E7 proteins from oncogenic human papillomavirus types transactivate p73: role in cervical intraepithelial neoplasia.
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ABSTRACT:
SUBMITTER: Brooks LA
PROVIDER: S-EPMC2375198 | biostudies-other | 2002 Jan
REPOSITORIES: biostudies-other
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Project description:Human papillomavirus (HPV) is the well-established etiologic factor for cervical neoplasia. Cervical conization constitutes an effective treatment for high-grade cervical intraepithelial neoplasia (HG-CIN). We conducted an observational study for long-term outcomes and HPV genotype changes after conization for HG-CIN. Between 2008 and 2014, patients with newly diagnosed HG-CIN before conization (surveillance new [SN] group) and those who had undergone conization without hysterectomy (surveillance previous [SP] group) were enrolled. HPV testing and Pap smear were performed periodically for the SN and SP (collectively S) groups. All other patients receiving conization for HG-CIN during the study period were identified from our hospital database. Those eligible but not enrolled into our study were assigned to the non-surveillance (non-S) group. For the S group (n = 493), the median follow-up period was 74.3 months. Eighty-four cases had recurrent CIN Grade 2 or worse (CIN2+) (5-year cumulative rate: 14.8%), of which six had invasive cancer. Among the 84 patients, 65 (77.4%) exhibited type-specific persistence in the paired HPV results, whereas only 7 (8.3%) harbored new HPV types that belonged to the 9-valent vaccine types. Among the 7397 non-S patients, 789 demonstrated recurrent CIN2+, of which 57 had invasive cancer. The stages distribution of those progressed to invasive cancer in the non-S group were more advanced than the S group (P = .033). Active surveillance might reduce the severity of those progressed to cancer. Because a majority of the patients with recurrent CIN2+ had persistent type-specific HPV infections, effective therapeutic vaccines are an unmet medical need.
| S-EPMC7754315 | biostudies-literature
Project description:Since cervical cancer still afflicts women around the world, it is necessary to understand the underlying mechanism of cervical cancer development. Infection with HPV is essential for the development of cervical intraepithelial neoplasia (CIN). In addition, estrogen receptor signaling is implicated in the development of cervical cancer. Previously, we have isolated human wings apart-like (WAPL), which is expected to cause chromosomal instability in the process of HPV-infected precancerous lesions to cervical cancer. However, the role of WAPL in the development of CIN is still unknown. In this study, in order to elucidate the role of WAPL in the early lesion, we established WAPL overexpressing mice (WAPL Tg mice) and HPV E6/E7 knock-in (KI) mice. WAPL Tg mice developed CIN lesion without HPV E6/E7. Interestingly, in WAPL Tg mice estrogen receptor 1 (ESR1) showed reduction as compared with the wild type, but cell growth factors MYC and Cyclin D1 controlled by ESR1 expressed at high levels. These results suggested that WAPL facilitates sensitivity of ESR1 mediated by some kind of molecule, and as a result, affects the expression of MYC and Cyclin D1 in cervical cancer cells. To detect such molecules, we performed microarray analysis of the uterine cervix in WAPL Tg mice, and focused MACROD1, a co-activator of ESR1. MACROD1 expression was increased in WAPL Tg mice compared with the wild type. In addition, knockdown of WAPL induced the downregulation of MACROD1, MYC, and Cyclin D1 but not ESR1 expression. Furthermore, ESR1 sensitivity assay showed lower activity in WAPL or MACROD1 downregulated cells than control cells. These data suggested that WAPL increases ESR1 sensitivity by activating MACROD1, and induces the expression of MYC and Cyclin D1. Therefore, we concluded that WAPL not only induces chromosomal instability in cervical cancer tumorigenesis, but also plays a key role in activating estrogen receptor signaling in early tumorigenesis.
