Risk Of Cervical Carcinogenesis Research Articles

Association of a Genetic Variant in Chromosome 9p21 with Increased Risk of Developing Cervical Cancer

Background: Cervical cancer is one of the most prevalent gynecologic cancers associated with high morbidity and mortality worldwide. There is mounting evidence indicating an association between the 9p21 locus genetic variants with susceptibility to various human malignancies. In this current study, we aimed to evaluate the potential relationship between the rs1333049 genetic variant in chromosome 9p21 and the risk of cervical carcinogenesis. Methods: The possible correlation between rs1333049 polymorphism and susceptibility to cervical cancer was investigated in 221 patients with or without cancer. DNAs were isolated and genotyped using a TaqMan-based real-time RT-PCR method. Results: The rs1333049 genetic variant was found to be correlated with an elevated risk of cervical neoplasia using recessive and additive genetic models (p < 0.001). Conclusion: Our findings indicated that the CDKN2A/B genetic variant (rs1333049) was significantly associated with an elevated risk of cancer, suggesting its potential as a novel predictive marker for cervical carcinogenesis.

Risk of cervical intraepithelial neoplasia grade 3 or more diagnoses for human papillomavirus16/18-positive women by cytology and co-infection status

BackgroundHuman papillomavirus (HPV) 16 and 18 cause approximately 70% of cervical cancer cases. The aim of this study was to evaluate whether co-infected with other HPV genotypes will affect the risk of cervical carcinogenesis in HPV16/18 positive-women.MethodsIn this cross-sectional study, cervical cytology and histological classifications from women who tested positive for HPV 16/18 and underwent colposcopy within 6 months, between January 2010 and May 2021 were obtained from West China Second University Hospital of Sichuan University.Main outcomes and measuresImmediate risk of cervical intraepithelial neoplasia grade 3 or more diagnoses (CIN 3+).ResultsA total of 7940 HPV 16/18-positive women were included, with a median age of 40 years (range 25–84 years). Among them, 2710 (34.1%) were infected with multiple genotypes, 6533 (82.28%) had cytology results and 2116 (26.65%) women were diagnosed with CIN 3+. The effects of HPV 16/18 coinfecting with other HPV on CIN3 + risk varied with specific HPV genotypes. After adjusting for cofactors, compared to single HPV 16 infection, the CIN 3 + risk was significantly reduced in women infected with HPV 16 + other high-risk HPV (hrHPV) [odds ratio (OR) = 0.621, 95% confidence interval (CI) 0.511–0.755], HPV 16 + low-risk HPV (lrHPV) (OR = 0.620, 95% CI 0.436–0.883), and HPV 16 + lrHPVs + other hrHPVs (OR = 0.248, 95% CI 0.157–0.391). The prevalence of CIN 3 + was associated with increased severity of cytologic abnormalities in HPV 16/18-positive women and peaked at cytology HSIL + (89.9% and 82.3%), which held a substantially greater risk than that of NILM (OR = 65.466, 95% CI 50.234–85.316).ConclusionsIn this cross-sectional study of HPV 16/18-positive women, the effects of multiple infection were likely complicated and varied with specific HPV genotypes. The coinfection of HPV 16 and other genotypes of HPV except HPV 18 was associated with decreased CIN 3 + risk. Cytologic results were informative when HPV 16/18 was positive. It might be reasonable to recommend expedited treatment for patients with HPV 16/18 positive and HSIL + cytology in the Chinese population.

