Human Papillomavirus-related Cancer Research Articles

The HPV viral regulatory mechanism of TLRs and the related treatments for HPV-associated cancers

Infection with human papillomavirus (HPV) typically leads to cervical cancer, skin related cancers and many other tumors. HPV is mainly responsible for evading immune tumor monitoring in HPV related cancers. Toll like receptors (TLRs) are particular pattern recognition molecules. When the body is facing immune danger, it can lead to innate and direct adaptive immunity. TLR plays an important role in initiating antiviral immune responses. HPV can affect the expression level of TLR and interfere with TLR related signaling pathways, resulting in sustained viral infection and even carcinogenesis. This paper introduces the HPV virus and HPV related cancers. We discussed the present comprehension of TLR, its expression and signaling, as well as its role in HPV infection. We also provided a detailed introduction to immunotherapy methods for HPV related diseases based on TLR agonists. This will provide insights into methods that support the therapeutic method of HPV related conditions with TLR agonists

Follow-up for human papillomavirus-related oropharynx cancer concentrated on unequal symptom change (FOCUS): Prospective patient-reported outcome collection.

Post-treatment surveillance recommendations for oropharyngeal cancer do not vary with p16 status despite the differences in outcomes. The optimal algorithm personalizing follow-up for these patients remains undefined. Here, we evaluate the feasibility and utility of incorporating electronic patient-reported outcomes (ePROs) and circulating tumor DNA (ctDNA) into routine surveillance for patients treated for p16+ oropharynx cancer. A prospective registry was developed in which ePROs and ctDNA were incorporated into routine surveillance among patients with oropharynx cancer. ePROs were emailed monthly for 1 year and blood HPV ctDNA testing was performed every 3-6 months. The primary objective was to assess patient compliance with ePRO-based surveillance with adequate compliance defined as ≥85% of patients completing monthly ePROs. Sensitivity, specificity, and positive/negative predictive values to detect recurrence were calculated for ePROs, HPV ctDNA, or the combination. Of 122 patients who initially expressed interest, 76 completed the electronic consent process and 44/76 (58%) were compliant with monthly surveys over 1 year; thus adequate compliance was not achieved. Technical difficulties associated with ePRO receipt through email largely limited participation. Provider feedback was significantly associated with heightened ePRO compliance. One hundred and six patients had ctDNA testing with a mean number of three tests per patient. Sensitivity to detect recurrence was 75% for the combination of ePROs and ctDNA. Despite lower than anticipated compliance with ePROs, our findings show promise for incorporation of HPV ctDNA into surveillance paradigms for HPV-related oropharynx cancer with suggestions of methods to optimize ePRO formats for personalized surveillance.

The indirect costs of human papillomavirus-related cancer in Central and Eastern Europe: years of life lost and productivity costs

Background Human papilloma virus (HPV) is a common cause of several types of cancer, including head and neck (oral cavity, pharynx, oropharynx, hypopharynx, nasopharynx, and larynx), cervical, vulval, vaginal, anal, and penile cancers. As HPV vaccines are available, there is potential to prevent HPV-related disease burden and related costs. Method A model was developed for nine Central Eastern European (CEE) countries (Bulgaria, Croatia, Czechia, Hungary, Poland, Romania, Serbia, Slovakia, Slovenia). This model considered cancer patients who died from 11 HPV-related cancers (oropharynx, oral cavity, nasopharynx, hypopharynx, pharynx, anal, larynx, vulval, vaginal, cervical, and penile) in 2019. Due to data limitations, Bulgaria only included four cancer types. The model estimated the number of HPV-related deaths and years of life lost (YLL) based on published HPV-attributable fractions. YLL was adjusted with labor force participation, retirement age and then multiplied by mean annual earnings, discounted at a 3% annual rate to calculate the present value of future lost productivity (PVFLP). Results In 2019, there were 6,832 deaths attributable to HPV cancers resulting in 107,846 YLL in the nine CEE countries. PVFLP related to HPV cancers was estimated to be €46 M in Romania, €37 M in Poland, €19 M in Hungary, €15 M in Czechia, €12 M in Croatia, €10 M in Serbia, €9 M in Slovakia, €7 M in Bulgaria and €4 M in Slovenia. Conclusions There is a high disease burden of HPV-related cancer-related deaths in the CEE region, with a large economic impact to society due to substantial productivity losses. It is critical to implement and reinforce public health measures with the aim to reduce the incidence of HPV-related diseases, and the subsequent premature cancer deaths. Improving HPV screening and increasing vaccination programs, in both male and female populations, could help reduce this burden.

