillomavirus (HPV) in the pathogenesis of oral squamous cell carcinoma (OSCC). The purpose of this study is to evaluate the relevance of HPV infection to the survival and prognosis of OSCC.
Methodology
Fifty-two patients with OSCC were followed from 4 to 88 months with a median of 50.7 months. HPV DNA was identified in formalin-fixed, paraffin-embedded tumor specimens by nested PCR with MY09/MY11 and GP5+/GP6+ primer pairs and the HPV genotype was determined by direct DNA sequencing. Association between the HPV status and risk factors for cancer as well as tumor-host characteristics were analyzed. Survival curves were calculated by the Kaplan-Meier method and analyzed using the log-rank test.
Results
HPV was found in 40.4% of the tumors with HPV16 accounting for 63.5%, HPV18 for 30.8%, HPV6 for 3.9% and HPV11 for 1.8%. No infection with more than one HPV genotype was detected. HPV infection was significantly associated with poor histological grade, TNM stage I–II, alcohol usage and no smoking status. Multi-variate analysis showed that HPV had an independent prognostic effect on the overall survival after adjusting other confounding factors such as histological grade, TNM stage and tobacco usage. The presence of HPV was significantly correlated with a better survival in patients with OSCC.
Conclusion
HPV infection can act as an independent predictor for the survival and prognosis of OSCC.
doi:10.4248/IJOS.09015
PMCID: PMC3475584  PMID: 20695077
human papillomavirus (HPV); oral squamous cell carcinoma (OSCC); survival analysis
22.  Somatic mutations of STK11 gene in human papillomavirus positive and negative penile cancer 
Background
Human papillomavirus (HPV) infection accounts for about 40-50% of all cases of penile carcinoma suggesting that other factors, including host genetic status, are involved in neoplastic transformation. In this perspective, STK11 gene, which has been found frequently mutated in HPV-related cervical carcinoma, has been analyzed in HPV-positive and HPV-negative invasive penile cancers to establish its mutational status and the possible correlation of HPV infection with specific genetic alterations.
Methods
Genomic DNAs extracted from 26 cases of penile squamous cell carcinoma were analyzed for genetic alterations in the exons 1 to 9 of STK11 gene by quantitative real-time PCR. Ratios of potentially deleted and non-deleted exons were indicative of specific loss of STK11 coding regions. DNA samples of 5 cancer cases were subjected to standard PCR amplification of STK11 exons 1 to 9 and analyzed for somatic mutations by direct nucleotide sequencing analysis.
Results
Heterozygous deletions of STK11 exon 1 and 2 were identified in 2 out of 14 HPV-positive (14.3%) and 1 out of 12 HPV-negative cases (8.3%). Complete nucleotide sequencing analysis of exons 1 to 9 showed a single nucleotide change upstream the exon 2 coding region in 1 out of 5 penile carcinoma samples.
Conclusions
The present results suggest that single nucleotide mutations and/or deletions of STK11 gene are rare events in penile cancer. Moreover, no significant association was observed between STK11 alterations and HPV infection in these tumors.
doi:10.1186/1750-9378-8-2
PMCID: PMC3584742  PMID: 23305393
HPV; STK11; Somatic mutations; Penile cancer
23.  Molecular analysis of ras oncogenes in CIN III and in stage I and II invasive squamous cell carcinoma of the uterine cervix. 
Journal of Clinical Pathology  1998;51(8):576-582.
