Lack of Conserved miRNA Deregulation in HPV-Induced Squamous Cell Carcinomas.

Squamous cell carcinomas (SCCs) in the anogenital and head and neck regions are associated with high-risk types of human papillomaviruses (HR-HPV). Deregulation of miRNA expression is an important contributor to carcinogenesis. This study aimed to pinpoint commonly and uniquely deregulated miRNAs in cervical, anal, vulvar, and tonsillar tumors of viral or non-viral etiology, searching for a common set of deregulated miRNAs linked to HPV-induced carcinogenesis. RNA was extracted from tumors and nonmalignant tissues from the same locations. The miRNA expression level was determined by next-generation sequencing. Differential expression of miRNAs was calculated, and the patterns of miRNA deregulation were compared between tumors. The total of deregulated miRNAs varied between tumors of different locations by two orders of magnitude, ranging from 1 to 282. The deregulated miRNA pool was largely tumor-specific. In tumors of the same location, a low proportion of miRNAs were exclusively deregulated and no deregulated miRNA was shared by all four types of HPV-positive tumors. The most significant overlap of deregulated miRNAs was found between tumors which differed in location and HPV status (HPV-positive cervical tumors vs. HPV-negative vulvar tumors). Our results imply that HPV infection does not elicit a conserved miRNA deregulation in SCCs.

Incidence, cost and gender differences of oropharyngeal and noncervical anogenital cancers in South Korea.

BACKGROUND: Human papillomavirus (HPV) is associated with a significant public health burden, yet few studies have been conducted in Asia, especially on noncervical cancers. We estimated the incidence and cost of oropharyngeal and noncervical anogenital (anal, vulvar, vaginal, penile) cancer in Korea. METHODS: We conducted a retrospective cohort study using Korea's National Health Insurance (NHI) claim database from 2013 to 2016. The main outcome measures were the number of respective cancer incidences during the study period and the annual costs per patient in the first year after diagnosis, which was adjusted by relevant variables based on the regression analysis. RESULTS: During the study period, 8022 patients with these cancers were identified, and oropharyngeal cancer comprised 46% of them. The crude incidence rate for male oropharyngeal cancer was significantly higher than that of females (3.1 vs. 0.7 per 100,000 as of 2016, respectively). Additionally, the crude incidence of male oropharyngeal cancer increased from 2.7 in 2013 to 3.1 in 2016, whereas that of female and other cancers was stable during the study period. The mean annual incidence-based cost per patient in 2016 was highest for oropharyngeal cancers (21,870 USD), and it was significantly higher in males than in females based on then regression analysis (p < .001). CONCLUSIONS: Oropharyngeal cancer comprises the highest number of HPV-associated noncervical cancer incidences in Korea, and the incidence and cost of oropharyngeal cancer was significantly higher among males than females. More aggressive public health policy toward males may decrease gender gap of oropharyngeal cancer.

Chronic hepatitis C virus infection and genitourinary cancers: A case-control study.

BACKGROUND: Chronic Hepatitis C virus (HCV) infection has been associated with extrahepatic cancers. Few studies have reported associations between HCV and genitourinary cancers such as kidney and prostate cancers with inconsistent findings. We sought to study associations between HCV and the most common genitourinary cancers including kidney, prostate and urinary bladder. MATERIAL AND METHODS: This case-control study included adult (≥18 years at diagnosis) cancer patients who were screened for HCV antibody (anti-HCV) at MD Anderson Cancer Center from June 2004 through January 2018. Cases had incident primary genitourinary cancers (cancers of the kidney, prostate, renal pelvis and ureter, or urinary bladder). Controls had smoking-associated cancers (esophagus, lung and pancreas). Multivariate logistic regression models were used. RESULTS: Among 42,244 patients screened for anti-HCV, 1,493 cases (527 kidney, 691 prostate, 58 renal pelvis and ureter, and 217 urinary bladder cancer) and 1,187 controls (242 esophagus, 709 lung, and 236 pancreas cancer) were studied. In the univariate analysis, the prevalence of anti-HCV positivity did not differ significantly between the controls and the cases with cancers of the renal pelvis and ureter (8% v9%, P = .81), prostate (10% v8%, P = .34), or urinary bladder (8% v 6%, P = .18). In contrast, the prevalence of anti-HCV positivity was lower among the cases with kidney cancer than among the controls (4% v 8%, P< .001). However, in the multivariate analyses after adjustment for cofounders, no significant association between anti-HCV positivity and any genitourinary cancer we evaluated. CONCLUSION: Our results do not support an association between chronic HCV and common genitourinary cancers.