Abstract 7382: Artificial intelligence derived features of collagen architecture identify high risk HPV associated oropharyngeal squamous cell carcinoma patients

Abstract Introduction: Human papilloma virus (HPV) induced oropharyngeal squamous cell carcinoma (OPSCC) is a common subtype of head and neck carcinoma. Dysregulation of the extracellular matrix (ECM), an important part of the tumor microenvironment (TME), is shown in HPV related cancers. We studied collagen fibers (CF), the amplest component of the ECM, and evaluated whether their characteristics within the TME can offer a prognostic value in OPSCC. Methods: Whole slide images (WSIs) of OPSCC patients were obtained from Washington University (WU, n=107), Houston Veterans Administration Hospital (HV, n=94), Cleveland Clinic (CC, n=336), John Hopkins University (JH, n=121) and Vanderbilt Medical Centre (VM, n=158). For the identified CF in tumor-stroma regions of WSIs, the extracted CF features included: CF fragmentation measure, CF bundling percentage, CF rigidity measure, CF anisotropy index, and CF density index. For survival analysis using overall survival (OS) and Disease-Free Survival (DFS) as endpoints, the median risk score in the training set (WU) was applied for risk stratification in the validation sets (HV, CC, JH, VM) by means of a Least Absolute Shrinkage and Selection Operator-Cox regression model. Multivariable Cox Proportional Hazards Regression was done for both OS and DFS. Results: The patients defined as “high risk” had worse OS than those identified as “low risk” (HV(p=0.03), CC(p=0.03), JH(p=0.02), VM(p=0.04)). Multivariable analysis showed that CF features were prognostic independent of T/N stages, age, sex, and smoking status with HR=1.99 (95% CI=1.46-2.72, p=0.00001) for OS and HR=1.73 (95% CI=1.21-247, p=0.002) for DFS (Table 1). Table 1: Multivariable Survival Analysis for OS and DFS, HR=Hazard Ratio, CI=Confidence Interval Variable Overall Survival Disease Free Survival HR (95% CI) P value HR (95% CI) P value Age (<65 years vs. >=65 years) 0.99 (0.93-1.06) 0.78444 0.96 (0.82-1.12) 0.62864 Sex (Female vs. Male) 0.56 (0.29-1.10) 0.09042 0.50 (0.22-1.13) 0.09385 Smoking status (Yes vs. No) 1.85 (1.31-2.62) 0.00051 1.03 (0.72-1.47) 0.86871 T-stage (T3/4 vs T1/2) 1.86 (1.38-2.50) 0.00004 1.91 (1.36-2.69) 0.00018 N-stage (N+ vs N0) 1.76 (1.31-2.37) 0.00016 2.04 (1.46-2.86) 0.00003 Collagen fiber features (High risk vs low risk) 1.99 (1.46-2.72) 0.00001 1.73 (1.21-2.47) 0.00286 Conclusion: Artificial intelligence derived features of CF architecture can help identify high vs low risk patients in HPV related OPSCC. These findings deserve further confirmation in larger prospectively collected OPSCC data sets and could impact future treatment paradigms. Citation Format: Reetoja Nag, Haojia Li, Germán Corredor, Pingfu Fu, Nabil F. Saba, Mehmet A. Bilen, Tilak Pathak, Paula Toro, Mojgan Mokhtari, Krunal Pandav, Michael Gilkey, Shlomo Koyfman, Deborah Chute, Wade L. Thorstad, Mitra Mehrad, Patricia D. Castro, Andrew G. Sikora, Rebecca D. Chernock, Jingqin Luo, Mitchell Frederick, Vlad Sandulache, David J. Adelstein, James Lewis Jr., Anant Madabhushi. Artificial intelligence derived features of collagen architecture identify high risk HPV associated oropharyngeal squamous cell carcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7382.

