Role Of High-risk Human Papillomavirus Research Articles

HPV18 L1 and long control region sequences variation and E6/E7 differential expression in nasopharyngeal and cervical cancers: a comparative study

BackgroundThe role of high-risk human papillomaviruses (hr-HPVs) in cervical cancer (CC) pathogenesis has long been established. Knowledge about the involvement of hr-HPVs in the etiology of nasopharyngeal cancers (NPC) was not well appreciated until the early 2000s when a clear link began to emerge. However, it is not clear whether HPV oncogenesis in the different epithelial cancers is associated with L1 gene and long-control region (LCR) sequences variation. This study aimed to investigate the HPV18 L1 gene and LCR sequences variation in cervical and nasopharyngeal biopsies, and assessed E6 and E7 genes expression level in both cancers.MethodFour-hundred and three (403) formalin-fixed paraffin-embedded tissues originating from nasopharyngeal (NPC) (279) and cervical (CC) (124) sites were collected from a pathology laboratory, Pathologist Without Borders, Accra, Ghana. Haematoxylin and eosin staining was carried out to confirm the presence of cancer on prepared biopsy sections. DNA was extracted from the confirmed cancer biopsies, followed by PCR using MY09/GP5+ /6+ primers to detect the presence of HPV and specific primers for the amplification of L1 gene and LCR. Sanger sequencing was carried out to determine HPV genotypes, and L1 and LCR sequences variant of HPV18s in CC and NPC biopsies. The HPV18 E6/E7 mRNA expression pattern in both cancers was determined using RT-qPCR.ResultsMost of the NPC (45%) and CC (55%) biopsies were HPV18 positive. Comparison of HPV18 L1 sequences obtained from cervical and nasopharyngeal cancer tissues, the L1 sequences from the NPC were highly dissimilar with a 59–100% variation among themselves, and in relation to the reference strains. However, the L1 sequences from the CC were more similar with a 91.0–100% variation among the amplified sequences. Also, the LCR sequences from CC were quite different relative to that of NPC. Results for the differential expression of E6/E7 in the two cancers showed a higher fold change in E6 expression in the CC tissues than the NPC tissues while a reverse expression pattern was found for E7 gene.ConclusionThe current study reports for the first-time variations in HPV18 L1 and LCR sequences, and differential expression of E6/E7 genes in NPC compared to CC, suggesting a possible adaptation mechanism of the virus at different cancer sites.

Role of Human Papilloma Virus 16/18 In Laryngeal Carcinoma with Correlation to the Expression of Cyclin D1, p53, p16 and EGFR.

To investigate the role of Human Papilloma Virus (HPV) (16/18) in relation to the molecular genetic mechanisms of Cyclin D1, p53, p16, and Epidermal growth factor receptor (EGFR) in Laryngeal Squamous Cell Carcinoma (LSSC). A cross-sectional study of 88 (Formalin-fixed Paraffin Embedded) FFPE laryngeal biopsies were done at Basic Medical Sciences Institute, Jinnah Postgraduate Centre, Karachi from 2010 to 2019 with the application of Polymerase chain reaction (PCR) for HPV 16/18and Immuno-histochemical staining for molecular genetic expression of proteins, Cyclin D1, p53, p16, and EGFR. Out of 88 cases of Laryngeal Squamous Cell Carcinoma (LSSC) there was female preponderance. Mean age of the participants was found as 50.7±12.8 years. High risk HPV 16/18 was positive in 28 cases (31.8%), largely related to Grade-II and Grade-III. Immunohistochemically, Cyclin D1 (87.5%) appeared as the most important driver mutation followed by p16 (86.4%), EGFR (65.9%), and, p53 was positive in (61.4%) of cases. The role of high-risk HPV 16/18 is concurred in the present study strongly in correlation to p16 as a surrogate marker. Moreover, the other driver mutations of Cyclin D1, p53, and EGFR are also implicated as cumulative molecular events in tumor progression as mostly seen in higher Grades.

Ficus carica Latex Modulates Immunity-Linked Gene Expression in Human Papillomavirus Positive Cervical Cancer Cell Lines: Evidence from RNA Seq Transcriptome Analysis.