Correlation of Cancer Development and Human Papilloma Virus Infection in Patients After Organ Transplantation.

Immunosuppressed patients are at higher risk of developing human papilloma virus (HPV) cancerous and precancerous lesions in the anogenital region Carcinogenesis after organ transplantation due to immunosuppressive therapy is the major cause of long-term negative transplantation results. This is a rationale for the improvement of transplantation programs with carcinogenesis risk stratification in patients referred for transplantation. There is a need for a study on HPV-related carcinogenesis also in terms of its risk factors in the population after organ transplantation. This study aimed to assess the morbidity of anogenital carcinoma in patients with HPV infection, including those after organ transplantation and evaluate risk factors for carcinoma occurrence in patients after organ transplantation and with HPV infection. Our analysis directly indicates the group of patients with a high risk of HPV-related oncological complications of immunosuppression in anogenital region.

A novel group of HPV-related adenocarcinomas of the lower anogenital tract (vagina, vulva, and anorectum) in women and men resembling HPV-related endocervical adenocarcinomas.

Human papillomavirus (HPV) is an oncogenic virus associated with the development of several human cancers. Primary vaginal, vulvar, and anal adenocarcinomas are rare and, to date, have rarely been shown to be associated with HPV infection. We report a series of nine HPV-related adenocarcinomas of the lower anogenital tract distal to the cervix. The tumors involved the vagina (4), anorectum (3), and vulva (2). Two of the three anorectal cases involved men. Patients presented with a vulvar or vaginal mass/nodule, painless rectal bleeding, or during screening colonoscopy. Lesions ranged in size from 3.2 to 8.4 cm. The most salient morphologic characteristic was the presence of papillary or villiform/villoglandular architecture in all cases. Tumors displayed features similar to those of usual type high-risk HPV-related endocervical adenocarcinoma, namely, mucinous or mucin-poor (pseudoendometrioid) features or a hybrid of these, with columnar cells with crowded, cigar-shaped to ovoid irregular nuclei. Mitoses (mostly apical) and apoptotic bodies were easily identified. Adenosis was present in two vaginal cases. One anal tumor featured abundant intracytoplasmic mucin that was multivacuolated in some areas imparting a "clear cell"-like appearance. All tumors were diffusely and strongly positive for p16. Seven of seven tested cases were positive for high-risk HPV by in situ hybridization or polymerase chain reaction. Follow-up information, available in five patients, revealed two local recurrences but no tumor related deaths or distant metastases. We report the first well-documented series of HPV-associated primary adenocarcinomas of the vagina, vulva, and anorectum and broaden the spectrum of HPV-related neoplasia involving the lower anogenital tract in both women and men.

A stepped-wedge cluster randomized trial designed to improve completion of HPV vaccine series and reduce missed opportunities to vaccinate in rural primary care practices.

OBJECTIVES: To test the effectiveness of a comprehensive team-based intervention to improve human papillomavirus (HPV) vaccination completion rates and reduce missed opportunities to vaccinate in rural Oregon. DESIGN: Stepped-wedge cluster randomized trial. PARTICIPANTS: Forty family physicians and pediatricians who are members of the Oregon Rural Practice-based Research Network. INTERVENTION: Tailored to individual practice needs, components will include (1) practice facilitation with clinicians, nurses, front office staff, and others who have patient contact to redesign patient care and communication strategies to optimize HPV vaccine series completion; (2) workflow mapping adapted to practice context to support HPV vaccine delivery; (3) a practice improvement model designed to firmly establish reminder and recall systems and then standing orders; (4) education for patients and parents that underscores HPV vaccination is safe, effective, and an important approach for reducing cancer risk; and (5) partnering with community organizations to plan and implement a social marketing campaign on HPV vaccination. MAIN OUTCOME MEASURES: Initiation and completion of the HPV vaccine series as well as reduction in rates of missed opportunities to vaccinate derived from Oregon Immunization Program data. TRIAL REGISTRATION: ClinicalTrials.govPRS, NCT03604393 : .Trial was registered on July 11, 2018. The first participant was enrolled on September 11, 2018.