Uptake of human papilloma virus vaccine and its determinants among females in East Africa: a systematic review and meta-analysis

IntroductionCervical cancer is the most common malignant tumor among women. It is the main cause of death among women in sub-Saharan African countries. Particularly, the incidence and mortality rates are highest in East Africa. Even though the burden of human papilloma virus-related cervical cancer is high in East Africa, there is no conclusive evidence about the prevalence of human papilloma virus vaccine uptake and its predictors.ObjectiveTo assess the pooled prevalence of human papilloma virus vaccine uptake and its determinants in East Africa.MethodEligible articles were searched on PubMed, Embase, Scopus, Cochrane Library, Google Scholar, and Google. Those articles incorporating the outcome of interest, both analytical and descriptive study designs, and published or unpublished articles at any time were included. Keywords and Medical Subjects Heading terms or synonyms of human papilloma virus vaccine and Boolean operators were used to retrieve the articles. To assure the quality of articles, Joana Brigg’s Institute critical appraisal checklist for cross-sectional studies was used. Sensitivity analysis was conducted to assess the heterogeneity among the studies, and a random effect model was used to analyze the pooled effect size.ResultA total of 29 articles were included, and the pooled prevalence of HPV vaccine uptake in East Africa was 35% (95% CI: 26–45%). Good knowledge (OR = 1.6, 95%CI; 1.43–1.8), positive attitude (OR = 2.54, 95% CI; 2.13–3.03), ever heard about HPV vaccine (OR = 1.41, 95% CI; 1.03–1.94), mother educational status above college (OR = 1.84, 95%CI; 1.03–3.31), middle wealth index (OR = 1.33, 95%CI; 1.04–1.7), ≥ 9 family size (OR = 0.76, 95%CI; 0.68–0.98), availability of promotion (OR = 2.53, 95%CI: 1.51–4.26), availability of adequate vaccine (OR = 4.84, 95%CI; 2.9–8.08), outreach vaccination practice (OR = 1.47, 95%CI; 1.02–2.12) and family support (OR = 4.3, 95% CI; 2.98–6.21) were the significant factors for the uptake of human papilloma virus vaccine.ConclusionAs compared to the global strategic plan, the pooled prevalence of HPV vaccine uptake in east Africa was low. The uptake of the HPV vaccine was higher among adolescents than youths. Knowledge about the HPV vaccine, attitude towards the HPV vaccine, ever hearing about the HPV vaccine, residence, mother’s educational status, mother’s occupational status, wealth index, and family size were the significant determinants of HPV vaccine uptake. Therefore, we recommend focusing on awareness creation and behavioral change to expand the uptake of vaccines in East Africa.

Self-Blame Attribution: Concept Analysis and Application to HPV-Related Cancers.

The attribution of self-blame for a negative physical health outcome can lead to further deterioration of one's mental and spiritual state. Using Walker and Avant's eight-step model for concept analysis, self-blame attribution is explored following the diagnosis of a human papillomavirus-related cancer in women. Conceptual case examples provide application of the concept to patient situations. Spiritual assessment tools for nurses caring for those who evidence self-blame are provided.

