Anogenital Cancers Research Articles

Prevalence and genotype distribution of human papillomavirus infection among HIV-infected men who have sex with men living in Lower Silesia, Poland.

Human papillomavirus (HPV) is the most common sexually transmitted infection worldwide and is associated with the risk of anogenital and oropharyngeal cancers. Men who have sex with men (MSM) are at a high risk of HPV infection. However, little up-to-date data are available regarding the prevalence of HIV and HPV co-infection in MSM in Poland. To evaluate the prevalence, genotype distribution and risk factors for HPV infection among HIV-positive MSM living in Lower Silesia. A total of 54 HIV-positive and 28 HIV-negative MSM participated in the study. The polymerase chain reaction was performed to detect HPV from oral and anal swabs. A self-applied written questionnaire was conducted to collect sociodemographic and behavioural data. The prevalence rates of oral and anal HPV infection were higher in HIV-infected MSM than in HIV-negative MSM. Statistical analysis showed that the prevalence of high oncogenic genotypes, HPV 16 and HPV 18, at the anal site was significantly higher in patients with lower CD4 cell counts, in addition, HPV 18 infection was significantly more frequent in patients with higher levels of HIV RNA. Moreover, HPV 33 and HPV 52 at the anal site were significantly more common in patients with lower nadir CD4. This is the first report of HPV infection among Polish HIV-infected MSM. Our results show that HIV-related immunodeficiency is associated with a higher prevalence of high-risk HPV infections, therefore early detection of HIV infection and initiation of antiretroviral therapy might reduce the risk of HPV-related diseases.

Identification of the Human Papillomavirus Genotypes, According to the Human Immunodeficiency Virus Status in a Cohort of Women from Maputo, Mozambique.

Background: Human papillomavirus (HPV) infection is now a well-established cause of cervical cancer and other anogenital cancers. An association between human immunodeficiency virus (HIV) infection and higher HPV incidence and prevalence are commonly reported. This study was conducted to demonstrate HPV prevalence, genotypes and its characteristics, according to the HIV status in women from Maputo in Mozambique. Methods: A total of 233 participants with ages ranging from fourteen to forty-five were included. Cervical samples were collected, DNA extracted, and HPV genotyping was performed using the HPV Direct Flow CHIP Kit. Results: In total, 177 HIV-negative and 56 HIV-positive women were included in the analysis. The overall HPV prevalence was 63% and was significantly higher among HIV-positive women (79% versus 58% among HIV-negative women; p = 0.005). The prevalence of multiple HPV type infections was 32%. High-risk HPV types 52, 68, 35, 18 and 16 were the most frequent. A higher proportion of HIV-positive women had multiple HPV types compared with HIV-negative women. Conclusions: This study demonstrated a high prevalence of HPV in the study cohort. HIV-positive women were identified as having the highest HPV prevalence and infection with multiple HPV types across all ages. High-risk genotypes were the most commonly found.

High Risk Human Papillomavirus genital infections in asymptomatic population: effectiveness of Micro-Immunotherapy

Background: persistent infection with high-risk human papillomavirus (HR-HPV) is the primary cause for the development of various anogenital cancers in females and males. Most infections are either latent or subclinical and the majority occur as asymptomatic. HPV infections are not currently treatable by antiviral compounds. Micro-immunotherapy (MI) medications using high dilutions of cytokines and specific nucleotide sequences have been developed to treat targeted viral infections and are currently prescribed in medical practice as immune regulators: 2L®PAPI (Labo’Life) is indicated for HPV infection and may represent a new therapeutic approach.
 
 
 
 Aims: this exploratory study was to assess the effectiveness of 2L®PAPI on HPV infection eradication in HR-HPV infected asymptomatic patients attending an STD Centre in a long-term microbiological follow-up population survey.
 