AIM: To examine the prevalence of genital type human papilloma virus (HPV) and mutations at codons 12, 13, and 61 in H, Ki, and N-ras in CIN III and early invasive squamous cell carcinomas of the cervix. METHODS: Prevalence of HPV was examined in 20 CIN III and 20 stage I and II cervical carcinomas, using non-isotopic in situ hybridisation (NISH) and solution phase polymerase chain reaction (PCR). In addition, mutations at codons 12, 13, and 61 were examined in H, Ki, and N-ras in these CIN III and early invasive squamous cell carcinomas, to assess the prevalence of ras gene point mutations and to define where in the pathobiology of squamous cell carcinoma such events occur. A non-isotopic PCR/RFLP assay was used to define these mutations. RESULTS: Of the 20 CIN IIIs examined, 19 contained HPV 16 DNA sequences by PCR and NISH. Dual infection was not uncovered. The 20 early (stage I and II) invasive squamous cell carcinomas showed predominant HPV 16 positivity (17/20), with one case HPV 18 positive, confirmed on PCR and NISH. Activating mutations were not identified in any of the CIN III cases. Only one stage I, HPV 16 positive carcinoma showed an activating mutation in H-ras codon 12, which was not present in adjacent normal ectocervical mucosa from the same patient. CONCLUSIONS: ras Activation does not appear to occur in conjunction with HPV infection, particularly of HPV 16 infected high grade cervical intraepithelial neoplasia, or to occur commonly in early cervical squamous cell carcinoma. The postulated model of HPV linked carcinogenesis suggests malfunctional control of viral transcription as a necessary component of neoplastic progression. It is also clear that host gene alterations are equally necessary for HPV linked carcinogenesis to occur.
Images
PMCID: PMC500848  PMID: 9828814
24.  HPV genotypes in paraffin sections of non-cervical squamous cell carcinoma in Qingdao of China 
Oncology Letters  2013;5(4):1219-1222.
Human papillomaviruses (HPVs) are the cause of cervical cancer and possibly a subset of squamous cell carcinomas (SCCs) in other sites. However, the prevalence and distribution of HPV subtypes remain unclear. In the present study, we collected and analyzed 511 paraffin sections of non-cervical SCC from patients in Qingdao, China, for the presence of HPV using polymerase chain reaction (PCR). We identified that 55.77% (285/511) of the samples were positive for HPV infection. There was a significant association between HPV type and the different sites of SCC. An association between HPV-positive cases and tobacco, alcohol, age and tumor differentiation was demonstrated. The information provided by this study may be important for further investigation into the association between HPV and SCC. High-risk HPV subtypes were associated with the malignant degree of SCC. This study provided a theoretical basis for the preventative treatment of non-cervical SCC using HPV vaccines.
doi:10.3892/ol.2013.1181
PMCID: PMC3629125  PMID: 23599766
squamous cell carcinomas; human papillomavirus genotype; polymerase chain reaction
25.  Differential Regulation of Cutaneous Oncoprotein HPVE6 by wtp53, Mutant p53R248W and ΔNp63α is HPV Type Dependent 
PLoS ONE  2012;7(4):e35540.
UV exposure and p53 mutations are major factors in non-melanoma skin cancer, whereas a role for HPV infections has not been defined. Previous data demonstrated the wtp53-mediated degradation of cutaneous HPV20E6 by caspase-3. ΔNp63α and hot-spot mutant p53R248W conveyed a protective effect on HPV20E6 under these conditions. We demonstrate a differential regulation by wtp53 of the E6 genes of cutaneous types HPV4, HPV5, HPV7, HPV27, HPV38, HPV48, HPV60 and HPV77. Caspase- or proteasome-mediated down-regulation was HPV type dependent. Mutant p53R248W up-regulated expression of all these E6 proteins as did ΔNp63α except for HPV38E6 which was down-regulated by the latter. None of these cellular proteins affected HPV41E6 expression. Ectopic expression of both mutp53R248W and ΔNp63α in the normal NIKS keratinocyte cell line harbouring endogenous p53 and p63however led to a down-regulation of HPV20E6. We demonstrate that HPV20E6 expression in these cells is modulated by additional, yet unidentified, cellular protein(s), which are not necessarily involved in apoptosis or autophagy. We further demonstrate proliferation of HPV20E6-expressing keratinocytes. Levels of proteins involved in cell cycle control, cyclin-D1, cdk6 and p16INK4a, phosphorylated pRB, as well as c-Jun and p-c-Jun, were all increased in these cells. HPV20E6 did not compete for the interaction between p16INK4a with cyclin-D1 or cdk6. Phosphorylation of pRB in the HPV20E6 expressing cells seems to be sufficient to override the cytokenetic block induced by the p16INK4a/pRB pathway. The present study demonstrates the diverse influence of p53 family members on individual cutaneous HPVE6 proteins. HPV20E6 expression also resulted in varying protein levels of factors involved in proliferation and differentiation.
doi:10.1371/journal.pone.0035540
PMCID: PMC3329482  PMID: 22530045

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