Cervical carcinogenesis is the leading cause of cancer-related deaths in women, and the role of high-risk human papillomavirus (HR-HPV) as a possible risk factor in the development of this cancer is well recognized. Despite the availability of multi-therapeutic approaches, there is still major concern regarding the prevention of metastatic dissemination and excessive tissue injuries. Therefore, it is imperative to develop a safer and more efficient treatment modality. Ficus carica, a natural plant, has shown potential therapeutic properties through its fruit latex when applied to HPV-positive cervical cancer cell lines. However, the mechanisms of action of Ficus carica (fig) latex are not well understood. This study aims to provide a deeper insight into the biological activities of fig latex on human cervical cancer cell lines expressing high-risk HPV types 16 and 18. The data obtained from this study reveal that fig latex influences the expression of genes involved in "Class I MHC-mediated antigen presentation" as well as "Antigen processing: Ubiquitination and Proteasome degradation". These genes play a crucial role in host immune surveillance and the resolution of infection. Notably, Western blot analysis corroborated these findings, demonstrating an increase in the expression of MHC class I in HeLa cells after fig latex treatment. Findings from this study suggest that fig latex may enhance T cell responses against oncogenic HPV, which could be beneficial for the clearance of early-stage cancer.

The features of high-risk human papillomavirus infection in different female genital sites and impacts on HPV-based cervical cancer screening

BackgroundThe causal role of high-risk Human papillomavirus (HR-HPV) in the pathogenesis of anogenital cancers is well established. In contrast, information on HR-HPV distribution of continuous anatomic sites within the female genital tract is limited, and the impact of sample type on the clinical performance in HPV-based cervical cancer screening warrants investigation.MethodsA total of 2,646 Chinese women were enrolled in the study from May 2006 to April 2007. We analyzed the infection features by infection status and pathological diagnoses of 489 women with complete HR-HPV type and viral load data on the cervix, upper vagina, lower vagina, and perineum samples. Additionally, we assessed the clinical performance for detecting high-grade cervical intraepithelial neoplasia of grade two or worse (≥ CIN2) among these four types of samples.ResultsHR-HPV positivity rate was lower in the cervix (51.53%) and perineum (55.83%), higher in the upper (65.64%) and lower vagina (64.42%), and increased with the severity of cervical histological lesions (all P<0.001). Single infection was more dominant than multiple infections at each anatomic site of the female genital tract. The proportion of single HR-HPV infection decreased successively from the cervix (67.05%) to the perineum (50.00%) (Ptrend=0.019) in cervical intraepithelial neoplasia grade 1 (CIN1) and was higher in samples of the cervix (85.11%) and perineum (72.34%) in ≥ CIN2. In addition, the highest viral load was observed in the cervix compared to the other three sites. The overall agreement of the cervical and perineum samples was 79.35% and increased continuously from normal (76.55%) to ≥ CIN2 (91.49%). As for the detection of ≥ CIN2, the sensitivity was 100.00%, 97.87%, 95.74%, and 91.49% for the cervix, upper vagina, lower vagina, and perineum samples, respectively.ConclusionsSingle HR-HPV infection predominated throughout the female genital tract, but the viral load was lower compared to multiple HR-HPV infections. Despite the decreasing viral load from cervix to perineum, the clinical performance for detecting ≥ CIN2 of the perineum sample was comparable to that of the cervix.

High-Risk Human Papillomavirus Infection in Lung Cancer: Mechanisms and Perspectives.

Lung cancer is a very prevalent and heterogeneous group of malignancies, and most of them are etiologically associated with tobacco smoking. However, viral infections have been detected in lung carcinomas, with high-risk human papillomaviruses (HR-HPVs) being among them. The role of HR-HPVs in lung cancer has been considered to be controversial. This issue is due to the highly variable presence of this virus in lung carcinomas worldwide, and the low viral load frequently that is detected. In this review, we address the epidemiological and mechanistic findings regarding the role of HR-HPVs in lung cancer. Some mechanisms of HR-HPV-mediated lung carcinogenesis have been proposed, including (i) HPV works as an independent carcinogen in non-smoker subjects; (ii) HPV cooperates with carcinogenic compounds present in tobacco smoke; (iii) HPV promotes initial alterations being after cleared by the immune system through a "hit and run" mechanism. Additional research is warranted to clarify the role of HPV in lung cancer.