Prevention of human papillomavirus-related oropharyngeal cancer

Prevention of human papillomavirus-related oropharyngeal cancer

Efficacy of Lactococcus lactis strain Plasma on clearance of anal HPV infection in men who have sex with men: A single-center, double-blinded, randomized placebo-controlled trial (CLEAR HPV study)

Background: Anal cancer is a human papillomavirus-related cancer; specifically, it is preceded by high-grade squamous intraepithelial lesions, which are less likely to regress spontaneously than low-grade intraepithelial lesions. Although most human papillomavirus (HPV) infections are thought to clear spontaneously, anal HPV infection persists, especially in people living with HIV. Preliminary results from a recent small randomized placebo-controlled trial of oral bacteriotherapy using a high dose of probiotics demonstrated clearance of anal high-risk HPV (hr-HPV) infection and lower onset of new high-grade squamous intraepithelial lesions among people living with HIV. Lactococcus lactis strain Plasma is a lactic acid bacterium directly activating plasmacytoid dendritic cells and inducing release of type I and III interferons via Toll-like receptor 9 stimulation. Based on these findings, oral bacteriotherapy with LC-plasma may contribute to clearing anal hr-HPV infection and reducing anal precancerous lesions by activating innate and acquired immune responses. This randomized placebo-controlled trial aims to investigate the efficacy and safety of LC-plasma therapy in clearing anal hr-HPV infection and reducing anal precancerous lesions among men who have sex with men with or without HIV infection. Methods: Participants with anal hr-HPV infection will be included and receive test capsules. A total of 150 patients will be included in the intervention group with follow-up, which will consist of HPV genotype test, cytology by anal pap smear, and biopsy with high-resolution anoscopy. The primary endpoint will be the clearance rate of the hr-HPV genotype infection at the anal site at 180 days. The secondary endpoints will be changes in anal epithelial neoplasia detected using high-resolution anoscopy at 180 days; change in abnormal cytology by anal pap smear at 180 days; change in hr-HPV genotype at the anal site at 180 days; change or percentage change in peripheral blood CD4 positive T-lymphocyte numbers in HIV-infected participants at 180 days; changes in quantitative hepatitis B surface antigen levels at 180 days in the HBV-infected participants; and adherence to the study drugs. Conclusion: This randomized controlled study will provide data on the efficacy and safety of LC-plasma as a treatment for anal HPV infection and grade 2 or 3 anal intraepithelial neoplasia.

Commentary on New Guidance for Human Papillomavirus-Related Cancer Screening Among Sexual and Gender Minority Populations.

Commentary on New Guidance for Human Papillomavirus-Related Cancer Screening Among Sexual and Gender Minority Populations.

Temporal Incidence and Patterns of Distant Failure for Human Papillomavirus (HPV) Related Oropharyngeal Cancer

HPV related oropharyngeal cancer (HPV-OPC) enjoys improved treatment outcomes relative to non-HPV related disease but suffers from similar rates of distant metastases (DM) following treatment. Emerging data supports radical intent therapy for oligometastatic relapsed HPV-OPC, suggesting early diagnosis of DM may be beneficial to outcome. We assess temporal patterns in distance relapse to investigate rationalization of post treatment imaging. A retrospective single center cohort study was carried out of consecutive HPV-OPC treated with radical intent (chemo)radiotherapy ((CT)RT) between 2011 and 2020. Electronic records were reviewed to identify location and timing of development of DM. Oligometastatic (OM) state was defined as </ = 5 metastasis in one system. A total of 793 HPV-OPC patients were identified with median follow-up 3.15 years (range 0.2-8.9). The median time to recurrence was 15.1 months (range: 2.6-63 months). 87% of DM occurred in the first two years after treatment. Pattern of failure by stage are shown in table 1. Indications for scans performed identifying DM alone were symptoms (66%), follow-up imaging based on previous radiological findings (15%), disease response assessment imaging (15%), and incidental findings (4%). Sites of distant metastasis were lung (64%), thoracic nodes (36.5%), bone (27%), visceral (23%), brain (4%) and skin (2%). The sites of visceral metastasis involvement included liver (92%), Adrenal (18%), kidney (18%), and spleen (9%). Treatment offered to patients with OM alone was best supportive care (46%), palliative chemotherapy (15.4%), palliative RT (23%), immunotherapy (8%), and one patient lost to follow up (8%). SBRT was not available during time period. Median survival following diagnosis was 17.5 months (range 4.4-85.4 months). Despite no routine imaging beyond initial treatment response assessment, we identify a small minority of HPV OPC patients with OM recurrence that is associated with better outcome and occasional long-term cure from aggressive therapy. The majority (69%) of DM occur in the thorax/upper abdomen of patients in the first two years post treatment. This finding supports the potential utility of regular imaging of thorax/upper abdomen during early follow.