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Project description:Recommendations for high-risk human papillomavirus (HR-HPV) testing as an adjunct to cytology for cervical cancer screening differ by age group, because HR-HPV tests lack adequate specificity in women aged <30. Here, we assess age-group differences in HPV types and other risk factors for cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) versus CIN0-2 in women from four colposcopy clinics.Women ages 18 to 69 (n = 1,658) were enrolled and completed structured interviews to elicit data on behavioral risk factors prior to their examinations. HPV genotyping was done on exfoliated cervical cell samples. We estimated relative risks (RR) for HPV types and cofactors for CIN3+, overall and stratified by age group.After 2 years of follow-up, we identified 178 CIN3+, 1,305 CIN0-2, and 175 indeterminate outcomes. Nonvaccine HR-HPV types were only associated with CIN3+ among women ? 30 (RR = 2.3, 95% CI: 1.5-3.4; <30: RR = 0.9). Among all HR-HPV-positive women, adjusting for age, significant cofactors for CIN3+ included current smoking (RR = 1.5), former smoking (RR = 1.8), regular Pap screening (RR = 0.7), current regular condom use (RR = 0.5), and parity ? 5 (RR = 1.6, P(trend) for increasing parity = 0.07). However, the parity association differed by age group (? 30: RR = 1.8, P(trend) = 0.008; <30: RR = 0.9; P(trend) =.55).Subgroup variation by age in the risk of CIN3+ points to the importance of the timing of exposures in relation to CIN3+ detection.Future screening strategies need to consider natural history and secular trends in cofactor prevalence in the pursuit of appropriately sensitive and specific screening tools applied to appropriate age groups.
| S-EPMC3266819 | biostudies-literature
Project description:Cervical cancer is one of the leading causes of cancer death in women globally, despite the widespread use of cytology/human papillomavirus (HPV) screening. In the present study, we aimed to identify the potential role of microRNA (miRNA) as a diagnostic biomarker in the detection of cervical pre-malignant lesions and cancer. In total, we recruited 582 patients with cervical diseases and 145 control individuals. The expression levels of six miRNAs (miR-20a, miR-92a, miR-141, miR-183*, miR-210 and miR-944) were found to be significantly up-regulated in cervical cancer and pre-malignant lesions compared to normal cervical samples, indicating that they are oncogenic miRNAs. Receiver operating characteristic curve analysis showed that these six miRNAs can be used to distinguish patients with cervical pre-malignant lesions or cancer from normal individuals and they also had a good predictive performance, particularly in cervical lesions. Combined use of these six miRNAs further enhanced the diagnostic accuracy over any single miRNA marker, with an area under the curve of 0.998, 0.996 and 0.959, a diagnostic sensitivity of 97.9%, 97.2% and 91.4%, and a specificity of 98.6%, 96.6% and 87.6% for low-grade lesions, high-grade lesions and cancer, respectively. This six oncogenic miRNA signature may be suitable for use as diagnostic marker for cervical pre-malignant lesions and cancer in the near future.
| S-EPMC6275249 | biostudies-literature
Project description:The objective was to assess the diagnostic test accuracy of high-risk human papillomavirus (hrHPV) testing of self-collected urine and cervicovaginal samples for the detection of cervical intraepithelial neoplasia grade 2 or higher (CIN2+). We recruited a convenience sample of women 25 to 65 years of age who were undergoing clinically indicated colposcopy at two medical centers in North Carolina between November 2016 and January 2019. Women with normal cytology results and positive hrHPV results were also recruited. Urine samples, self-collected cervicovaginal samples, provider-collected cervical samples, and cervical biopsy samples were obtained from all enrolled women. Samples were tested for hrHPV DNA using the Onclarity assay (Becton Dickinson, Sparks, MD). Biopsy samples were histologically graded as CIN2+ or <CIN2. We calculated the sensitivity and specificity for detection of CIN2+ and assessed agreement between sample collection methods. We included 307 women (median age, 36 years) with valid histology results and triple-matched urine, self-collected cervicovaginal, and provider-collected cervical hrHPV results; 83 women (27%) had CIN2+. Urine-based hrHPV testing correctly identified 80% of CIN2+ cases (95% confidence interval [CI], 71 to 88%) using the PCR cycle threshold (CT ) established for provider-collected cervical samples, but sensitivity remained below the estimates for self-collected cervicovaginal and provider-collected cervical samples (both 94% [95% CI, 89 to 99%]). Using a higher CT cutoff value of ≤40, 90% sensitivity was achieved for urine-based hrHPV testing. Agreement between results for urine samples and self-collected cervicovaginal samples (kappa = 0.58) or provider-collected cervical samples (kappa = 0.54) was moderate. Urine-based hrHPV testing may be a promising approach to improve cervical cancer screening coverage, especially among women with limited access to health care.
