The association of the <i>TNFα</i> gene <i>rs1800629</i> and <i>TLR3</i> gene <i>rs3775291</i> polymorphisms with cervical cancer risk and its survival outcomes

Background:In spite of substantial declines in both incidence and mortality rates in the past 50 years, cervical cancer remains one of the leading causes of cancer associated mortality among women globally. We performed this meta-analysis to explore the role of XRCC3 rs861539, MTHFR rs1801133, IL-6 rs1800795, IL-12B rs3212227, TNF-α rs1800629 and TLR9 rs352140 polymorphism with susceptibility to cervical carcinoma. Methods:The search databases include PubMed, SciELO, MedRxiv, Web of Science, Scopus, Cochrane Library, China National Knowledge Infrastructure, and China Biology Medicine disc up to 30 June 2021. The language is limited to English and Chinese. The comparison between the polymorphisms and cervical cancer was assessed using pooled odds ratio (OR) and 95% confidence interval (CI). The data are statistically analyzed by Comprehensive Meta-Analysis (CMA) 2.0 software. Results:A total of 59 studies including seven studies with 1,112 cases and 1,233 controls on XRCC3 rs861539, 14 studies with 2,694 cases and 3349 controls MTHFR rs1801133, four studies with 1,121 cases and 1,109 controls on IL-12B rs3212227, seven studies with 1,452 cases and 2,186 controls on IL-6 rs1800795, 20 studies with 4,781 cases and 4909 controls on TNF-α rs1800629, and seven studies with 1743 cases and 2292 controls on TLR9 rs352140 were included. There was a significant association between XRCC3 RS861539, TNF-α rs1800629, and IL-6 rs1800795 polymorphisms and an increased risk of cervical carcinoma in overall population. However, the MTHFR rs1801133, IL-12B rs3212227 and TLR9 rs352140 polymorphisms were not associated. Conclusion:The pooled analysis showed that XRCC3 RS861539, TNF-α rs1800629, and IL-6 rs1800795 were associated with cervical carcinoma susceptibility, but not MTHFR rs1801133, IL-12B rs3212227 and TLR9 rs352140 polymorphisms.

Introduction: Cervical cancer (CC) is a prevailing malignant tumor in women, mainly caused by human papillomavirus (HPV) infection. This study investigated miR-106a expression in the serum of HPV-positive CC patients and estimated its value in diagnosis and prognosis. Methods: We enrolled 120 CC patients as study subjects, with another 80 healthy women as controls. Clinical baseline data and clinicopathological indexes including age, tumor size, differentiation degree, FIGO stage, lymph node metastasis, and squamous cell carcinoma antigen (SCC-Ag) were recorded. Serum miR-106a expression was measured using reverse transcription-quantitative polymerase chain reaction. Receiver operating characteristic curve was employed to estimate the efficacy of miR-106a in diagnosing CC or HPV-positive CC. Under a 5-year follow-up, patient survival was recorded, and the impact of miR-106a on overall survival rate was analyzed by the Kaplan-Meier method. The logistic regression model was used to analyze whether miR-106a was an independent prognostic factor for HPV infection in CC patients. Results: Serum miR-106a was upregulated in CC patients and the level >1.365 assisted the CC diagnosis. miR-106a expression in HPV-positive CC patients was elevated relative to HPV-negative CC patients, and serum miR-106a level >1.300 distinguishing HPV positive and HPV negative. HPV positivity was linked with tumor differentiation degree, FIGO stage, lymph node metastasis, and SCC-Ag in CC patients, but not with age and tumor size. High expression of miR-106a in HPV-positive CC patients increased the risk of poor prognosis, and miR-106a expression is an independent prognostic factor for HPV infection in CC patients. Conclusion: High expression of miR-106a assists in the diagnosis of HPV-positive CC and predicts poor prognosis.