Role of High-Risk HPV Testing in Papanicolaou Tests With Atypical Glandular Cells With and Without Concurrent Squamous Cell Abnormalities.

Data on Papanicolaou (Pap) tests with atypical glandular cells (AGCs) with concurrent squamous cell abnormalities (AGC + Sq) are limited. We evaluated histologic outcomes and the role of high-risk human papillomavirus (HR-HPV) testing in this setting compared with AGCs without concurrent squamous cell abnormalities (AGC-alone). This study used a retrospective cohort of patients with Pap test diagnoses of AGC + Sq and AGC-alone between October 2013 and August 2021. We included 287 Pap tests from 278 patients. The HR-HPV test was positive in 55% of AGC + Sq cases and 14% of AGC-alone cases (P < .0001). Most AGC + Sq cases displayed squamous lesions (41.5%) or were benign (41.5%) on histology, whereas AGC-alone cases were predominantly benign (72%) or extracervical neoplasms (18%). AGC + Sq cases showed higher rates of significant histologic lesions (P = .0001), which were associated with positive HR-HPV status (P = .0012). In AGC-alone cases, HR-HPV status was associated with significant histology only in patients 50 years of age or younger. In both groups, 20% or more of HR-HPV-negative patients harbored significant lesions. AGC + Sq represents a distinct group of patients. HR-HPV testing and patient age provide useful information in the evaluation of AGC, but triage based on HR-HPV testing is not recommended because of the potential for missing significant lesions.

Expression of miR-34a and miR-15b during the progression of cervical cancer in a murine model expressing the HPV16 E7 oncoprotein.

The high-risk human papillomavirus (HR-HPV) E7 oncoprotein appears to be a major determinant for cell immortalization and transformation altering critical processes such as cell proliferation, apoptosis, and immune response. This oncoprotein plays an essential role in cervical carcinogenesis, but other cofactors such as long-term use of hormonal contraceptives are necessary to modulate the risk of cervical cancer (CC). The role of HR-HPVs in the alteration of microRNA (miRNA) levels in persistent viral infections currently remains unclear. The aim of this study was to evaluate the miR-34a and miR-15b expression levels in the murine HPV16K14E7 (K14E7) transgenic model after chronic estrogen (E2) treatment and their involvement in CC. Interestingly, results showed that, although miR-34a expression is elevated by the HPVE7 oncogene, this expression was downregulated in the presence of both the E7 oncoprotein and chronic E2 in cervical carcinoma. On the other hand, miR-15b expression was upregulated along cervical carcinogenesis mainly by the effect of E2. These different changes in the expression levels of miR-34a and miR-15b along cervical carcinogenesis conduced to low apoptosis levels, high cell proliferation and finally, to cancerous cervical tissue development. In this work, we also determined the relative mRNA expression of Cyclin E2 (Ccne2), Cyclin A2 (Ccna2), and B cell lymphoma 2 (Bcl-2) (target genes of miR-34a and miR-15b); Sirtuin 1 (Sirt1), Cmyc, and Bax (miR-34a target genes); and p21/WAF1 (mir15b target gene) and the H-ras oncogene. Given the modifications in the expression levels of miR-34a and miR-15b during the development of cervical cancer, it will be useful to carry out further investigation to confirm them as molecular biomarkers of cancer.

Relation of Human Papilloma Virus Infection with Pre Malignant and Malignant Endometrial Lesions

Endometrial carcinoma is the second most common gynecologic cancer worldwide. Hyperplasia is aprecursor to endometrioid adenocarcinoma. There are few studies on the association of HPV with endometrialadenocarcinoma.Aim of the Study: To determine the relation of HPV with premalignant and malignant endometrial lesions.Patients and Method: This study achieved on a total number of 90 patients with histopathologicalexamination revealing endometrial hyperplasia in 30 patient, endometrial carcinoma in 30 patient in additionto 30 cases who underwent hystrectomy, for all patients detection of HR-HPV done by RT-PCR.Results: The HR-HPV positivity was recorded in 23 patients. For the studied cases with endometrialcarcinoma, endometrial hyperplasia and controls the positivity rates were about (16.7%), (36.7%) and(23.3%) respectively. Highest rate of HR-HPV positivity for the studied patients was found in the age group(45-49). Highest rate of HR-HPV positivity in cases with endometrial carcinoma was reported in older agegroups [(45-49) and (50-54)], compared to endometrial hyperplasia and controls [(40-44) and (45-49)]. TheHR-HPV positivity was most frequently observed in cases with well-differentiated (22.2%). Higher HRHPV positivity rate was reported in the hyperplasia without atypia.Conclusion: No role of HR-HPV in the pathogenesis of endometrial carcinoma.