Cervical carcinogenesis risk association of HPV33 E6 and E7 genetic variations in Taizhou, Southeast China

BackgroundHuman papillomavirus (HPV) 33 belongs to the Alphapapillomavirus 9 (α-9 HPV) species group, which also contains types 16, 31, 35, 52, 58 and 67. The purpose of this study was to investigate the genetic variations of HPV33 and to explore its carcinogenicity among women in Taizhou, Southeast China.MethodsExfoliated cervical cells were collected for HPV genotyping. Only single HPV33 infection cases were selected, and their E6 and E7 genes were sequenced using the ABI 3730xl sequencer and then analysed using MEGA X.ResultsFrom 2014 to 2020, a total of 185 single HPV33-positive specimens were successfully amplified. We obtained 15 distinct HPV33 E6/E7 variants, which were published in GenBank under accession numbers OQ672665-OQ672679. Phylogenetic analysis revealed that all HPV33 E6/E7 variants belonged to lineage A, of which 75.7% belonged to lineage A1. Compared with CIN1, the proportion of sublineage A1 in CIN2/3 was higher, but there was no significant difference (76.5% vs. 80.6%, P > 0.05). Altogether, 20 single nucleotide substitutions were identified, of which 6 were novel substitutions, including T196G (C30G), A447T, G458T (R117L), G531A, A704A, and C740T. In addition, no significant trends were observed between the nucleotide substitutions of HPV33 E6/E7 variants and the risk of cervical lesions.ConclusionThis study provides the most comprehensive data on genetic variations, phylogenetics and carcinogenicity of HPV33 E6/E7 variants in Southeast China to date. The data confirmed that cervical lesions among women in Taizhou are attributable to HPV33, which may be due to the high infection rate of sublineage A1 in the population.

Diagnostic value of high-risk HPV other than type 16/18 in high-grade cervical neoplasia among cytology-negative women: A multicenter retrospective study.

Human papillomavirus (HPV) is a necessary cause of cervical cancer, and a tool more sensitive than cytology for the early screening of cervical precancers. The two most carcinogenic genotypes HPV 16/18 have been reported in the majority of studies. High-risk HPVs other than HPV 16/18 (non-16/18-hrHPVs) cause approximately a quarter of cervical cancers, and we aimed to analyze the genotype-specific prevalence, risk and diagnostic efficiency of non-16/18-hrHPVs in cervical carcinogenesis among Chinese cytology-negative women. A total of 7043 females who had abnormal cervical testing results from January 2018 to October 2021 were enrolled, among them 3091 were cytology-negative. Descriptive statistics was used to estimate the HPV genotype-specific prevalence, and multivariable logistic regression was used to estimate the genotype-specific non-16/18 hrHPVs risk of cervical carcinogenesis. The evaluation of diagnostic value among HPV genotypes included the possibility of predicting cervical intraepithelial neoplasia grade 2/3 or worse (CIN2+/CIN3+) and the diagnostic efficiency measured by increased referral rate and referral numbers of colposcopies per additional CIN2+/CIN3+ detected. Among HPV-positive cytology-negative women, the five dominant genotypes for CIN2+/CIN3+ were HPV 31/33/35/52/58. HPV 52/58/33 had comparatively high sensitivity and specificity in predicting CIN2+/CIN3+, while the referral strategy of multiple HPV58 required 26 colposcopies to detect 1 CIN3+, compared with 14, 12, and 8 required by multiple HPV52, 31, and 33, respectively. HPV31/33/35/52/58 infections are significant risk factors for cervical lesions, and multiple HPV 31/33/52 infections should be included in the previously recommended HPV16/18 genotyping triage for colposcopy in China, as the benefits of disease prevention may outweigh the disadvantages of increasing requirements for colposcopy services.

Trichomonas vaginalis infection is associated with increased risk of cervical carcinogenesis: A systematic review and meta-analysis of 470 000 patients.