Currently, studies highlighting features of emergence, development, clinical score and prognosis for patients with HPV-negative cervical cancer are scarce. However, the data regarding high recurrence rate and mortality in patients with HPV-negative head and neck cancer are demonstrated. Here, cervical canal and exocervical scraping samples collected from 116 patients with primary cervical cancer, I–IV stages, aged 24 to 79 years, were examined with real-time PCR assay for assessing prevalence of 12 high oncogenic risk human papillomavirus (HPV) strains, genotyping and viral load. It was found that 84 (72.4%) and 32 cervical cancer patients (27.6%) were positive and negative, respectively, for high oncogenic risk (HR) HPV strains. Based on these data, patients were further subdivided into two groups: HPV-positive and HPVnegative patient group. Genotyping HPV-positive samples revealed that HPV genotype 16 was found in 67.8% of cases that agrees with data published worldwide. In addition, relapse-free and overall survival (HPV-positive and HPV-negative patients) rate were also evaluated in both groups. It was demonstrated that survival rate was significantly decreased in HPVnegative cervical cancer patients additionally characterized by less favorable prognosis. Moreover, length of relapse-free survival as well as overall survival for HPV-positive vs. HPV-negative patients was 102 vs. 68 months as well as 52 vs. 83 months, respectively. On the other hand, it was demonstrated that recurrence rate, clinical score and progression of cervical cancer directly depend on cancer spread observed at primary medical examination. Of note, the majority of primary cervical cancer relapses are diagnosed within the first 2 years after completing treatment. In addition, an increasing relapse rate has been documented in cervical cancer patients at advanced stages. Upon that, biological cancer behavior remains poorly predictable even in patients at similar disease stage. Therefore, it is essential that HPV as an important prognostic factor would be taken into account for choosing proper therapeutic strategy for treatment of patients with cervical cancer.

IntroductionHigh-risk human papillomavirus (HPV) has been detected in distant metastases from cervical cancer (CC) patients, suggesting a role of HPV. Material and methodsHere, we included 26 patients with recurrence of CC (2019–2023). With next generation sequencing (NGS) and immunohistochemical staining, primary and recurrent tissues were analyzed for HPV DNA and HPV RNA, p16INK4a expression, and somatic TP53 and RB1 mutations. ResultsAll primary and corresponding recurrent tissues were HPV DNA and HPV RNA positive. Within the same tissue, we found complete DNA/RNA agreement in 25/26 (96.2 %) primary and 25/25 (100 %) recurrent tissues, and partial agreement in the remaining sample. There was complete agreement between primary and recurrent tissue in 23/26 (88.5 %) and 23/25 (92.0 %) patients on DNA and RNA, respectively, whereas the remaining showed partial agreement with two genotypes detected in primary and only one of these in recurrent tissue. Except for one sample, all samples from high-risk HPV-positive patients were p16INK4a positive. The low-risk HPV11-positive patient was p16INK4a negative and had a pathogenic TP53 mutation, while the remaining samples were TP53/RB1 mutation negative. ConclusionIn high-risk HPV-positive CC patients, HPV seems to play a role in recurrent disease. Our findings support ongoing research on targeting HPV oncogenes in CC, also in metastatic disease.

The aims of the study were to evaluate the prevalence and prognosis of human papillomavirus (HPV)-negative cervical cancer (CC) and to compare these to data for HPV-positive CC. This retrospective cohort study compared between HPV-negative CC and HPV-positive CC patients. Primary end points were disease-free survival and overall survival. Secondary end points were demographic and clinical variables including histological diagnosis, stage, and treatment. Of 233 women with CC, 18 (8%) tested HPV-negative. During a median follow-up of 45 months, 33 (14%) recurrences and 41 (18%) deaths were observed. Eleven of the 18 women (61%) who tested HPV-negative and 41 of the 215 (19%) who tested HPV-positive had only adenocarcinoma (p < .001). In a multivariate logistic regression analysis, advanced age (p = .003) and primary treatment with chemotherapy and/or radiotherapy (p < .001) remained statistically significant for recurrence or mortality (disease-free survival). The factors associated with lower survival were advanced age (p = .008), higher stage at diagnosis (p < .001), and HPV negativity (p = .062). Median overall survival for HPV-positive CC was not reached, compared with 24 months for HPV-negative CC. Kaplan-Meier curves showed lower rates of disease-free survival (p = .008) and overall survival (p = .011), for women with HPV-negative compared with HPV-positive CC. The relatively poor prognosis of HPV-negative CC is important in light of its relatively high prevalence, which could increase proportionally to HPV-positive CC due to increased HPV screening and vaccination. Further studies are needed to confirm whether HPV status is truly an independent prognostic factor in CC.