Assessment of Human Papillomavirus Infection and Risk Factors in Egyptian Women With Breast Cancer.

Numerous risk factors for breast cancer (BC) have been identified. High-risk human papilloma virus (HR-HPV) is the etiological agent of cervical cancer and in some cases of head and neck cancer, specifically oropharyngeal cancer, but the role of HR-HPV in evoking neoplasia in BC is still unclear. In this study, all women above the age of 18 visiting the oncology clinic at Al-Azhar university hospital and Ain Shams specialized hospital between the period of February 2017 and March 2018 were invited to participate. We determined the prevalence of HR-HPV genotypes 16, 18, and 31 in breast tissue samples from 72 women with treatment-naïve BC and 15 women with benign breast lesions (BBL) by quantitative real-time PCR (qRT-PCR) and primer sets targeting the E6 and E7 regions. High-risk human papilloma virus DNA was detected in 16 of 72 (22.2%) BC cases (viral load range = 0.3-237.8 copies/uL) and 0 of 15 women with BBL. High-risk human papilloma virus was detected in 14 of 16 (87.5%), 2 of 16 (12.5%), and 0 of 16 (0%) for genotypes 16, 18, and 31, respectively. Forty-three age-matched healthy Egyptian women were enrolled as controls for assessment of local risk factors that can be used to initiate a strategy of BC prevention in Egypt. Assessment of the risk factors demonstrated that low education level, passive smoking, lack of physical activity, family history of cancer, and use of oral contraception were significant risk factors for BC. In conclusion, our results lead us to postulate that HR-HPV infection may be implicated in the development of some types of BC in Egyptian women. In addition, identification of local risk factors can support practical prevention strategies for BC in Egypt.

Follow-up Findings in Postconservative Treatment Surveillance for Women With Cervical Adenocarcinoma In Situ

The risks of adenocarcinoma in situ (AIS) recurrence or progression after conservative treatment are uncertain. The aim of this study was to examine the role of high-risk human papillomavirus (hrHPV) and cytology in the posttreatment surveillance of AIS patients. Follow-up results of hrHPV status, cytology results, and clinicopathological features of 207 patients were retrospectively analyzed, in whom AIS was initially treated by loop electrosurgical excision procedure (LEEP)/cone biopsy between September 2009 and June 2018. Among 207 patients diagnosed AIS on LEEP/cone biopsy, 30.9% (64/207) had positive margins. Persistent/recurrent AIS rate was substantially higher in the patients with positive margins than in those with negative margins (47.2% vs 9.3%, p < .001). Of 74 patients with hrHPV surveillance, 17 (17/74, 23.0%) were found to have positive hrHPV and 4 (4/17, 23.5%) had the persistent/recurrent AIS regardless of margin status. On the contrast, no AIS were found in negative surveillant hrHPV patients (23.5% vs 0%, p < .001). Lastly, 27.8% patients (22/79) were reported atypical glandular cells on surveillant cytology, and 9 persistent/recurrent AIS cases were further identified on second biopsy or hysterectomy with a positive detection rate of 40.9%. In this study, we concluded the positive margin on LEEP/cone biopsy in AIS patients was associated with a significantly greater risk of disease persistence or recurrence. The posttreatment surveillance by cytology and adjunct hrHPV would be an ideal strategy in predicting AIS persistence and recurrence, which will warrant further treatments.

Association of Human Papilloma Virus and Epstein-Barr Virus with Ovarian Cancer in Shiraz, Southwestern Iran.