 
 
 Methodology: adult patients of both genders, diagnosed with HR-HPV infection, with no evidence of symptomatic HPV or anogenital cancer, were followed during a 2 year-period (2009-2010). Selected patients had not previously been vaccinated for HPV or treated with medications having an impact on the immune system. HPV testing was performed on biological samples using PCR detection (Innogenetics, Italy). In addition, detection of E6/E7 mRNA of five carcinogenic HPV types was performed by EasyQ HPV (BioMerieux, Italy). HPV-positives were requested by their urology specialist to take 2L®PAPI (composition in table 1) during 4 months (1 caps/day by sublingual route). Globally 46 patients were followed: 23 treated with MI medication, and 23 not treated.
 
 
 
 Results: one third of selected patients were lost at the control visit (15/46). At the end of the study period, HR-HPV negativity was observed in 50% (8/16) of patients under MI medication in comparison with only 7% (1/15) of the non treated patients who were HPV-DNA negative at the follow-up visit (p=0.01071, Mid-P exact test). This result is in accordance with our previous results which showed long lasting persistence of HR-HPV infection in a male cohort.
 
 
 
 Conclusions: the relevant percentage of lost patients at follow-up reflects the scarce information and awareness of this infection within asymptomatic people in Italy. 2L®PAPI was efficient in eradicating 50% of HR-HPV infections in treated patients, including 60% of HPV-16. These promising data emphasize the importance of redirecting immune responses in viral infections.
 
 
 
 
 
 
 
 
 
 
 
 
 
 Table 1: 2L®PAPI composition
 
 
 
 Compounds Dilutions
 
 Interleukin-1 (IL-1): 17-10 CH*
 
 Interleukin-2 (IL-2): 17-10 CH
 
 Interferon-α (IFN-α): 17-10 CH
 
 SNA-HLA II: 16-10 CH
 
 Ciclosporin A (CsA): 7-10-17 CH
 
 Ribonucleic acid (RNA): 18-10 CH
 
 SNA-PAPI: 16-10 CH
 
 * CH: Centesimal Hahnemannian (1/100)

Human papillomavirus prevalence and genotype distribution in Vietnamese male patients between 2016 and 2020.

Human papillomavirus (HPV) infection in men is a serious issue because it is associated with genital warts, anogenital cancers, and HPV transmission to their sex partners. This study aimed to investigate the prevalence and genotypes of HPVs in Vietnamese male patients hospitalized with sexually transmitted infection (STI) symptoms between 2016 and 2020 by using polymerase chain reaction and reverse dot blot hybridization analysis. HPV DNA was detected in 191/941 (20.3%) penile cell samples. The HPV patient's mean age was 30.3 in the range of 16- and 69-year-old. The highest HPV prevalence (84.7%) was found in patients between 20- and 39-year-old. A total of 313 HPV genotypes were identified. The multiple-infection rate was 42.9%. The most common high-risk (HR)-HPV genotypes were HPV-16 (8.0%), HPV-51 (7.7%), HPV-52 (4.8%), HPV-56 (4.2%), and HPV-18 (3.8%). Furthermore, HPV-11 and HPV-6 genotypes were the two most common low-risk (LR)-HPV genotypes with the rate of 36.7% and 21.4%, respectively. Notably, HPV-52 was found circulating in Vietnam for the first time. In conclusion, this study results showed that HPV prevalence in Vietnamese male patients was common and diverse. In addition, regarding public health and cancer prevention, the inclusion of the HPV vaccination into the national vaccination program for both men and women is recommended.

Exogenous Vimentin Supplementation Transiently Affects Early Steps during HPV16 Pseudovirus Infection.

Understanding and modulating the early steps in oncogenic Human Papillomavirus (HPV) infection has great cancer-preventative potential, as this virus is the etiological agent of virtually all cervical cancer cases and is associated with many other anogenital and oropharyngeal cancers. Previous work from our laboratory has identified cell-surface-expressed vimentin as a novel HPV16 pseudovirus (HPV16-PsVs)-binding molecule modulating its infectious potential. To further explore its mode of inhibiting HPV16-PsVs internalisation, we supplemented it with exogenous recombinant human vimentin and show that only the globular form of the molecule (as opposed to the filamentous form) inhibited HPV16-PsVs internalisation in vitro. Further, this inhibitory effect was only transient and not sustained over prolonged incubation times, as demonstrated in vitro and in vivo, possibly due to full-entry molecule engagement by the virions once saturation levels have been reached. The vimentin-mediated delay of HPV16-PsVs internalisation could be narrowed down to affecting multiple steps during the virus’ interaction with the host cell and was found to affect both heparan sulphate proteoglycan (HSPG) binding as well as the subsequent entry receptor complex engagement. Interestingly, decreased pseudovirus internalisation (but not infection) in the presence of vimentin was also demonstrated for oncogenic HPV types 18, 31 and 45. Together, these data demonstrate the potential of vimentin as a modulator of HPV infection which can be used as a tool to study early mechanisms in infectious internalisation. However, further refinement is needed with regard to vimentin’s stabilisation and formulation before its development as an alternative prophylactic means.