Association between Human Papillomavirus and Non-cervical Genital Cancers in Brazil: A Systematic Review and Meta-Analysis

Background: Human papillomavirus (HPV) infection is associated with cervical cancer; however, it is controversial whether it is involved in non-cervical genital cancers. Objective: This study aimed to evaluate articles on the prevalence of HPV in penile cancer, vulvar cancer, colorectal cancer, prostate cancer and anal canal cancer in studies conducted in Brazil. Methods: The study was conducted in accordance with the Preferred Reporting of Systematic Reviews and Meta-Analysis Statement. Comprehensive searches for HPV and cancer for the years 2006 to 2016 were conducted in two databases (PubMed and Web of Knowledge) and Google Scholar system. We also tracked the references of all eligible articles to identify additional non-captured publications through online surveys. Results: Eighteen studies, with a combined sample size of 1,552 patients were analyzed. The overall prevalence of HPV was 43% (95% CI: 36­51%; p < 0.001). The pooled prevalence of HPV in penile cancer was 42% (95% CI: 32­55%; p < 0.001), in colorectal cancer it was 67% (95% CI: 64­70%; p < 0.001) and in vulvar cancer 43% (95% CI: 34­55%; p < 0.001). HPV 16 was the most prevalent in all sites evaluated, with prevalence estimated at 54% (95% CI: 44­66%; p < 0.001), followed by genotypes 33 (21%; 95% CI: 17­28; p < 0.001), 6 (15%; 95% CI: 8­26%; p < 0.001), 11 (13%; 95% CI: 5­32%; p < 0.001) and 18 (12%; 95% CI: 7­22%; p < 0.001), respectively. The pooled prevalence of single infection was 82% and infection by multiple genotypes of HPV was 22%. Conclusion: Our study demonstrated a high prevalence of HPV in non-cervical genital cancers in Brazil, with predominance of genotype 16, providing evidence for the need for preventive and control measures to avoid future harm to the population.

Quality Improvement Initiative to Improve Human Papillomavirus Vaccine Initiation at 9 Years of Age.

OBJECTIVE: Adolescent human papillomavirus (HPV) vaccine rates remain low. Early vaccination may improve the efficacy of the vaccine and immunization rates; however, clinicians have not routinely made a strong recommendation for younger adolescents. This study assessed the feasibility of routine vaccination at 9 years of age. METHODS: Three sequential quality improvement (QI) interventions were implemented to shift the initiation of the HPV vaccine to 9 years of age in a primary care network in low-income neighborhoods in Columbus, Ohio. The first intervention changed the electronic medical record alert for the HPV vaccine from 11 to 9 years of age and focused on cancer prevention when discussing the vaccine with families. The second intervention was formation of an HPV QI team. The third intervention was a clinic incentive for HPV captured opportunity rates. Immunization rates were monitored using statistical process control charts to compare the HPV immunization rate in a sample of 9- and 10-year-old children with a sample of 11- and 12-year-old children. RESULTS: The percentage of patients receiving an HPV vaccine before 11 years increased from 4.6% to 35.7% during the 6 months after the QI initiative began and to 60.8% 18 months after the project began. In comparison, the HPV vaccination rate in the sample of 11- and 12-year-olds increased from 78.7% to 82.8% 18 months later. CONCLUSIONS: This QI project used multiple interventions to increase HPV vaccination at 9 years of age in a large primary care network serving a diverse low-income population.

De Novo Human Herpesvirus 8 Tumors Induced by Rituximab in Autoimmune or Inflammatory Systemic Diseases.