Introduction/Background*To evaluate the prevalence and prognosis of human papillomavirus (HPV)-negative cervical cancer (CC), and compare these to data for HPV-positive CC.MethodologyThis retrospective cohort study compared between HPV-negative CC and HPV-positive...

Single-Cell and Spatial Transcriptomics Revealing the Role of IDO1 in HPV+ Cervical Cancer Tumor Immune Microenvironment and Its Implications in Radiotherapy and Immunotherapy

1597 Background: CC develops through progression from normal cervical epithelium through squamous intra-epithelial lesions (SILs) to cancer. CC is classically associated with oncogenic human papillomavirus (HPV). Yet, not all CC patients demonstrate HPV infection at diagnosis. HPV+ and HPV– subsets of CC patients may thus represent distinct entities. HPV binds to P53, promoting its degradation; the Arg variant of p53 Arg72Pro binds more ardently to HPV than the Pro variant. Although there have been meta-analyses of Arg72Pro in CC risk, none has evaluated the relationship between Arg72Pro and HPV status together. We hypothesize that p53 Arg72Pro modifies aspects of the carcinogenic process in HPV+ (but not HPV-) subsets of CC. Methods: Pubmed/Embase databases identified 1494 potential studies; 51 were eligible and included. Separate analyses were performed to evaluate CC risk (CC vs normal), initiation of cancer (SIL vs normal), and progression towards cancer (CC vs SIL), by HPV status. Pooled odds ratios (pOR) were generated using RevMan 5.1 software. Results: p53 Arg72Pro was not associated with CC risk in either HPV+ or HPV- patient subsets (pORs 0.92; 95%CI, 0.6-1.3 and pORs 1.07; 95%CI, 0.7-1.7, respectively). Similarly, there was no association with the initiation of disease (SIL vs normal): pORs 0.96; 95%CI, 0.7-1.3 (HPV+ subset); 1.11; 95%CI, 0.9-1.4 (HPV- subset). There was no association with disease progression from SIL to CC in the HPV- subset (pOR, 0.98; 95%CI, 0.7-1.4). However, in the HPV+ subset, comparing the progression from SIL through to CC, there was strong and significant association: pOR, 1.37; 95%CI, 1.2-1.6 (p=4.0x10E-4), with no evidence of heterogeneity (I2 = 0%) or bias (by funnel plot). Sensitivity analyses demonstrated similarly significant results, even after taking into account differing quality of methodological designs and type of biological sample analyzed (tumour vs. blood) of the underlying studies. Associations were mainly restricted to Caucasian studies. Conclusions: In this meta-analysis, the Arg variant of p53 Arg72Pro was associated with progression of SIL to CC only in HPV+ subsets, but not to disease initiation or risk of CC.

Infection of high risk human papillomaviruses (HPVs) specifically the types 16 and 18 has been strongly implicated in the development of cervical cancer. The E6 oncoproteins of these high risk HPVs are known to bind and induce degradation of p53 tumour suppressor protein through the ubiquitin pathways. This degradation is controlled by a common polymorphism of the p53 gene encoding either a proline or an arginine at its codon 72 in exon 4. Recently, it has been demonstrated that the presence of homozygous arginine at codon 72 renders p53 about seven times more susceptible to E6-mediated proteolytic degradation as well as to cervical cancer than those with proline homozygotes or proline/arginine heterozygotes. In India, prevalence of HPV as well as cancers of the uterine cervix and the oral cavity are highest in the world. We have examined this allele-specific predisposition in cervical and oral cancer which is associated with HPV as well as in a non-HPV-linked cancer of the breast. We have carried out investigation in women comprising whole spectrum of cervical lesions with 128 HPV 16/18 positive and 35 HPV negative invasive cervical carcinomas and 34 cases of HPV (16/18) positive and 16 HPV negative cervical dysplasias (mild, moderate and severe) and 104 age-group-matched healthy women as controls. Additionally, we have analysed p53Arg-Pro polymorphism in 13 high risk HPV positive and 31 HPV negative oral cancers along with 20 normal controls and 77 breast cancers with 41 age-matched healthy controls. We observed more than two fold higher risk for homozygous arginine (chi2 = 6.3, df = 2, p = 0.04; OR = 2.3; 95% CI: 1.08-5.16) for HPV 16/18-positive cervical carcinomas when comparison was made only between HPV positive cervical cancers and normal controls but most interestingly, no significant association either in the frequency of homozygous arginine or proline alleles or their heterozygotes could be observed when all the three groups i.e. HPV-positive, HPV-negative cervical cancers and controls were considered simultaneously. No difference was also observed for either arginine or proline polymorphism between women with precancerous lesions of the uterine cervix carrying HPV 16/18 infection and controls. Similarly, increased risk of oral or breast cancer could not be correlated with the polymorphism of arginine/proline allele. Thus the interaction between HPV oncoproteins and the p53 gene polymorphism specifically, homozygous arginine at codon 72 appears to play no role in the development of either cervical or oral cancer and also it can not serve as a biomarker for early identification of cervical, oral or breast cancer.