Maternal HPV Infection: Effects on Pregnancy Outcome.

The human papilloma virus (HPV) infection, caused by a ubiquitous virus typically transmitted through the direct contact of infected organs, either through the skin or mucosa, is the most common sexually transmitted infection, placing young women at a high risk of contracting it. Although the vast majority of cases spontaneously clear within 1–2 years, persistent HPV infection remains a serious concern, as it has repeatedly been linked to the development of multiple malignancies, including cervical, anogenital, and oropharyngeal cancers. Additionally, more recent data suggest a harmful effect of HPV infection on pregnancy. As the maternal hormonal environment and immune system undergo significant changes during pregnancy, the persistence of HPV is arguably favored. Various studies have reported an increased risk of adverse pregnancy outcomes among HPV-positive women, with the clinical impact encompassing a range of conditions, including preterm birth, miscarriage, pregnancy-induced hypertensive disorders (PIHD), intrauterine growth restriction (IUGR), low birth weight, the premature rupture of membranes (PROM), and fetal death. Therefore, understanding the mechanisms employed by HPV that negatively impact pregnancy and assessing potential approaches to counteract them would be of interest in the quest to optimize pregnancy outcomes and improve child survival and health.

Gaps and Opportunities to Improve Prevention of Human Papillomavirus-Related Cancers.

Human papillomavirus (HPV) infections cause more than 35,900 cancers annually in the United States. Although cervical cancer is the most prevalent HPV-related malignancy in women, the virus is also responsible for a significant percentage of anal, vaginal, and vulvar cancers. A comprehensive approach to mitigating cervical cancer includes HPV vaccination (primary prevention), screening and treatment of precancerous lesions (secondary prevention), and diagnosis and treatment of invasive cancer (tertiary prevention). Although a successful strategy, there are opportunities to innovate and increase access that can also be adapted to address the unique clinical care gaps that exist with the other anogenital cancers. The Society for Women's Health Research held a series of interdisciplinary meetings and events, during which expert researchers, clinicians, patient advocates, and health care policy leaders evaluated the current landscape of HPV-related cancers and their effects on women's health. This report summarizes the discussions of this working group and areas it identified in which to address gaps in primary and secondary prevention approaches to improve access and health outcomes for women with HPV-related anogenital cancers.

Inactivation of Polyomavirus SV40 as Surrogate for Human Papillomaviruses by Chemical Disinfectants.

Human papillomaviruses (HPV) are non-enveloped DNA viruses infecting cutaneous and mucosal squamous epithelia. Sexually transmitted HPV-types that are carcinogenic to humans such as HPV16 can induce cervical and other anogenital cancers. Virus transmission through fomites such as inadequately disinfected gynecological equipment is a further potential transmission route. Since HPV cannot be easily grown in cell culture, polyomavirus SV40 has been used as a surrogate virus when testing the virucidal activity of chemical disinfectants. So far, studies that have compared the virucidal activity of different disinfectants against HPV and SV40 are lacking. Here, we evaluated the susceptibility of HPV16 pseudovirus and SV40 to seven active biocidal substances using quantitative suspension tests. Ethanol, glutaraldehyde (GTA), dodecyldipropylentriamin (DPTA), and ortho-phthalaldehydes (OPA) were able to reduce the infectivity of HPV16 pseudovirus >99.99% after 5 min. In contrast, isopropanol, peracetic acid (PAA), and quaternary ammonium compounds with alkylamines (QAC) only led to a slight or no reduction in infectivity. Concerning SV40, only GTA (60 min contact time), PAA, and OPA had virus-inactivating effects. In conclusion, the virucidal activity of three out of seven disinfectants tested was different for HPV16 pseudovirus and SV40. In this study, SV40 was shown to be a reliable surrogate virus for HPV when testing isopropanol-, GTA-, QAC-, and OPA-based disinfectants.