OBJECTIVE: Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma (KS)-associated herpesvirus, is involved in KS and other tumors, including multicentric Castleman's disease and primary effusion lymphoma. Rituximab (RTX) is currently used for the treatment of several autoimmune or inflammatory diseases and humoral organ transplant rejection. De novo HHV-8 tumors induced by RTX used for these indications have not been reported previously. This study was undertaken to evaluate de novo HHV-8 tumors induced by RTX. METHODS: In this retrospective study, we investigated the clinical, virologic, and pathologic features of 5 HIV-negative male patients with HHV-8 tumors induced by RTX therapy. RESULTS: Patients were all immunocompromised by previous treatments, which consisted of steroids and/or immunosuppressive agents, and received RTX for insufficient response, disease progression, or transplant rejection. They developed HHV-8 tumors a median of 4 months after beginning treatment with RTX (range 3-13 months). Four patients had at least 1 risk factor for HHV-8, including a high Fitzpatrick skin phototype (of >3) (n = 3) and homosexuality (n = 1). Four patients developed KS (all 4 had skin lesions and 2 had visceral involvement), and 1 patient developed a solid primary effusion lymphoma. RTX was discontinued in all patients, and immunosuppressants were reduced when feasible. After a median follow-up of 20 months, 2 patients died. Remission of KS was complete in 1 patient and partial in 1 patient, and 1 patient had progression. CONCLUSION: Our findings indicate that patients who have a high skin phototype and are at risk of HHV-8 should be carefully screened for HHV-8 before RTX therapy. The safety of RTX, especially in nonlymphomatous disorders, should be carefully evaluated in patients at risk of HHV-8 tumors.

A functional polymorphism in the NKG2D gene modulates NK-cell cytotoxicity and is associated with susceptibility to Human Papilloma Virus-related cancers.

Human papillomavirus (HPV) is the most common sexually transmitted agent worldwide and is etiologically linked to several cancers, including cervical and genital cancers. NKG2D, an activating receptor expressed by NK cells, plays an important role in cancer immune-surveillance. We analyzed the impact of a NKG2D gene variant, rs1049174, on the incidence of HPV-related cancers in Vietnamese patients and utilized various molecular approaches to elucidate the mechanisms of NKG2D receptor regulation by rs1049174. In a group of 123 patients with HPV+ anogenital cancers, the low cytotoxicity allele LNK was significantly associated with increased cancer susceptibility (p = 0.016). Similar results were also observed in a group of 153 women with cervical cancer (p = 0.05). In functional studies, NK cells from individuals with LNK genotype showed a lower NKG2D expression and displayed less efficient NKG2D-mediated functions than NK cells with HNK genotype. Notably, the rs1049174 variant occurs within a targeting site for miR-1245, a negative regulator of NKG2D expression. Compared with the higher cytotoxicity allele HNK, the LNK allele was more efficiently targeted by miR-1245 and thus determined lower NKG2D expression in NK cells with the LNK genotype. The NKG2D variants may influence cancer immunosurveillance and thus determine susceptibility to various malignancies, including HPV-induced cancers.

Genomic characterization of viral integration sites in HPV-related cancers.

Persistent infection with carcinogenic human papillomaviruses (HPV) causes the majority of anogenital cancers and a subset of head and neck cancers. The HPV genome is frequently found integrated into the host genome of invasive cancers. The mechanisms of how it may promote disease progression are not well understood. Thoroughly characterizing integration events can provide insights into HPV carcinogenesis. Individual studies have reported limited number of integration sites in cell lines and human samples. We performed a systematic review of published integration sites in HPV-related cancers and conducted a pooled analysis to formally test for integration hotspots and genomic features enriched in integration events using data from the Encyclopedia of DNA Elements (ENCODE). Over 1,500 integration sites were reported in the literature, of which 90.8% (N = 1,407) were in human tissues. We found 10 cytobands enriched for integration events, three previously reported ones (3q28, 8q24.21 and 13q22.1) and seven additional ones (2q22.3, 3p14.2, 8q24.22, 14q24.1, 17p11.1, 17q23.1 and 17q23.2). Cervical infections with HPV18 were more likely to have breakpoints in 8q24.21 (p = 7.68 × 10(-4) ) than those with HPV16. Overall, integration sites were more likely to be in gene regions than expected by chance (p = 6.93 × 10(-9) ). They were also significantly closer to CpG regions, fragile sites, transcriptionally active regions and enhancers. Few integration events occurred within 50 Kb of known cervical cancer driver genes. This suggests that HPV integrates in accessible regions of the genome, preferentially genes and enhancers, which may affect the expression of target genes.