Trichomonas vaginalis infection is the most prevalent non-viral sexually transmitted infection (STI) in women and has been suggested as a risk factor for developing cervical cancer. We aimed to investigate the associations between T. vaginalis infection and cervical carcinogenesis. A comprehensive systematic search was conducted in five databases on 21 October 2021. Studies assessing the relationship between T. vaginalis infection, HPV co-infections, cervical dysplasia, and cervical cancer were found eligible. Summary estimates for pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated with a random-effects model. Statistical heterogeneity was measured with I2 and Cochran's Q tests. The 29 articles included 473 740 women, of whom 8518 were T. vaginalis-positive. Our results showed that T. vaginalis-infected women had 1.79 times higher odds of being diagnosed with HPV co-infection (95% CI 1.27-2.53; I2 95%). We also found that T. vaginalis infection was associated with high-grade squamous intraepithelial lesion diagnosis (OR 2.34, 95% CI 1.10-4.95; I2 75%) and cervical cancer (OR 5.23, 95% CI 3.03-9.04; I2 3%). Our results showed an association between T. vaginalis and cervical carcinogenesis in sexually active women.

Abstract C029: The pattern of mutant p53 protein expression in cervical cancer-associated single and co-infection with human papillomavirus and Epstein-Barr virus

Abstract Introduction: There is mounting evidence indicating that the co-existence of Human papillomavirus (HPV), and Epstein-Barr virus (EBV) is associated with aggressive and poorly differentiated squamous cell carcinomas (SCC) phenotype. However, there is a paucity of data on the prevalence of EBV in cases of cervical cancer in Southern Nigeria or the effect of both viruses on p53 gene expression among patients diagnosed with cervical cancer. Therefore, this study investigated the prevalence of mutant p53 (mtp53) in single and co-presence of HPV and EBV-LMP1 in invasive and non-invasive cases of cervical cancer in order to determine the role of EBV in cervical carcinogenesis. Methods: This retrospective cohort study included 105 viable archived formalin-fixed paraffin-embedded tissues of cervical cancer, diagnosed between 2016 and 2019 in two tertiary health care facilities in Southern Nigeria. Tissue sections were stained for mtp53, EBV-LMP1, and HPV using the immunohistochemical technique and scored based on staining intensity and documented as 0, +1, +2, and +3. Tissues with scores of 0 and +1 were considered negative whereas those with scores of +2 and +3 were considered positive. Descriptive, Chi-square test and Pearson’s correlation were carried out and statistical significance was set at ≤0.05. Result: The mean age of participants with cervical cancer was 53.32 ± 12.54 years. The prevalence of invasive and non-invasive cases of cervical cancer were 62.9% and 37.1%, respectively. The prevalence of well, moderately, and poorly differentiated cervical cancer were 54.3%, 34.3%, and 11.4%, respectively. The prevalence of single EBV-LMP1, and HPV antigen were 21.0% (n= 21) and 14.2% (n= 15), respectively whereas the prevalence of EBV-LMP1/HPV co-infection was 42.9% (n= 45). The prevalence of HPV/EBV-LMP1 co=presence was high in invasive cervical cancer compared with non-invasive cervical cancer cases (45.5% versus 30.8%) at p= 0.154. The prevalence of mtp53 was higher in EBV-LMP1/HPV co-presence compared with HPV, and EBV-LMP1 mono-presence (80.0%, 60.0%, and 14.3%, respectively) at p= 0.001. Conclusion: This study suggests that EBV increases the risk of cervical carcinogenesis in HPV-infected individuals in Southern Nigeria. Thus, EBV DNA should equally be investigated during HPV testing of suspected cervical cancer cases to identify individuals with poorer prognoses. Citation Format: Jude Okoye, Anthony Ajuluchukwu Ngokere, Charles Chinedum Onyenekwe, Ukpai Eze, Okechi Obioma. The pattern of mutant p53 protein expression in cervical cancer-associated single and co-infection with human papillomavirus and Epstein-Barr virus [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C029.