Long-Term Results of Induction Chemotherapy Followed by 50 Gy Radiation Therapy Alone for Low-Risk HPV-Positive Oropharynx Cancer

The standard of care for non-operative management of human papillomavirus-related oropharynx cancer (HPV-OPC) consists of concurrent cisplatin chemotherapy with radiotherapy (RT) to a total dose of 70 Gy. While the oncologic outcomes of this treatment approach have been excellent, there are considerable acute and late toxicities. Here, we report the 5-year survival and toxicity outcomes of 2 prospective HPV-OPC response-adapted de-escalation trials, in which low-risk (LR) patients were treated with dose-reduced RT to 50 Gy, without concurrent chemotherapy. Patients with LR HPV-OPC and ≥50% response to induction by RECIST 1.1 treated per 2 prospective phase II trials as well as on a prospective cohort registry were included for analysis. Patients were considered LR if the following criteria were met: T1-T3, N0-N2b (AJCC 7th edition), and ≤20 pack-year smoking history. Patients were treated with induction chemo- or chemoimmunotherapy followed by RT alone to 50 Gy. In the early trial iteration, patients underwent a planned neck dissection following RT to confirm pathologic clearance of lymph nodes. Clinicodemographic characteristics were summarized using descriptive statistics. Overall survival (OS), progression-free survival (PFS), and local control (LC) were estimated using the Kaplan-Meier method. From January 2015 through March 2020, 73 patients met LR criteria, of which, 54 (74%) had ≥50% response by RECIST and were de-escalated to RT alone. The median follow-up was 58 (range 10-92) months. The median age was 58 (range 38-84) years, and 92.6% were male. 57.4% of patients never smoked, and 42.6% smoked no more than 20 pack-years. The primary site was tonsil for 53.7% and base of tongue for 46.3%. 24.1% were T1, 53.7% were T2, and 22.2% were T3. 1.9% were N0, 5.6% were N1, 11.1% were N2a, and 81.5% were N2b. The 5-year OS, PFS, and LC were 96.3% (95% CI 91.3%-100%), 96.2% (95% CI 91.2%-100%), and 98.1% (95% CI 94.6%-100%), respectively. 2 (3.7%) patients required a G-tube during RT and none at 1 year following completion of RT. Of the 30 patients with a planned neck dissection, 2 (6.7%) had residual pathologic nodal disease. With a median follow-up of 5 years, this analysis demonstrates excellent long-term local control, survival, and swallowing function among patients with low-risk HPV+ oropharynx cancer treated with induction systemic therapy followed by radiotherapy to 50 Gy without concurrent chemotherapy, including a large proportion of patients with N2b disease. Chemo-selection provides a means of identifying a favorable cohort of HPV+ oropharynx cancer patients who can safely receive RT dose de-escalation. Further work is needed to identify this population by other means, including radiographic and genomic factors.

Abstract PO-037: Biomarkers for early diagnosis of human papillomavirus-related oropharyngeal cancer

Abstract PO-037: Biomarkers for early diagnosis of human papillomavirus-related oropharyngeal cancer

Immunoinformatics studies of heat shock proteins 27 and 70: Development of potent therapeutic vaccine constructs against human papillomavirus-related cancers