A NOVEL GAMMAHERPESVIRUS IN NORTHERN FUR SEALS (CALLORHINUS URSINUS) IS CLOSELY RELATED TO THE CALIFORNIA SEA LION (ZALOPHUS CALIFORNIANUS) CARCINOMA-ASSOCIATED OTARINE HERPESVIRUS-1.

Otarine herpesvirus 1 (OtHV1) is strongly associated with California sea lion (CSL, Zalophus californianus) urogenital carcinoma, the most common cancer documented in marine mammals. In addition to CSL, OtHV1 has also been found in association with carcinoma in South American fur seals (Arctocephalus australis), demonstrating it can infect related species. Northern fur seals (NFS, Callorhinus ursinus) are sympatric with CSL, and copulation between these species has been observed; yet, there are no reports of urogenital carcinoma in NFS. We describe a new Otarine herpesvirus found in vaginal swabs from NFS, herein called OtHV4. Partial sequencing of the polymerase gene and the glycoprotein B gene revealed OtHV4 is closely related to OtHV1, with 95% homology in the region of polymerase sequenced, and phylogenetic analyses demonstrate that they are sister taxa. An OtHV4-specific hydrolysis probe quantitative PCR was developed and validated, and its use on vaginal swabs revealed 16 of 50 (32%) wild adult female NFS were positive for OtHV4. The identification of a virus highly similar to the carcinoma-associated OtHV1 in a sympatric species without carcinoma suggests that comparative genomics of OtHV1 and OtHV4 may identify candidate viral oncogenes.

Committee Opinion Summary No. 641: Human Papillomavirus Vaccination.

Human papillomavirus (HPV) is associated with the development of anogenital cancer (including cervical, vaginal, vulvar, penile, and anal), oropharyngeal cancer, and genital warts. Human papillomavirus vaccination can significantly reduce the incidence of anogenital cancer and genital warts. Despite the benefits of HPV vaccines, only approximately one third of girls in the recommended age group have received all three vaccines. Compared with other vaccines recommended in the same age bracket, HPV vaccination rates in the United States are unacceptably low. It is crucial that obstetrician-gynecologists and other providers educate parents and patients on the benefits and safety of HPV vaccination. The Centers for Disease Control and Prevention and the American College of Obstetricians and Gynecologists recommend routine vaccination with HPV vaccine for girls and boys. The 9-valent HPV vaccine is recommended by the Advisory Committee on Immunization Practices and was licensed by the U.S. Food and Drug Administration in December 2014 for girls and boys aged 11-12 years.

[Current problems and recent advances in the molecular diagnosis of genital human papillomavirus infections]. / Genital insan papillomavirus enfeksiyonlarinin moleküler tanisinda karsilasilan sorunlar ve yeni gelismeler.

It was proven in the early 1980s that cervical cancer (CC) biopsy specimens and CC cell lines contain human papillomavirus (HPV) DNA sequences. In subsequent years, researchers discovered that the E6 and E7 genes of HPV are expressed in CC tissues and these oncoproteins interact with cellular proteins, including pRb and p53. Establishment of the relationship between HPV infections and CC led to increasing interest on this topic. Comprehensive epidemiological studies determined that specific types of HPV are major risk factors for CC. These HPV types, called high-risk or oncogenic types, are associated with other anogenital cancers and a subset of head and neck cancers. A number of commercial and in-house diagnostic techniques, each of which has a different approach and methodology, have been developed to diagnose HPV infections. HPV testing based on the detection of viral DNA has become an important part of CC screening programs. These screening-typing methods and combined approaches, which are used to diagnose and follow-up (management) HPV infections, have advantages and disadvantages. The choice of method is complicated by several factors and challenges that arise owing to the nature of the virus and the assay methodology. For example, a number of different HPV types can cause genital infections, multiple sequence variations are often observed even in the same HPV genotype, the detection sensitivity of the available methods is variable depending on the HPV genotypes and the viral DNA copy number in the samples examined. The capability for the detection of multiple infections and the ability to perform genotyping differ between the methods. The aim of this review is to summarize the methods used for the diagnosis and follow-up of HPV infections, and to share the current informations that may be helpfull for the choice of appropriate method. For this purpose, molecular-based HPV tests that were used in the past and their development processes were described briefly, then currently accepted and widely used methods for diagnosis, screening, and typing were discussed in detail, along with their advantages and disadvantages.