Genetic diversity of E6, E7 and the long control region in human papillomavirus type 16 variants in Beijing, China

BackgroundHigh-risk human papillomavirus type 16 (HPV16) is a risk factor for cervical cancer. The progression from initial infection to cervical cancer has been linked to properties of the viral sequences. However, the distribution of HPV16 variants among Chinese women has not been extensively addressed and the role of HPV16 variants in the risk of cervical carcinogenesis remains poorly understood. MethodsHPV16 positive cervical exfoliated cell samples were collected from 249 women living in Beijing, China. PCR products from two fragments of E6-E7 and LCR of HPV16 in these samples were sequenced and analyzed. ResultsLineage A was found in the subjects, including A1, A2, A3 and A4 sublineages. Based on the HPV16 reference sequences, 26 nucleotide mutations of A4 sublineage and 39 nucleotide mutations of A1-3 sublineages were found in the E6, E7 and LCR of HPV16 isolates. Point mutations T843C, A7287C and A7872G of A4 sublineage were significantly associated with high-grade cervical lesions. The high-frequency sites in HPV16 LCR located at regions that can bind to multiple transcription factors. ConclusionsThis study contributes to the identification of unique variants in the E6, E7 and LCR of HPV16 isolates infected in Chinese women. Mutations of T843C, A7287C and A7872G in A4 sublineages were significantly associated with high-grade cervical lesions, suggesting that mutations in the E7 and LCR region have potential effects on viral replication and progression of cervical cancer.

Association of cervical carcinogenesis risk with HPV16 E6 and E7 variants in the Taizhou area, China

BackgroundHuman papillomavirus (HPV) type 16 accounts for a larger share of cervical cancer and has been a major health problem worldwide for decades. The progression of initial infection to cervical cancer has been linked to viral sequence properties; however, the role of HPV16 variants in the risk of cervical carcinogenesis, especially with longitudinal follow-up, is not fully understood in China.MethodsWe aimed to investigate the genetic variability of HPV16 E6 and E7 oncogenes in isolates from cervical exfoliated cells. Between December 2012 and December 2014, a total of 310 single HPV16-positive samples were selected from women living in the Taizhou area, China. Sequences of all E6 and E7 oncogenes were analysed by PCR-sequencing assay. Detailed sequence comparison, genetic heterogeneity analyses and maximum-likelihood phylogenetic tree construction were performed with BioEdit Sequence Alignment Editor and MEGA X software. Data for cytology tests and histological diagnoses were obtained from our Taizhou Area Study with longitudinal follow-up for at least 5 years. The relationship between HPV16 variants and cervical carcinogenesis risk was analysed by the chi-square test or Fisher’s exact test.ResultsIn this study, we obtained 64 distinct variation patterns with the accession GenBank numbers MT681266-MT681329. Phylogenetic analysis revealed that 98.3% of HPV16 variants belong to lineage A, in which the A4 (Asian) sublineage was dominant (64.8%), followed by A2 (12.1%), A1 (11.4%), and A3 (10.0%). The A4 (Asian) sublineage had a higher risk of CIN2+ than the A1–3 (European) sublineages (OR = 2.69, 95% CI = 1.04–6.97, P < 0.05). Furthermore, nucleotide variation in HPV16 E6 T178G is associated with the development of cervical cancer.ConclusionThese data could provide novel insights into the role of HPV16 variants in cervical carcinogenesis risk in China.

Circulating miR-15b, miR-34a and miR-218 as promising novel early low-invasive biomarkers of cervical carcinogenesis.

Circulating biological markers, such as miRNAs, hold the greatest possibilities to complement tissue biopsy and clinical diagnostic tests. The objective of this study was to evaluate the relative abundance ofthree circulatingmiRNAsin serum from 17 HPV16-positive patients with early cervical lesions known as Low-Grade Squamous Intraepithelial Lesions (LSILs). The expression of circulating microRNAs miR-15b, miR-34a and miR-218 in patients with LSILs was compared to 23 HPV-negative individuals showing normal cervical epithelium (healthy women) and 23 Squamous Cell Carcinoma (SCC) samples. The expression levels of miR-15b remained unchanged while those of miRNAs 34a and 218 were relatively high in serum obtained from LSIL patients in comparison with healthy women (results were statistically significant with a p of<0.01 or<0.001). According to previous findings, miR-15b was overexpressed and miRNAs 34a and 218 were underexpressed in serum from SCC patients. Additionally, the mRNA expression levels of some selected gene targets were determined [Cyclin D1 (CCND1), Cyclin E1 (CCNE1), B-cell lymphoma 2 (Bcl-2) and MutShomolog 2 (MSH-2)]. All serum results correlated with tissue samples from the same patients. We propose that circulatingmicroRNAs can be valuable as molecular markers for theearly follow-up of cervical carcinogenesis risk.