Heat shock proteins (HSPs) improve cross-presentation of linked tumor antigens, thus they can be exploited in therapeutic vaccine design. Herein, in silico analyses of different vaccine constructs were performed based on human papillomavirus (HPV)-16 E7 protein linked to Homo sapiens/Mus musculus Hsp27 or Hsp70 in multiepitope and whole sequence forms. Then, computational comparison between different orientations of Hsp/E7 was carried out in both forms. Finally, molecular docking was performed between the designed constructs and signaling (TLRs) or endocytic (CD14, LOX-1 and SREC-1) receptors. Our data represented the high-ranked T-cell epitopes and the potential B-cell epitopes of Homo sapiens/Mus musculus Hsp27 and Hsp70. Moreover, molecular docking showed that whole sequence of Hsp27 had better interaction with all receptors than whole sequence of Hsp70 suggesting likely stronger stimulation of innate and adaptive immunity. All designed Homo sapiens/Mus musculus Hsp27/E7 constructs had better docking scores with the endocytic receptors especially SREC-1 than all designed Homo sapiens/Mus musculus Hsp70/E7 constructs in both orientations. Generally, the multiepitope-/whole sequence-based Homo sapiens/Mus musculus Hsp27-E7 fusion constructs showed more conservancy and immunogenicity than other designed constructs. These fusion constructs were non-allergenic, non-toxic and stable suggesting them as promising vaccine candidates against HPV-related cancers.

The association between YouTube use and knowledge of human papillomavirus-related cancers

ObjectiveTo examine the association between YouTube usage and HPV-related cancer knowledge (cervical, anal, oral and penile). Study designCross-sectional study using data from the Health Information National Trends survey conducted between 2017 and 2020 (N = 16,092). Logistic regression was used to analyze the independent effect of YouTube use on cancer knowledge, controlling for sociodemographic characteristics. ResultsRespondents' knowledge of HPV-related cancers varied: 49.9% about cervical, 18% anal, 20.1% oral and 20.4% penile cancers. YouTube use was associated with increased knowledge for all cancers (cervical: OR 2.66, 95% CI 2.04, 3.46; anal: OR 1.83, 95% CI 1.32, 2.53; oral: OR 1.89, 95% CI 1.37, 2.61; penile OR 2.00, 95% CI 1.44, 2.77) in models adjusted for all covariates. Other independent predictors of HPV-related cancer knowledge included female gender, younger age, a higher income, and higher education. Conclusion(s)YouTube could play an important role in educating people about HPV-related cancers and should also target other populations, such as males and those with less formal education. InnovationThe study provides novel insights into the potential of YouTube as an educational tool for promoting cancer knowledge with the goal of cancer prevention.

Diverse intratumoral heterogeneity and immune microenvironment of two HPV-related cervical cancer types revealed by single-cell RNA sequencing.

Cervical squamous cell carcinoma (SCC) and adenocarcinoma (AD) are the main histological types of human papillomavirus-related cervical cancer. However, there are few reports on cell type-specific molecular differences between SCC and AD. Here, we used unbiased droplet-based single-cell RNA sequencing to elucidate the cellular differences between SCC and AD in tumor heterogeneity, and tumor microenvironment (TME). A total of 61 723 cells from three SCC and three AD patients, were collected and divided into nine cell types. Epithelial cells exhibited high intra- and interpatient heterogeneity and functional diversity. Signaling pathways, such as epithelial-to-mesenchymal-transition (EMT), hypoxia and inflammatory response were upregulated in SCC, while cell cycle-related signaling pathways were highly enriched in AD. SCC was associated with high infiltration of cytotoxicity CD8 T, effector memory CD8 T, proliferativenatural killer (NK), and CD160+ NK cells as well as tumor-associated macrophages (TAMs) with high major histocompatibility complex-II genes. AD exhibited a high proportion of naive CD8 T, naive CD4 T, Treg CD4, central memory CD8, and TAMs with immunomodulatory functions. Additionally, we also observed that the majority of cancer-associated fibroblasts (CAFs) were from AD, and participated in inflammation regulation, while SCC-derived CAFs exhibited similar functions to tumor cells, such as EMT and hypoxia. This study revealed the widespread reprogramming of multiple cell populations in SCC and AD, dissected the cellular heterogeneity and characteristics in TME, and proposed potential therapeutic strategies for CC, such as targeted therapy and immunotherapy.