Background & Objective:Ovarian cancer is one of the most common cancers amongst women. The association of Human papillomavirus (HPV) and Epstein-Barr virus (EBV) with ovarian cancer is inconclusive; therefore, the aims of this study were to evaluate the frequency of HPV and EBV in malignant, borderline, benign and normal ovarian tissues.Methods:In this case-control study, 205 Paraffin-embedded ovarian tissue specimens including 68 malignant, 27 borderline, 65 benign, and 45 normal tissues were included from December 2014 to January 2018 and subjected to DNA extraction. The β-globin gene was amplified using PCR to confirm the quality of the extracted DNA. The genomes of HPV (genotypes 16 and 18) and EBV were identified, using specific primers by PCR.Results:The mean age of participants was 43.42 ± 15.4 years. The frequency of HPV was statistically significant between malignant versus benign (P=0.02) and control groups (P=0.002), but not with borderline tumor group (P=0.78). Amongst HPV infected samples, 1 (4.5%) and 14 (63.6%) samples were infected with types 16 and 18, respectively. Also 4 (18.2 %) samples were infected with both genotypes. Eleven samples including 7(10.3%) malignant, 1 (3.7%) borderline, 3 (4.6%) benign and none (0%) of normal control groups were infected with EBV, which was statistically different between malignant and the normal control group (P=0.03).Conclusion:The results of our study showed the possible role of high risk HPVs as well as EBV in pathogenesis of ovarian cancer, and further studies are recommended to confirm these findings.

Prevalence of high-risk human papillomavirus in primary squamous cell carcinoma of urinary bladder

Studies have demonstrated an etiologic role of high-risk human papillomavirus (HR-HPV) infection for epithelial malignancies, including most cervical carcinomas, anogenital cancers, and carcinomas of the head and neck; however, a causative role of HPV infection for bladder cancer is controversial. The purpose of this study was to investigate the prevalence of HR-HPV in primary bladder carcinoma to determine the association between HPV infection and the squamous cell component of urothelial carcinoma of the bladder. Furthermore, we evaluated the utility of p16 overexpression as a surrogate marker for HPV infection in these cancers and the correlation of this with tumor stage. Our study included 33 cases of squamous cell carcinoma (SCC) of the urinary bladder. Tumors deemed primary from the bladder were selected and either showed predominant (>50 %) or pure squamous differentiation. Immunohistochemical study for p16 and HR-HPV by RNA in situ hybridization (ISH) was performed in all cases. p16 expression was detected in 7 cases (28 %, 7/25) of urothelial carcinoma with squamous differentiation and not detected in any of the 8 cases (0%, 0/8) of pure SCC. Detection of HR-HPV by ISH was negative in all 33 cases (0%, 0/33). There was no association between p16 overexpression and the presence of HPV infection in squamous cell carcinomas of the bladder. p16 should not be used as a surrogate marker for evidence of HPV infection. Our study suggests that HPV infection does not play an etiologic role in the development of bladder cancer and should not be used as a diagnostic adjunct for these cases.

Abstract B07: High-risk human papillomavirus association with oropharyngeal squamous cell carcinoma in Taiwan