[Molecular classification of urogenital cancers]. / Az urogenitális daganatok molekuláris klasszifikációja.

The molecular genetic dogma is valid that the histological variants of a given cancer represent genetic variants. Basis of this subclassification is known in clear cell renal cancer but still a mistery in prostate or bladder cancers. Meanwhile another genetic dogma developed recently that a given histological variant of a cancer can further be subdivided based on molecular characteristics. Best examples are clear cell renal cancer, adenocarcinoma of the prostate or transitional cell carcinoma of the bladder. This new knowledge helps in the differential diagnostics of cancer, and in determining prognosis, but also provides an opportunity to better tailor existing therapies even to consider novel target agents. Discovery of the molecular subtypes of cancers (such as leukemia or lung adenocarcinoma) contributed significantly to the extension of the progression-free or overall survival of cancer patients, and it is expected that it could lead to similar effects in case of urogenital cancers.

The biology of human papillomaviruses.

Human papillomaviruses (HPVs) are small, double-stranded DNA viruses that cause lesions in cutaneous and mucosal tissue and are responsible for carcinomas of the cervix, vagina, vulva and penis. HPVs sort into 5 genera with a total of approximately 150 species that have been sequenced. Its genome is comprised of an early (E) region encoding the viral regulatory proteins, a late (L) region encoding the viral structural proteins and a noncoding region that is essential to the viral life cycle. For infection to occur, the virus must access the basal epidermal layer where, following endocytosis and viral capsid disassembly, the L2 protein mediates viral genome transfer to the nuclei of mitotic keratinocytes. The viral genome is maintained in episomal form during the normal life cycle and replicates in synchrony with the host cell DNA under the mediation of E1, E2, E4 and E5 viral proteins. In most high-grade cervical neoplasms, however, the viral DNA is integrated into the host genome through the disruption of the E2 open reading frame. The oncoproteins E6 and E7, which were previously suppressed by E2, are then free to inhibit the Rb and p53 tumor suppressor pathways. The viral life cycle concludes with the packaging of the viral genome and virus release, which entails the E2-mediated recruitment of L2 to regions of replication, the expression of L1 and the assembly of the icosahedral capsid in the nucleus. Overall, the complex biology of HPV continues to be an important area of research with substantial implications for public health.

Human papillomavirus genomics: past, present and future.

Human papillomaviruses (HPV) are a group of divergent DNA viruses, of which a select few evolutionarily related HPVs have emerged to be highly oncogenic and of significant medical importance. Essentially all cases of cervical cancer, as well as a subset of other anogenital and oral cancers are caused by this limited set of HPV types. At present, over 150 HPV types have been identified and may be classified into genera, species and types based upon comparison of the viral genome. Established nucleotide phylogenies sort the highly pathogenic HPV types to the genus Alphapapillomavirus (α-PV). A species group includes viral types with 60-70% genomic nucleotide similarity that share a most-recent common ancestor; for example the species group's alpha-9 (HPV16-related) and alpha-7 (HPV18-related), contain the majority of known oncogenic HPV types. Genomes from the same HPV type with 1-10% nucleotide differences designate HPV variant lineages. The established nucleotide variations observed in extant HPV genomes have been fixed through evolutionary processes prior to human population expansion and global dissemination. To characterize viral types and variants associated with pathology for clinical applications (e.g. screening), molecular epidemiological studies have proven essential for identifying links between HPV natural history and carcinogenicity. This chapter presents a historical account of HPV genomics in the context of major discoveries and advances over the past 2 thousand years.