Genetic Predisposition to Persistent Human Papillomavirus-Infection and Virus-Induced Cancers.

Human papillomaviruses (HPVs) are the most common sexually transmitted pathogens worldwide and among the more than 200 identified HPV types, approximately 15 high risk (HR-HPV) types are oncogenic, being strongly associated with the development of cervical cancer, anogenital cancers and an increasing fraction of head and neck squamous cell carcinomas (HNSCC). HPV-associated cervix cancer accounts for 83% of HPV-attributable cancers, and more than two-thirds of those cases occur in developing countries. Despite the high frequency of HPV infections, in most cases, the virus is cleared by the host immune response and only a small proportion of infected individuals develop persistent infections that can result in malignant transformation, indicating that other elements, including biological, genetic and environmental factors may influence the individual susceptibility to HPV-associated cancers. Previous studies have quantified that heritability, in the form of genetic variants, common in the general population, is implicated in nearly 30% of cervical cancers and a large number of studies conducted across various populations have identified genetic variants that appear to be associated with genes that predispose or protect the host to HPV infections thereby affecting individual susceptibility to HPV-associated cancers. In this article, we provide an overview of gene association studies on HPV-associated cancers with emphasis on genome-wide association study (GWAS) that have identified novel genetic factors linked to HPV infection or HPV-associated cancers.

Cancer in HIV-positive and HIV-negative adolescents and young adults in South Africa: a cross-sectional study

ObjectiveTo determine the spectrum of cancers in adolescents and young adults (AYAs) living with and without HIV in South Africa.DesignCross-sectional study with cancer records provided by the National Cancer Registry...

Genomic Instability and DNA Damage Repair Pathways Induced by Human Papillomaviruses.

Human papillomaviruses (HPV) are the causative agents of cervical and other anogenital cancers as well as those of the oropharynx. HPV proteins activate host DNA damage repair factors to promote their viral life cycle in stratified epithelia. Activation of both the ATR pathway and the ATM pathway are essential for viral replication and differentiation-dependent genome amplification. These pathways are also important for maintaining host genomic integrity and their dysregulation or mutation is often seen in human cancers. The APOBEC3 family of cytidine deaminases are innate immune factors that are increased in HPV positive cells leading to the accumulation of TpC mutations in cellular DNAs that contribute to malignant progression. The activation of DNA damage repair factors may corelate with expression of APOBEC3 in HPV positive cells. These pathways may actively drive tumor development implicating/suggesting DNA damage repair factors and APOBEC3 as possible therapeutic targets.

Human Papillomaviruses Target the DNA Damage Repair and Innate Immune Response Pathways to Allow for Persistent Infection.

Persistent infection with high-risk human papillomaviruses (HPVs) is the major risk factor associated with development of anogenital and oropharyngeal cancers. Initial infection by HPVs occurs into basal epithelial cells where viral genomes are established as nuclear episomes and persist until cleared by the immune response. Productive replication or amplification occurs upon differentiation and is dependent upon activation of the ataxia-telangiectasia mutated (ATM), ataxia telangiectasia and RAD3-related (ATR) DNA damage repair (DDR) pathways. In addition to activating DDR pathways, HPVs must escape innate immune surveillance mechanisms by antagonizing sensors, adaptors, interferons and antiviral gene expression. Both DDR and innate immune pathways are key host mechanisms that crosstalk with each other to maintain homeostasis of cells persistently infected with HPVs. Interestingly, it is still not fully understood why some HPV infections get cleared while others do not. Targeting of these two processes with antiviral therapies may provide opportunities for treatment of cancers caused by high-risk HPVs.