Abstract Introduction: Taiwan has a high rate of oropharyngeal squamous cell carcinoma (OPSCC). The etiologic factors are primarily tobacco and alcohol abuse. High-risk human papillomaviruses (hrHPV) have been reported in oral cancers in Taiwan, but their role in oropharyngeal cancer has not been studied. We investigated the possible role of hrHPV in OPSCC Taiwanese patients. Materials and Methods: We identified 546 OPSCC tumors from patients undergoing standard care and informed consent, between 1998 and 2016, at the Chang Gung Memorial Hospital (CGMH) in Taiwan. Formalin-fixed, paraffin-embedded (FFPE) tissue sections from 504 patients were screened by p16 immunostaining, a surrogate marker for active HPV (Ventana antibody, Cat. No. 725-4713, prediluted), and scored for intensity and proportion of positive tumor cells according to the 2018 College of American Pathologists recommendations. Genomic DNA was extracted from FFPE sections (AllPrep Kit, Qiagen) and HPV was detected and genotyped by Multiplex PCR-Mass Array (PCR-MA) analysis designed to detect 15 high-risk, 1 intermediate-risk, and 2 low-risk HPV types. Results: Of the 504 OPSCC tumors tested for p16, 104 (20.6%) were positive, 380 (75.4%) negative, and 20 (4.0%) could not be scored. Spearman nonparametric correlation analysis demonstrated a linear increase in p16 positivity with time from 1998 to 2015 in this Taiwanese population (r= 0.6320, p= 0.003; R2= 0.4901, p= 0.0012). To date, HPV genotyping in 179 Taiwan tumors showed that 38 (21.2%) were hrHPV positive, 120 (67.0%) negative, and 21 (11.7%) had insufficient DNA. Of the 38 HPV-positive tumors, HPV16 alone was found in 31 (81.6%), HPV39 and HPV59 were each found once in separate tumors, and several tumors had two HPV types present: HPV16 and HPV18 were present together in 2 tumors, and each of the following pairs were found in one tumor each: HPV16 with HPV35, HPV16 with HPV59, and HPV16 with HPV6. Of the tumors tested by both p16 and PCR-MA, there was 97% concordance between the results (130/134). Conclusion: Our preliminary findings indicate that the proportion of hrHPV positive OPSCC tumors in this Taiwanese population is increasing over the period from 1998 to 2015 in Taiwan. The concordance of p16 and HPV DNA is very high (p&amp;lt;0.0001), demonstrating that the hrHPV in the tumors is transcriptionally active and likely is an etiologic factor in the majority of OPSCC patients treated at CGMH in the past 18 years. This is consistent with the increasing role of hrHPV in OPSCC in Western countries and may reflect changing socioeconomic trends in Taiwan. Citation Format: Guadalupe Lorenzatti Hiles, Chun-I Wang, Lisa M. Pinatti, Christine M. Goudsmit, Lila Peters, Hannah L. Briggs, Trey B. Thomas, Mohammed Charara, Reem A. Khatib, Macy A. Afsari, Anna C. Morris, Nadine Jawad, Devraj Som, Kai-Ping Chang, Thomas E. Carey, Heather M. Walline. High-risk human papillomavirus association with oropharyngeal squamous cell carcinoma in Taiwan [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr B07.

Human Papillomaviruses and Epstein-Barr Virus Interactions in Colorectal Cancer: A Brief Review.

Human papillomaviruses (HPVs) and the Epstein–Barr virus (EBV) are the most common oncoviruses, contributing to approximately 10%–15% of all malignancies. Oncoproteins of high-risk HPVs (E5 and E6/E7), as well as EBV (LMP1, LMP2A and EBNA1), play a principal role in the onset and progression of several human carcinomas, including head and neck, cervical and colorectal. Oncoproteins of high-risk HPVs and EBV can cooperate to initiate and/or enhance epithelial-mesenchymal transition (EMT) events, which represents one of the hallmarks of cancer progression and metastasis. Although the role of these oncoviruses in several cancers is well established, their role in the pathogenesis of colorectal cancer is still nascent. This review presents an overview of the most recent advances related to the presence and role of high-risk HPVs and EBV in colorectal cancer, with an emphasis on their cooperation in colorectal carcinogenesis.

Frequency of CD4+ regulatory T cells, CD8+ T cells, and human papilloma virus infection in Egyptian Women with breast cancer.

Several subsets of regulatory CD4+ T cells (CD4+ Tregs) have been described in peripheral blood and tumor microenvironment of breast cancer (BC) patients and may play a role in the progression of BC. High-risk human papilloma virus (HR-HPV) has a causal role in cervical, head, and neck tumors but the role of HR-HPV in evoking neoplasia in BC is still unclear. In this study we assessed the prevalence of CD4+CD25+ FOXP3+ regulatory T cells (CD4+Tregs) and CD3+ CD8+ T cells by flow cytometry in peripheral blood from a total of 55 Egyptian women, including 20 treatment-naïve BC, 15 with breast benign lesions (BBL), and 20 healthy volunteers (HV). HR-HPV genotypes type 16, 18, and 31 were investigated in breast tissue from all BC and BBL patients using Real-Time PCR. HR-HPV was detected in 4/20 (20%) and 0/15 (0%) BC and BBL patients respectively. The frequency of CD4+ Tregs was significantly higher in BC compared to BBL and HV, (P < 0.001). In addition, we observed a significantly higher frequency of CD3+ CD8+ T cells in peripheral blood of patients with late stage III BC compared to early stage I and II BC (P = 0.011). However, there was no significant association between the ratio of CD8+ T cell to CD4+ Tregs frequencies and the expression of Estrogen Receptor (ER), Progesterone Receptor (PR), and Human Epidermal Growth Factor Receptor 2 (HER2). These results lead us to postulate that the association between the frequency of CD4+ Tregs and CD8+ T cells in the peripheral blood may be a prognostic or predictive parameter in Egyptian women with BC. In addition, HR-HPV infection may be implicated in the development of some types of BC in Egyptian women.