Co-infections of HPV16/18 with other high-risk HPV types and the risk of cervical carcinogenesis: A large population-based study

ObjectiveHuman papillomavirus (HPV) 16/18 genotyping is an effective method for triage of high-risk (hr) HPV-positive women in primary hrHPV screening for cervical cancer. The present study aimed to evaluate whether co-infected with other hrHPV types will affect the risk of cervical carcinogenesis in HPV16/18 positive women. MethodsA total of 313,704 women aged ≥30 years were screened in China. Among them, 4,933 HPV16/18-positive participants underwent colposcopy-directed biopsy. The HPV genotypes were identified using the Cobas HPV genotyping system. Multinomial logistic regression was used to model different HPV16/18 infection patterns. ResultsThe overall prevalence rates of hrHPV and HPV16/18 were 7.85% (24,456/311,382) and 1.95% (6,086/311,382) respectively. Among HPV16/18 positive individuals, 33.24% (2,023/6,086) were co-infection with multiple types. Of the 4933 women who underwent colposcopy, their HPV16/18 infection patterns were as follows: 52.38% (2,584/4,933) HVP16 only, 23.54% (1,161/4,933) HPV16 + other hrHPVs, 14.98% (739/4,933) HPV18 only, 6.83% (337/4,933) HPV18 + other hrHPVs, 1.13% (56/4,933) HPV16 + 18, 1.13% (56/4,933) HPV16 + 18+other hrHPVs. After adjusting for cofactors, compared with single HPV16 infection, the risk of developing cervical intraepithelial neoplasia (CIN) grade 3 or greater (CIN3+) was significantly lower in HPV16 + other hrHPVs group (odds ratio [OR] = 0.637, 95% confidence interval [CI] = 0.493-0.822). ConclusionHPV16/18 co-infection with other hrHPVs is a common phenomenon. Different HPV16/18 infection patterns may influence the risk of cervical carcinogenesis. HPV16 co-infected with other hrHPVs appears to have a lower associated risk of CIN3+ in ≥30 years old women.

Dietary Inflammatory Index and Its Relationship with Cervical Carcinogenesis Risk in Korean Women: A Case-Control Study.

Several studies have reported that diet’s inflammatory potential is related to chronic diseases such as cancer, but its relationship with cervical cancer risk has not been studied yet. The aim of this study was to investigate the association between Dietary Inflammatory Index (DII®) and cervical cancer risk among Korean women. This study consisted of 764 cases with cervical intraepithelial neoplasia (CIN)1, 2, 3, or cervical cancer, and 729 controls from six gynecologic oncology clinics in South Korea. The DII was computed using a validated semiquantitative Food Frequency Questionnaire (FFQ). Odds ratios and 95% CI were calculated using multinomial logistic regression. Higher DII scores were associated with higher cervical carcinogenesis risk. A significant association was observed between the DII and risk among CIN2/3 [Odds Ratio (OR) = 3.14; 95% Confidence Intervals (CI) = 1.57–6.29] and cervical cancer patients (OR = 1.98; 95% CI = 1.01–3.88). Among Human Papilloma Virus (HPV)-positive women, a significant association was found between DII and cervical carcinoma risk with CIN2/3 (OR = 5.65; 95% CI = 1.38–23.2). Moreover, women with CIN2/3 and cervical cancer showed a significant association with proinflammatory diet in people without of physical activity (OR = 3.79; 95% CI = 1.81–7.93). These findings suggest that high intake of proinflammatory diets is associated with increased risk of cervical carcinogenesis among women with CIN2/3. Further evaluation in future studies to confirm this association is warranted.