Abstract 5763: Risk factors, trends, and disparities in HPV-associated subsequent malignant neoplasms among adolescent and young adult cancer survivors

Abstract Background: Subsequent malignant neoplasms (SMN) are a leading cause of premature mortality among adolescent and young adult (AYA) cancer survivors, who have unique health needs. Human Papillomavirus-related second cancers (HPV-SMN) are generally preventable through screenings and vaccination. We identified disparities in HPV-SMN among AYA survivors by demographics and first cancer therapy, and examined temporal trends in incidence of HPV-SMN. Methods: We identified diagnoses of any HPV-SMN, oropharyngeal-SMN, and cervical-SMN among AYA survivors in the SEER 9 1976-2015 registries starting two months after the first cancer. Standardized incidence ratios (SIR) compared risk between AYA survivors and general population. We used Fine and Gray competing risk models to estimate hazard ratios (HR) of therapy on risk for HPV-SMN while controlling for cancer site and demographic confounders. Age-period-cohort (APC) models identified temporal trends in HPV-SMN incidence. Results: Of 374,408 survivors diagnosed with a first primary cancer ages 15-44, a total of 1,369 had an HPV-SMN occurring on average five years after the first cancer. Compared to the general population, AYA survivors had increased risks of 70% for any HPV-SMN (95%CI=1.61-1.79) and 117% for oropharyngeal-SMN (95%CI=2.00-2.35). Cervical-SMN risk was generally lower in survivors (SIR=0.85, 95%=CI 0.76-0.95). Hispanic AYA survivors had a significant increase in cervical-SMN relative to the general population (SIR=1.46, 95%CI=1.01-2.06). AYAs who were uninsured or on Medicaid at diagnosis had significant increases in HPV-SMN risk relative to the general populations (Uninsured SIR=5.23, 95%CI=2.26-10.31; Medicaid SIR=5.95, 95%CI=4.07-8.40). AYAs first diagnosed with Kaposi sarcoma, leukemia, Hodgkin, and Non-Hodgkin lymphoma had increased risk for HPV-SMN relative to the general population. Among survivors with HPV-related first primary cancers, radiation was associated with increased risk for HPV-SMN (HR=1.35, 95%CI-1.03-1.77). Among survivors whose first primary cancer was not HPV-related, chemotherapy was associated with increased risk for HPV-SMN (HR=1.20, 95%CI=1.00-1.44) but the general effect of treatment was not significant (p=0.16). In APC models, incidence of oropharyngeal-SMN significantly declined over time. Conclusion and Impact: While the overall risk is low, AYA survivors are at higher risk for HPV-SMNs than the general population, largely driven by oropharyngeal-SMN. Hispanic survivors are the only group at higher risk for cervical-SMN than the general population suggesting a need to improve their cervical cancer screening. Uninsured/Medicaid AYA survivors also face higher HPV-SMN risks. Improving access to screening and HPV vaccination is needed to reduce the burden of HPV-SMN in AYA survivors. Citation Format: Judy Y. Ou, Natalie Bennion, Kellee Parker, Douglas Fair, Heidi A. Hanson, Deanna Kepka, Echo L. Warner, Joemy M. Ramsay, Heydon K. Kaddas, Anne C. Kirchhoff. Risk factors, trends, and disparities in HPV-associated subsequent malignant neoplasms among adolescent and young adult cancer survivors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5763.

"From molecular to clinic": The pivotal role of CDC42 in pathophysiology of human papilloma virus related cancers and a correlated sensitivity of afatinib.