Effect of high-risk human papillomavirus in esophageal squamous cell carcinoma in Somalian and Turkish cases.

This study aimed to investigate the role of high-risk human papillomavirus (Hr-HPV) in Somalian and Turkish patients with esophageal squamous cell carcinoma (ESCC). In the sections obtained from paraffin-embedded blocks, the results of invasive tumor, peripheral tumor dysplasia and normal mucosa were examined. Samples containing 45 and 47 ESCC, 46 and 42 dysplasia in Somalian (n=52) and Turkish (n=53) cases, respectively, were included in the study. We examined the presence of 14 types of Hr-HPV in ESCC collected from Somalia and Turkey by Aptima® Panther System. Hr-HPV types were not detected in Somalian cases. p16INK4a is positive in 5 (11.4%) tumors and 6 (13%) dysplasia. p53 is positive in 28 (62.2%) tumors and 35 (76.1%) dysplasia. HPV16-18/45 are positive only in one of the Turkish cases. p16INK4a is positive in 5 (10.6%) tumors and 4 (9.5%) dysplasia. p53 is positive in 31 (63.3%) tumors and 24 (57.1%) dysplasia. No reaction was detected in normal mucosa samples in both countries. This study is regional. Although the findings did not reflect the general population, the present study shows that the effect of HPV on carcinogenesis in Somalian and Turkish ESCC patients was not significant.

Human papillomavirus 16E6/E7 activates autophagy via Atg9B and LAMP1 in cervical cancer cells.

BackgroundsAlthough the role of high‐risk human papillomavirus (HPV) E6 and E7 in cellular malignant transformation has been elucidated， the function of both genes in cellular homeostasis is still unknown. Autophagy functions in maintenance of cellular homeostasis play a key role in the initiation and development of cancer and infectious disease.MethodsCervical cancer cell lines SiHa and CaSki were utilized in this study.ResultsWe found that HPV 16E6/E7 (16E6/E7) downregulation inhibited autophagy, and consequently suppressed cell proliferation and promoted early apoptosis. Transcriptome sequencing demonstrated that Atg9B and LAMP1 were downregulated in 16E6/E7 knockdown cells. Gene function experiments revealed that 16E6/E7 downregulation depressed Atg9B and LAMP1, and Atg9B and LAMP1 overexpression compensated, at least partially, autophagy blockage induced by 16E6/E7 knockdown. Immunoprecipitation assay showed that 16E7 interacted with Atg9B and dual‐luciferase reporter system revealed that 16E6 most likely regulated −1750 to −2000 nt in Atg9B and −1800 to −2000 nt in LAMP1 promoter region.ConclusionsOur findings verified that 16E6/E7 activated autophagy via accelerating autophagosome formation and degradation, and Atg9B and LAMP1 were involved in the process of 16E6/E7 modulating autophagy, suggesting that targeting autophagy may be a potential approach in cervical cancer therapeutics.

Clinical relevance of human papillomavirus outside of oropharynx.

The role of HPV in oropharyngeal cancer is well recognized. HPV DNA is also found in a fraction of head and neck tumors outside of oropharynx but its clinical importance is unknown. The purpose of this review is to sum up the present knowledge about the prevalence and possible impact of HPV presence in head and neck tumors in nonoropharyngeal sites. The data demonstrating prevalence of HPV presence in tumors outside of oropharynx are inconsistent. However, it can be stated that it is substantially lower than in oropharynx. Most articles report the HPV DNA presence only but very few prove also the transcriptionally active viral presence. The fraction of really HPV-induced tumors is probably very small. The majority of literature shows no impact of HPV on prognosis in nonoropharyngeal locations. Also the role of high-risk HPV in malignant transformation of lesions potentially linked to malignancy like inverted papillomas, recurrent respiratory papillomatosis or laryngeal dysplasia was up to date not demonstrated. Despite of the unknown role of HPV and lack of evidence regarding any clinical use of HPV knowledge in other than oropharyngeal tumors, further research is warranted.