| S-EPMC7041584 | biostudies-literature
Project description:Human papillomavirus type 58 (HPV-58) exists in a relatively high prevalence in certain parts of the world, including East Asia. This study examined the T-cell response to HPV-58 L1, E6, and E7 peptides among women with cleared infection, cervical intraepithelial neoplasia grade 2 (CIN2) or CIN3, or invasive cervical cancer (ICC). Peptides found to be reactive in the in vitro peptide binding assay or mouse-stimulating study were tested with a gamma interferon (IFN-gamma) enzyme-linked immunospot (ELISPOT) assay to detect peptide-specific responses from the peripheral blood mononuclear cells (PBMC) collected from 91 HPV-58-infected women (32 with cleared infection, 16 CIN2, 15 CIN3, and 28 ICC). Four HLA-A11-restricted HPV-58 L1 peptides, located at amino acid positions 296 to 304, 327 to 335, 101 to 109, and 469 to 477, showed positive IFN-gamma ELISPOT results and were mainly from women with cleared infection. Two HLA-A11-restricted E6 peptides (amino acid positions 64 to 72 and 94 to 102) and three HLA-A11-restricted E7 peptides (amino acid positions 78 to 86, 74 to 82, and 88 to 96) showed a positive response. A response to E6 and E7 peptides was mainly observed from subjects with CIN2 or above. One HLA-A2-restricted E6 peptide, located at amino acid position 99 to 107, elicited a positive response in two CIN2 subjects. One HLA-A24-restricted L1 peptide, located at amino acid position 468 to 476, also elicited a positive response in two CIN2 subjects. In summary, this study has identified a few immunogenic epitopes for HPV-58 E6 and E7 proteins. It is worthwhile to further investigate whether responses to these epitopes have a role in clearing an established cervical lesion.
| S-EPMC2944455 | biostudies-literature
Project description:A substantial effect of human papillomavirus (HPV) vaccines on reducing HPV-related cervical disease is essential before modifying clinical practice guidelines in partially vaccinated populations.To determine the population-based cervical intraepithelial neoplasia (CIN) trends when adjusting for changes in cervical screening practices that overlapped with HPV vaccination implementation.The New Mexico HPV Pap Registry, which captures population-based estimates of both cervical screening prevalence and CIN, was used to compute CIN trends from January 1, 2007, to December 31, 2014. Under New Mexico Administrative Code, the New Mexico HPV Pap Registry, a statewide public health surveillance program, receives mandatory reporting of all cervical screening (cytologic and HPV testing) and any cervical, vulvar, and vaginal histopathological findings for all women residing in New Mexico irrespective of outcome.Prespecified outcome measures included low-grade CIN (grade 1 [CIN1]) and high-grade CIN (grade 2 [CIN2] and grade 3 [CIN3]).From 2007 to 2014, a total of 13?520 CIN1, 4296 CIN2, and 2823 CIN3 lesions were diagnosed among female individuals 15 to 29 years old. After adjustment for changes in cervical screening across the period, reductions in the CIN incidence per 100?000 women screened were significant for all grades of CIN among female individuals 15 to 19 years old, dropping from 3468.3 to 1590.6 for CIN1 (annual percentage change [APC], -9.0; 95% CI, -12.0 to -5.8; P?<?.001), from 896.4 to 414.9 for CIN2 (APC, -10.5; 95% CI, -18.8 to -1.2; P?=?.03), and from 240.2 to 0 for CIN3 (APC, -41.3; 95% CI, -65.7 to 0.3; P?=?.05). Reductions in the CIN2 incidence were also significant for women 20 to 24 years old, dropping from 1027.7 to 627.1 (APC, -6.3; 95% CI, -10.9 to -1.4; P?=?.02).Population-level decreases in CIN among cohorts partially vaccinated for HPV may be considered when clinical practice guidelines for cervical cancer screening are reassessed. Evidence is rapidly growing to suggest that further increases in raising the age to start screening are imminent, one step toward integrating screening and vaccination.