Abstract 20: Development of International Cancer Research Partnerships Through the NCI US-Latin American-Caribbean HIV/HPV-Cancer Prevention Clinical Trials Network (ULACNet)

Abstract Purpose: Persons living with HIV have elevated risks of HPV-related cervical, anogenital, and oropharyngeal cancers. Yet, research on optimization and implementation of prevention interventions (prophylactic HPV vaccination, cervical and anogenital cancer screening and triage, and precancer therapeutics) for HPV-related cancers among persons living with HIV has been limited. With a goal to expand this evidence, and building on strong academic research partnerships developed for HIV research between institutions in the US and the Latin American and the Caribbean (LAC) region, the US National Cancer Institute (NCI) initiated ULACNet, a new Cooperative Agreement clinical trials network in 2019. Methods: ULACNet comprises of three Partnership Centers each led by US-based institutions (University of California San Francisco, Weill Medical College of Cornell University, and Fred Hutchinson Cancer Research Center), working collaboratively with US and LAC institutions and with the NCI to develop and conduct multicenter prevention clinical trials focused on filling key scientific gaps and evaluating novel interventions. Results: ULACNet encompasses six countries (US, Mexico, Puerto Rico, Brazil, Peru, and Dominican Republic), twenty partner institutions, and over 100 collaborating scientific investigators, clinical and public health practitioners, research staff, and patient advocates. ULACNet will collaboratively conduct nine prevention clinical trials (two prophylactic HPV vaccine trials in adults and perinatally-HIV infected adolescents, three trials for clinical validation of molecular biomarkers and imaging technologies for screening and triage, two candidate HPV therapeutic vaccine trials, and two trials of topical therapeutic agents). Facilitation across network partners is achieved via a Coordinating Committee and three Working Groups (focused on HPV testing and screening, precancer treatment, and recruitment and retention activities). Conclusion: ULACNet seeks to leverage established academic global health partnerships to conduct high quality collaborative clinical trials to inform clinical practice and ultimately reduce the burden of highly preventable HPV-related cancers in persons living with HIV worldwide. Citation Format: Emma Brofsky, Margaret House, Brandy Heckman-Stoddard, Mostafa Nokta, Satish Gopal, Vikrant Sahasrabuddhe. Development of International Cancer Research Partnerships Through the NCI US-Latin American-Caribbean HIV/HPV-Cancer Prevention Clinical Trials Network (ULACNet) [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 20.

Prevalence and risk factors for anogenital HPV infection and neoplasia among women living with HIV in China

ObjectivesTo explore the prevalence and risk factors of anogenital human papillomavirus (HPV) infection and neoplasia among women living with HIV (WLHIV) in China.MethodsA cross-sectional survey was conducted from 2019 to...

Regulation of the Human Papillomavirus Lifecyle through Post-Translational Modifications of the Viral E2 Protein.

The human papillomavirus (HPV) is a DNA tumor virus that infects cutaneous and mucosal epithelia where high-risk (HR) HPV infections lead to cervical, oropharyngeal, and anogenital cancers. Worldwide, nearly 5% of all cancers are caused by HR HPV. The viral E2 protein is essential for episomal replication throughout the viral lifecycle. The E2 protein is regulated by phosphorylation, acetylation, sumoylation, and ubiquitination. In this mini-review, we summarize the recent advancements made to identify post translational modifications within E2 and their ability to control viral replication.

Establishment of specifcations of the multiplex real-time PCR kit (NIHE-RealtimePCR hrHPV) for the detection of high-risk HPV genotypes