Human papilloma virus (HPV)-related cancers are global health challenge. Insufficient comprehension of these cancers has impeded the development of novel therapeutic interventions. Bioinformatics empowered us to investigate these cancers from new entry points. DNA methylation data of cervical squamous cell carcinoma (CESC) and anal squamous cell carcinoma (ASCC) were analyzed to identify the significantly altered pathways. Through analyses integrated with RNA sequencing data of genes in these pathways, genes with strongest correlation to the TNM staging of CESC was identified and their correlations with overall survival in patients were assessed. To find a potential promising drug, correlation analysis of gene expression levels and compound sensitivity was performed. In vitro experiments were conducted to validate these findings. We further performed molecular docking experiments to explain our findings. Significantly altered pathways included immune, HPV infection, oxidative stress, ferroptosis and necroptosis. 10 hub genes in these pathways (PSMD11, RB1, SAE1, TAF15, TFDP1, CORO1C, JOSD1, CDC42, KPNA2 and NUP62) were identified, in which only CDC42 high expression was statistically significantly correlated with overall survival (Hazard Ratio: 1.6, P = 0.045). Afatinib was then screened out to be tested. In vitro experiments exhibited that the expression level of CDC42 was upregulated in HaCaT/A431 cells transfected with HPV E6 and E7, and the inhibitory effect of afatinib on proliferation was enhanced after transfection. CDC42-GTPase-effector interface-EGFR-afatinib was found to be a stable complex with a highest ZDOCK score of 1264.017. We identified CDC42 as a pivotal gene in the pathophysiology of HPV-related cancers. The upregulation of CDC42 could be a signal for afatinib treatment and the mechanism in which may be an increased affinity of EGFR to afatinib, inferred from a high stability in the quaternary complex of CDC42-GTPase-effector interface-EGFR-afatinib.

Incidence of human papillomavirus-related cancers among males and females aged 15-34 years in the United States.

Postmarket surveillance of the incidence of human papillomavirus (HPV)-related cancers is essential to monitor the effectiveness of HPV vaccines. We directly compared HPV-related cancer incidences during the pre- and postvaccine era to assess the effects of HPV vaccination among vaccine-eligible age groups in the United States using data from the US Cancer Statistics database. The 5-year average annual incidence rates for HPV-related cancers decreased in 2015-2019 compared with 2002-2006 among females aged 15-24 years and 25-34 years. Overall, a decrease in young males was not observed, whereas males aged 25-34 years experienced a slight decline in oropharyngeal squamous cell carcinoma between 2005-2009 and 2015-2019. Incidence rates for HPV-related cancers statistically significantly decreased in the vaccine era compared with the prevaccine era among females aged 15-34 years, suggesting the potential early effects of the introduction of HPV vaccination in the United States.

Leveraging 16S rRNA data to uncover vaginal microbial signatures in women with cervical cancer.

Microbiota-relevant signatures have been investigated for human papillomavirus-related cervical cancer (CC), but lack consistency because of study- and methodology-derived heterogeneities. Here, four publicly available 16S rRNA datasets including 171 vaginal samples (51 CC versus 120 healthy controls) were analyzed to characterize reproducible CC-associated microbial signatures. We employed a recently published clustering approach called VAginaL community state typE Nearest CentroId clAssifier to assign the metadata to 13 community state types (CSTs) in our study. Nine subCSTs were identified. A random forest model (RFM) classifier was constructed to identify 33 optimal genus-based and 94 species-based signatures. Confounder analysis revealed confounding effects on both study- and hypervariable region-associated aspects. After adjusting for confounders, multivariate analysis identified 14 significantly changed taxa in CC versus the controls (P < 0.05). Furthermore, predicted functional analysis revealed significantly upregulated pathways relevant to the altered vaginal microbiota in CC. Cofactor, carrier, and vitamin biosynthesis were significantly enriched in CC, followed by fatty acid and lipid biosynthesis, and fermentation of short-chain fatty acids. Genus-based contributors to the differential functional abundances were also displayed. Overall, this integrative study identified reproducible and generalizable signatures in CC, suggesting the causal role of specific taxa in CC pathogenesis.

The Knowledge of Human Papillomavirus Infections and Association with Oro-Pharyngeal Cancers among Tertiary Students in Ghana

Studies have shown sufficient evidence to associate a subtype of Human papillomavirus (HPV) 16 with oro- pharyngeal cancers and these organisms are typically transmitted through sexual contact making HPV the world’s most common sexually transmitted infection. Fortunately, quadrivalent and bivalent vaccines for HPV infections have shown some evidence of effectiveness in reducing the incidence of oro-pharyngeal cancers (OPC). The knowledge level of people concerning HPV infection, related cancers and vaccines can influence the incidence and prevalence of the infection and its consequences.