LC/MS-Based Polar Metabolite Profiling Identified Unique Biomarker Signatures for Cervical Cancer and Cervical Intraepithelial Neoplasia Using Global and Targeted Metabolomics

Cervical cancer remains one of the most prevalent cancers among females worldwide. Therefore, it is important to discover new biomarkers for early diagnosis of cervical intraepithelial neoplasia (CIN) and cervical cancer, preferably non-invasive ones. In the present study, we aimed to identify unique metabolic signatures for CINs and cervical cancers using global and targeted metabolomic profiling. Plasma samples (69 normal, 55 CIN1, 42 CIN2/3, and 60 cervical cancer) were examined by ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-QTOF-MS) coupled with multivariate statistical analysis. Metabolic pathways were analyzed using the integrated web-based tool MetaboAnalyst. A multivariate logistic regression analysis was conducted to evaluate the combined association of metabolites and human papillomavirus (HPV) status with the risk of cervical carcinogenesis. A total of 28 metabolites exhibiting discriminating levels among normal, CIN, and cervical cancer patients (Kruskal–Wallis test p < 0.05) were identified in the global profiling analysis. The pathway analysis showed significantly altered alanine, aspartate, and glutamate metabolic pathways (FDR p-value < 0.05) in both the discovery and validation phases. Seven metabolites (AMP, aspartate, glutamate, hypoxanthine, lactate, proline, and pyroglutamate) were discriminated between CINs and cervical cancer versus normal (area under the curve (AUC) value > 0.8). The levels of these metabolites were significantly high in patients versus normal (p < 0.0001) and were associated with increased risk of developing CIN2/3 and cervical cancer. Additionally, elevated levels of the seven metabolites combined with positive HPV status were correlated with substantial risk of cancer progression. These results demonstrated that metabolomics profiling is capable of distinguishing CINs and cervical cancers from normal and highlighted potential biomarkers for the early detection of cervical carcinogenesis.

Significant association between IL10-1082/-819 and TNF-308 haplotypes and the susceptibility to cervical carcinogenesis in women infected by Human papillomavirus

Human papillomavirus (HPV) is responsible for high-grade cervical lesions and cervical cancer. The inflammation plays a key role in cervical cancer progression. In this context, studies propose an association between TNFα and IL10 SNPs and susceptibility to HPV infection. The present work aimed to investigate the possible association between IL10 and TNFα promoter polymorphisms and HPV infection in the cervical carcinogenesis risk in women from Brazil. A total of 654 samples was evaluated in this study. HPV detection was performed by PCR and HPV genotyping was performed by PCR and sequencing of positive MY09/11 PCR product. Genotyping of IL10 SNPs (rs1800871 and rs1800896) was performed by High Resolution Melt analysis. Genotyping of TNFα SNP (rs1800629) was performed by fluorogenic allele-specific probes. The distribution of TNF-308 (rs1800629) allelic (p = 0.03) and genotype (p = 0.03) frequencies and HPV-58 infection has showed a statistically significant difference between case and control groups for the assessed TNFα polymorphism. When it comes to TNFα (rs1800629) allelic and genotypic distribution and HPVs 18 and 31 infections, no statistically significant differences between case and control groups were observed for the studied TNFα polymorphism. The allelic and genotypic distribution of IL10-819 (rs1800871) and IL10-1082 (rs1800896) and HPV infection (HPVs 58, 18 and 31) has showed no statistically significant differences between case and control groups for the assessed IL10 polymorphisms. Furthermore, it was observed that haplotypes were associated with an increased cervical cancer risk in HPVs 16, 18 and 58-positive women. It was observed that women carrying the GTA and ATG haplotypes had 3.85 and 17.99-fold, respectively, increased cervical cancer susceptibility when infected by HPV-58. In women infected with HPV-16 and HPV-18, statistically significant results in women carrying the GTA and ATA haplotypes was observed. They had a 2.32 and 3.67-fold, respectively, increased cervical cancer susceptibility when infected by these two HPV types. The analysis of the haplotypes distribution in women infected with HPV-31 has showed no statistically significant results. Our study indicates that the association of genetic polymorphism in inflammation-related genes represents a risk to the susceptibility in the development of cervical cancer in women infected by HPVs 16, 18 and 58.