| S-EPMC5765871 | biostudies-literature
Project description:BACKGROUND:Self-sampling for human papillomavirus (HPV) offered to women who do not participate in cervical cancer screening is an increasingly popular method to increase screening coverage. The rationale behind self-sampling is that unscreened women harbour a high proportion of undetected precancer lesions. Here, we compare the cervical intraepithelial neoplasia grade 2 or worse (?CIN2) detection rate between non-attenders who participated in self-sampling and women attending routine screening. METHODS:A total of 23?632 women who were qualified as non-attenders in the Copenhagen Region were invited for HPV-based self-sampling. Of these, 4824 women returned a self-sample, and HPV-positive women were referred for cytology and HPV co-testing as follow-up. The entire cohort and a reference cohort (3347 routinely screened women) were followed for histopathology confirmed ?CIN2. Odds ratio (OR) and the relative positive predictive value of ?CIN2 detection between the two populations were estimated. RESULTS:Women participating in self-sampling had a higher ?CIN2 detection than women undergoing routine cytology-based screening (OR=1.83, 95% CI: 1.21-2.77) and a similar detection as routinely screened women tested with cytology and HPV testing (OR=1.03, 95% CI: 0.75-1.40). The positive predictive value for ?CIN2 was higher in screening non-attenders than in routinely HPV- and cytology-screened screened women (36.5% vs 25.6%, respectively). CONCLUSIONS:Self-sampling offered to non-attenders showed higher detection rates for ?CIN2 than routine cytology-based screening, and similar detection rates as HPV and cytology co-testing. This reinforces the importance of self-sampling for screening non-attenders in organised cervical cancer screening.
| S-EPMC5765223 | biostudies-literature
Project description:Laboratories now can choose from >100 human papillomavirus (HPV) assays for cervical screening. Our previous analysis based on the data from the Danish Horizon study, however, showed that four widely used assays, Hybrid Capture 2 (HC2), cobas, CLART, and Aptima, frequently do not detect the same HPV infections. Here, we determined the characteristics of the concordant samples (all four assays returning a positive HPV test result) and discordant samples (all other HPV-positive samples) in primary cervical screening at 30 to 65 years of age (n = 2,859) and in a concurrent referral population from the same catchment area (n = 885). HPV testing followed the manufacturers' protocols. Women with abnormal cytology were managed according to the routine recommendations. Cytology-normal/HPV-positive women were invited for repeated testing in 18 months. Screening history and histologically confirmed cervical intraepithelial neoplasia (CIN) in 2.5 years after the baseline testing were determined from the national pathology register. HPV-positive women undergoing primary screening having concordant samples were more likely to harbor high-risk infections and less likely to harbor only low-risk infections than women with discordant samples. Additionally, assay signal strengths were substantially higher in concordant samples. More than 80% of ?CIN2 results were found for women with concordant samples, and no ?CIN2 results were found when the infection was detected by only one assay. These patterns were similar in the referral population despite the younger age and higher number of HPV infections. HPV test result discordance identified a cluster of low-risk HPV infections that were hardly ever associated with high-grade CIN and, almost exclusively, represented false-positive screening findings.
| S-EPMC5078541 | biostudies-literature
Project description:Given that only a small percentage of human papillomavirus (HPV)-positive women develop cancer, HPV is necessary but insufficient for carcinogenesis. Mucosally transmitted viral cofactors appear to contribute to HPV-related cervical cancer, such as Epstein-Barr virus (EBV), but previous studies have shown inconsistent outcomes. The exact role of EBV in cervical cancer remains unclear, and more studies are needed to determine its involvement. In this study, we describe the prevalence of EBV and HPV coinfection in HIV-positive women and explore how abnormal host immune status induced by viral coinfections modulates epithelial gene expression. We found a significant correlation between EBV-HPV coinfection and the incidence of high-grade cervical intraepithelial neoplasia (CIN2+). RNA sequencing indicated that CIN tissues coinfected with EBV and HPV led to significant changes in the gene expression of epithelial differentiation and development compared to normal tissues with HPV infection alone. In particular, several differentially expressed genes (DEGs) are closely associated with cancer, such as CACNG4, which was confirmed to be upregulated at both the mRNA and protein levels. Therefore, these findings provide some evidence that EBV may act as a cofactor or mediator in HPV-related cervical cancer. Specific genes or proteins, such as CACNG4, may serve as biomarkers that can risk stratify patients based on pathological changes in the cervix.
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