Mitochondrial C150T polymorphism increases the risk of cervical cancer and HPV infection

Human papillomaviruses 16 (HPV16) is the primary causative agent of cervical cancer (CC). E6 oncoprotein plays a crucial role in cervical carcinogenesis and commonly cause the dysregulation of the long noncoding RNAs (lncRNAs) expression. However, the biological function of lncRNAs in HPV16-related CC remains largely unexplored. In the present study HPV16 E6-induced differential expression of lncRNAs, miRNA, and mRNA were identified using microarray-based analysis and verified in tumor r cell lines and tumor tissues, and the function of lncRNA in CC was investigated in vitro and in vivo. We found that an lncRNA, named GABPB1-AS1, was significantly upregulated in HPV16-positive CC tissues and cell lines. GABPB1-AS1 expression in HPV16-positive CC tissues was positively associated with tumor size, lymph node metastasis, and FIGO stage. High expression of GABPB1-AS1 was correlated with a poor prognosis for HPV16-positive CC patients. Functionally, E6-induced GABPB1-AS1 overexpression facilitated CC cells proliferation and invasion in vitro and in vivo. Mechanistically, GABPB1-AS1 acted as a competing endogenous RNA (ceRNA) by sponging miR-519e-5p, resulting in the de-repression of its target gene Notch2 which is well known as an oncogene. Therefore, GABPB1-AS1 functioned as a tumor activator in CC pathogenesis by binding to miR-519e-5p and destroying its tumor suppressive function. Collectively, current results demonstrate that GABPB1-AS1 is associated with CC progression, and may be a promising biomarker or target for the clinical management of CC.

BackgroundHuman papillomavirus (HPV) is a crucial etiological factor for cervical cancer (CC) development. From a diagnostic view-point, the consistent presence of HPV in CC allows the viral DNA to be used as a genetic marker. The aims of this study were to evaluate the presence, physical status and clinical significant of HPV DNA in circulation of CC patients.ResultsWhereas 6 out of 50 (12%) HPV positive CC patients revealed plasma HPV DNA, it was detected in none of 20 normal controls or 13 HPV negative CC cases. The plasma DNA exhibited an HPV type identical to the HPV in the primary tumors and the DNA from both sources was integrated into host genome. Interestingly, several findings suggested an association between plasma HPV DNA and metastasis. First, three of the HPV DNA positive cases were CC patients with clinical stage IVB or recurrence with distance metastases (P = 0.001, RR = 15.67). Second, the amount of plasma HPV DNA from metastatic patients to be three times more than three other patients without metastases. Finally, the later cases had tendency to develop recurrence distant metastases within one year after complete treatment when compared with other HPV associated CC patients with the same stage but without the present of plasma HPV DNA.ConclusionsThe plasma HPV DNA originated from the CC, was associated with metastasis and could be used as a marker representing the circulating free CC DNA.