High-risk human papillomavirus (HPV) genotypes are the leading causes of anogenital cancer, including cervical cancer. Screening these genotypes will potentially alleviate the disease burden that HPV causes. Therefore, NIHERealtime PCR hrHPV was developed based on the principle of multiplex real-time PCR. The objective of this study is to establish the specifcations of this assay in detecting and identifying 14 high-risk genotypes of HPV. The specifcations of this assay including cross-reactivity, sensitivity and specifcity, the limit of detection and stability, were evaluated with clinical samples, HPV positive control code 06/202 and 06/206 (National Institute for Biological Standards and Control) and in-house plasmids. Four different real-time systems and two commercial assays were applied for comparison. No cross detection of bacteria and viruses related to other genital-anal was observed. The sensitivity and the specifcity of this kit both reached 100% for HPV-18, 92.3% and 100% for HPV-16, and ranged from 90.0% - 100% for the other 12 high-risk genotypes (n = 92) with the detection limit of 5 copies/µl for HPV-16 and HPV-18, and 10 copies/µl for the other 12 high-risk genotypes HPV. This test was stable for up to 12 months under -20oC condition. Equivalent performance was demonstrated on all four real-time systems. Finally, the product was highly comparable with the Sacace kit, Italy (HPV Genotypes 14 Real-™ Quant, V67-100FRT), evaluated by the World Health Organization. The NIHE kit has the potential to be used in the early detection of HPV infection to improve control, prevention and treatment of HPV-related anogenital diseases.

Incidence of HPV-related Anogenital Intraepithelial Neoplasia and Cancer in Men With Diabetes Compared With the General Population.

Diabetes may increase risk of human papillomavirus (HPV)-related precancer and cancer. We estimated incidence of penile and anal high-grade intraepithelial neoplasia (hgPeIN, hgAIN) and squamous cell carcinoma (SCC) in men with diabetes compared with the entire Danish male population without diabetes. In this registry-based cohort study, we included all men born 1916-2001 and residing in Denmark (n = 2,528,756). From nationwide registries, we retrieved individual-level information on diabetes, educational level, and diagnoses of hgPeIN, hgAIN, penile SCC, and anal SCC. We used Poisson regression models to estimate incidence of hgPeIN, hgAIN, penile SCC, and anal SCC as a function of diabetes status, attained age, calendar period, and education. We estimated incidence rate ratios (IRRs) of each outcome in men with diabetes compared with nondiabetic men, both for diabetes overall and separately for type 1 (T1D) and type 2 diabetes (T2D). Men with diabetes had increased incidence rate of penile SCC compared with nondiabetic men (IRR = 1.5, 95% CI = 1.2, 1.9). We saw similar trends for anal SCC, hgPeIN, and hgAIN. The combined incidence rate of penile and anal SCC was increased in men with T2D (IRR = 1.5, 95% CI = 1.3, 1.8), but not with T1D (IRR = 0.53, 95% CI = 0.20, 1.4) compared with men without diabetes. The incidence of penile and anal high-grade intraepithelial neoplasia and SCC in men with diabetes was increased compared with men without diabetes. For penile and anal SCCs, this was primarily due to an increased risk in men with T2D.

Snapshot of Clinical Implications of p16 Overexpression in Carcinogenesis

Molecular markers are needed to decide the treatment plans of certain cancer types when the histological and other clinical diagnoses are not sufficient to decide the tumor nodular metastasis (TNM) stage. The ubiquitous p16 gene is one of them gained popularity by fulfilling criteria to be a useful biomarker. Over expression of p16, to compensate the inactivity of another two tumor suppressor genes (TSG)s, pRb and p53 due to the integration of E7 and E6 high risk Human Papilloma viral oncoprotein respectively into the host keratinocytes is useful to consider the clinical impact of p16 biomarker in carcinogenesis. The p16 immunohistochemistry helps the diagnosis as well as prognosis of cervical and oropharyngeal squamous cell carcinoma, though there are ambiguities in the cutoff values of p16 positivity. There is also a re-emerging interest on clinical impact of p16 positivity in lung, breast, and colorectal cancer types. High risk HPV genotypes have been already established as the aetiological agents of cervical, other rare ano-genital and oropharyngeal (especially tonsils and base of the tongue) cancers. The HPV associated subset of head and neck cancers demonstrate a unique tumor biology, when compared with HPV non associated ones thus, most effective treatment planning including counselling is much needed to maximize the overall survival of HPV associated cancer patients, in the era of personalized precision medicine. In the shed of light, this communication glimpses on clinical implications of p16 overexpression in carcinogenesis not limiting to cervical and a subset of head and neck carcinomas (HNSCC).

Incidence of cervical intraepithelial lesions and human papilloma virus infection in female renal transplant recipients.