Combined Transcriptome and Proteome Analysis of Immortalized Human Keratinocytes Expressing Human Papillomavirus 16 (HPV16) Oncogenes Reveals Novel Key Factors and Networks in HPV-Induced Carcinogenesis.

Although the role of high-risk human papillomaviruses (hrHPVs) as etiological agents in cancer development has been intensively studied during the last decades, there is still the necessity of understanding the impact of the HPV E6 and E7 oncogenes on host cells, ultimately leading to malignant transformation. Here, we used newly established immortalized human keratinocytes with a well-defined HPV16 E6E7 expression cassette to get a more complete and less biased overview of global changes induced by HPV16 by employing transcriptome sequencing (RNA-Seq) and stable isotope labeling by amino acids in cell culture (SILAC). This is the first study combining transcriptome and proteome data to characterize the impact of HPV oncogenes in human keratinocytes in comparison with their virus-negative counterparts. To enhance the informative value and accuracy of the RNA-Seq data, four different bioinformatic workflows were used. We identified potential novel upstream regulators (e.g., CNOT7, SPDEF, MITF, and PAX5) controlling distinct clusters of genes within the HPV-host cell network as well as distinct factors (e.g., CPPED1, LCP1, and TAGLN) with essential functions in cancer. Validated results in this study were compared to data sets from The Cancer Genome Atlas (TCGA), demonstrating that several identified factors were also differentially expressed in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and HPV-positive head and neck squamous cell carcinomas (HNSCs). This highly integrative approach allows the identification of novel HPV-induced cellular changes that are also reflected in cancer patients, providing a promising omics data set for future studies in both basic and translational research.IMPORTANCE Human papillomavirus (HPV)-associated cancers still remain a big health problem, especially in developing countries, despite the availability of prophylactic vaccines. Although HPV oncogenes have been intensively investigated for decades, a study applying recent advances in RNA-Seq and quantitative proteomic approaches to a precancerous model system with well-defined HPV oncogene expression alongside HPV-negative parental cells has been missing until now. Here, combined omics analyses reveal global changes caused by the viral oncogenes in a less biased way and allow the identification of novel factors and key cellular networks potentially promoting malignant transformation. In addition, this system also provides a basis for mechanistic research on novel key factors regulated by HPV oncogenes, especially those that are confirmed in vivo in cervical cancer as well as in head and neck cancer patient samples from TCGA data sets.

2509. High-Risk Human Papillomavirus Infection and the Risk of Cardiovascular Disease: A Cohort Study

BackgroundA study using National Health and Nutrition Examination Survey (NHANES) 2003 to 2006 demonstrated the association between high-risk (oncogenic) human papillomavirus (HPV) and an increased prevalence of the self-reported cardiovascular diseases (CVD). However, this study was limited by temporal ambiguity between HPV and CVD, because of its cross-sectional design. We investigated the longitudinal effect of HPV infection on the development of CVD events in a cohort study of Korean women free of CVD at baseline.MethodsWe conducted a cohort study of 63,411 women aged 30 or older without CVD at baseline who underwent a high-risk HPV test and were followed annually or biennially from 2011 to 2016 for new-onset CVD. CVD was ascertained through the linkage to the Health Insurance and Review Agency database. A Cox-proportional hazards regression model was used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of incident CVD.ResultsThe prevalence of high-risk HPV infection was 7.6%. During 261,598.9 person-years of follow-up, 1,122 cases of new-onset CVD were identified (incidence rate of 4.3 per 103 person-years). The age-adjusted HR (95% CI) comparing high-risk HPV-positive- to high-risk HPV-negative participants was 1.26 (1.03–1.53). After further adjustment for possible confounders, a significant association between high-risk HPV infection and incident CVD was still observed, with a corresponding HR (95% CI) of 1.25 (1.03–1.53). This association was stronger in obese (BMI ≥25 kg/m2) compared with non-obese individuals (BMI <25 kg/m2). Otherwise, the associations between high-risk HPV infection and incident CVD did not differ by various clinically relevant subgroups.ConclusionIn this large cohort of apparently healthy young and middle-aged women, high-risk HPV infection was significantly associated with an increased risk of developing CVD, indicating a possible role for high-risk HPV in the pathogenesis of CVD.Disclosures All authors: No reported disclosures.