Cervical cancer, one of the prevalent malignancies among females, is closely associated with human papillomavirus (HPV) infection. Homologous to the E6-AP carboxyl terminus (HECT) domain and ankyrin repeat containing E3 ubiquitin-protein ligase 1 (HACE1) plays pivotal roles in various cancers. This study aimed to elucidate the expression of HACE1 in cervical cancer and its correlation with clinical features. From The Cancer Genome Atlas Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA-CESC) and Gene Expression Omnibus (GEO, GSE6791) datasets, we obtained RNA-Seq profiles and associated clinical information. Differential gene analysis was conducted using the R "limma" package. Implications for HPV infection and the overall survival (OS) of cervical cancer were determined by performing differential expression analysis and the Cox proportional hazards regression model. Immunohistochemical analyses were used to validate the expression in cervical cancer and normal cervical tissue. Further, nomogram was constructed to predict OS in cervical cancer. Whether the model was credible was evaluated according to receiver operating characteristic (ROC) curves and concordance curves. To further evaluate the potential functions of HACE1, we conducted functional enrichment analysis. Finally, we assessed methylation levels in HPV+ and HPV- patients in the TCGA-CESC dataset. Utilizing TCGA and GSE6791 datasets, we observed significant upregulation of HACE1 in cervical cancer patients, particularly linked to HPV infection. Immunohistochemical staining revealed enhanced HACE1 expression in tumor tissues. Further analysis demonstrated a significant positive correlation between elevated HACE1 and HPV-associated proteins (E1, E6, and E7). Moreover, high HACE1 expression was associated with adverse prognosis in cervical cancer patients. Multivariate Cox analysis indicated that HACE1 could serve as an independent prognostic factor. We developed a prognostic model integrating HPV subtypes, the International Federation of Gynecology and Obstetrics (FIGO) staging, and HACE1, exhibiting strong predictive efficacy for cervical cancer prognosis. Gene enrichment analysis indicated HACE1's potential involvement in multiple signaling pathways during cervical cancer progression, while the demethylation of cg03002526 in HPV-positive patients might contribute to HACE1 upregulation. Our study reveals that HACE1 upregulation is associated with cervical cancer, particularly in HPV-positive patients. HACE1 emerges as an independent prognostic factor, linked to unfavorable outcomes.

Polymorphisms in TLR4 and IL6 and their association with obesity and insulin resistance in a Venezuelan population.

Objectives The aim of this study was to investigate the role of ESR1 rs1643821 and TNF-α rs1800629 as potential genetic factors regulating anterior disc displacement without reduction-mediated inflammatory pathway. Background The temporomandibular joint is a complex synovial joint that allows mandibular movement in three directions. Although temporomandibular disorders are widespread, limited data is available on the biochemical characteristics of the displaced disc and quality of the surrounding soft tissue. Changes in degenerative tissue provoke disc displacement which involves secretion of inflammatory markers and sequential conversion of fibroblast-like cells into chondrocyte-like cells. Due to the high occurrence in female adolescents, the potential role of sex hormones in temporomandibular joint disorders has been speculated. Furthermore, anterior disc displacement without reduction severely affects the quality of life. Methods 124 Caucasian patients with a history of at least one anterior disc displacement without reduction within 3 months were enrolled. Anterior disc displacement without reduction was diagnosed based on clinical examination, diagnostic criteria (DC)/TMD, and cone-beam computed tomography/magnetic resonance imaging (CBCT/MRI). The control group consisted of 126 patients with no temporomandibular joint disorders. Genotyping of two single nucleotide polymorphisms, estrogen receptor 1 (ESR1) rs1643821, and tumor necrosis factor α (TNF-α) rs1800629 was performed. Results ESR1 rs1643821 showed significant P values (using chi-square analysis) revealing the difference in anterior disc displacement without reduction frequencies while TNF-α rs1800629 polymorphism was found to be statistically insignificant when compared to the control group. Furthermore, patients with a genotype of ESR1 rs1643821 showed a decreased probability (OR = 0.412) against anterior disc displacement without reduction when compared to the GG genotype (OR = 1). Conclusion ESR1 rs1643821 with A allele frequency was lower in patients with anterior disc displacement without reduction compared to the control group. Thus, the rs1643821 variant is significantly associated with susceptibility to the anterior disc displacement without a reduction in European Caucasians. Conversely, TNF-α rs1800629 was a statistically insignificant factor against anterior disc displacement without reduction when compared to the control group.