Female renal transplant recipients (RTR) are at high risk of human papillomavirus (HPV)-related anogenital premalignancies and cancer. The aim of this study was to estimate the incidence of cervical intraepithelial lesions (IL) and HPV infection, and their associated factors, in Mexican RTR. This is a prospective cohort study conducted between January 2011 and December 2017. Demographic, clinical, and gynecological data were collected using a previously designed questionnaire. Gynecological examination, cervical cytology, and detection of high- and low-risk HPV DNA were undertaken prior to and after the renal transplant (RT). Colposcopically guided biopsies were obtained from patients who presented high grade squamous intraepithelial lesions (HSIL) during the follow-up period. Diagnoses were established according to the Bethesda system. Among 130 RTR, 62 were eligible for our study. The overall incidence of IL was 17.7% (95% CI, 8% to 27%), (11/62 patients), at 25.6±10.7months post-RT. Nine out of the eleven affected patients had low-grade squamous intraepithelial lesions (81.8%) and only two had HSIL (18.2%). The incidence of HPV infection, determined in a subgroup of 30 RTR, was 53.3% (95% CI, 35% to 71%), (16 out of 30 patients), at 18.3±8.9months post-RT. High-risk HPV genotypes were present in 62.5% of HPV positive cases (10/16). In 11 patients (36.6%), HPV infection was not associated to IL. HPV infection and cervical IL are common in the early posttransplant period. Our findings support the need of screening for cervical cancer to detect precancerous changes in RTR and the need of strengthening the knowledge of medical personnel on this issue.

Role of IQGAP1 in Papillomavirus-Associated Head and Neck Tumorigenesis.

Simple SummaryHuman papillomaviruses (HPVs) are the most common sexually transmitted pathogens in the United States and are associated with 25% of head and neck cancers (HNCs). To study the genesis of papillomavirus-associated HNC in a physiologically relevant pre-clinical model, we recently developed an infection-based murine model that uses the recently discovered mouse papillomavirus, MmuPV1. In this MmuPV1 HNC model, as in HPV-associated HNCs, the PI3K/AKT/mTOR signaling pathway is upregulated. Components of this pathway are known to be assembled by the scaffolding protein IQGAP1. Utilizing our MmuPV1 HNC model, we tested and demonstrated the importance of IQGAP1 in papillomavirus-induced HNC, in which IQGAP1 is required for optimal induction of the PI3K/AKT/mTOR pathway by MmuPV1 and contributes quantitatively to MmuPV1-induced HNC. Further investigation into how IQGAP1 promotes disease progression may shed additional insights into papillomavirus-induced carcinogenesis and provide new drug targets for treating HPV-associated neoplastic disease.Approximately 25% of head and neck squamous cell carcinomas (HNSCC) are associated with human papillomavirus (HPV) infection. In these cancers as well as in HPV-associated anogenital cancers, PI3K signaling is highly activated. We previously showed that IQ motif-containing GTPase activating protein 1 (IQGAP1), a PI3K pathway scaffolding protein, is overexpressed in and contributes to HNSCC and that blocking IQGAP1-mediated PI3K signaling reduces HPV-positive HNSCC cell survival and migration. In this study, we tested whether IQGAP1 promotes papillomavirus (PV)-associated HNSCCs. IQGAP1 was necessary for optimal PI3K signaling induced by HPV16 oncoproteins in transgenic mice and MmuPV1 infection, a mouse papillomavirus that causes HNSCC in mice. Furthermore, we found that, at 6 months post-infection, MmuPV1-infected Iqgap1−/− mice developed significantly less severe tumor phenotypes than MmuPV1-infected Iqgap1+/+ mice, indicating a role of IQGAP1 in MmuPV1-associated HNSCC. The tumors resulting from MmuPV1 infection showed features consistent with HPV infection and HPV-associated cancer. However, such IQGAP1-dependent effects on disease severity were not observed in an HPV16 transgenic mouse model for HNC. This may reflect that IQGAP1 plays a role in earlier stages of viral pathogenesis, or other activities of HPV16 oncogenes are more dominant in driving carcinogenesis than their influence on PI3K signaling.