Interaction between abnormal expression of fragile histidine triad and methyl-CpG-binding protein 2 on cervical cancerization

Objective: To explore the relationship between abnormal expression of fragile histidine triad (FHIT) gene and methyl-CpG-binding protein 2 (MeCP2) as well as their interaction on cervical cancerization. Methods: A total of 73 patients with cervical squamous cell carcinoma (SCC), 113 patients with cervical intraepithelial neoplasia (CIN Ⅰ, n=45; CINⅡ/Ⅲ, n=68) and 60 women with normal cervix (NC) were included in the study. Real time PCR and Western blot were performed to detect the expression levels of mRNA and protein about FHIT and MeCP2, respectively. The methylation status of FHIT gene CpG island was tested by methylation-specifc PCR (MSP). Kruskal-Wallis H test, χ(2) test, trend χ(2) test and Spearman correlation analysis were conducted with software SPSS 20.0. The interaction was evaluated by generalized multifactor dimensionality reduction (GMDR) model. Results: With the deterioration of cervical lesion, the methylation rates of FHIT gene CpG island (χ(2)=18.64, P<0.001; trend χ(2)=18.08, P<0.001) increased gradually, while the expression levels of FHIT mRNA (H=27.32, P<0.001; trend χ(2)=12.65, P<0.001) and protein (H=47.10, P<0.001; trend χ(2)=29.79, P<0.001) decreased gradually. There was a negative correlation between the methylation rates of FHIT gene CpG island and the expression level of FHIT protein (r=-0.226, P<0.001). The levels of MeCP2 mRNA (H=26.19, P<0.001; trend χ(2)=11.81, P=0.001) and protein (H=69.02, P<0.001; trend χ(2)=47.44, P<0.001) increased gradually with the aggravation of cervical lesions. There was a positive correlation between the expression level of MeCP2 protein and the FHIT mRNA Ct ratio (r=0.254, P<0.001). Expression of proteins were negatively correlated between MeCP2 and FHIT (r=-0.213, P=0.001). The results analyzed by GMDR model showed that there were interactions among high MeCP2 protein expression, the CpG island methylation of FHIT and mRNA and protein expression in CINⅡ/Ⅲ group, and among high MeCP2 mRNA and protein expression, the CpG island methylation of FHIT and low mRNA and protein expression in SCC group. Conclusion: High expression of MeCP2 mRNA and protein, the CpG island methylation and low mRNA and protein expression of FHIT could increase the risk of cervical carcinogenesis, and there might be a synergistic effect on cervical carcinogenesis.

Clinical significance of hWAPL polymorphisms in the risk of cervical carcinogenesis.

To investigate the clinical significance of human wings apart-like (hWAPL) genetic polymorphisms in cervical carcinogenesis. hWAPL polymorphisms and human papillomavirus (HPV) types were examined in 175 cervical smears of exfoliated cervical cell samples using a real-time polymerase chain reaction system. A significant difference was detected in the frequency of the CC genotype between the HPV(+) low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL) groups [Odds ratio 0.21, 95% confidence interval (CI) 0.0723-0.61; P=0.0029]. A significant difference was noted in the frequency of the CC genotype between the high-risk HPV-positive LSIL and HSIL groups (odds ratio 0.2955, 95% CI 0.0893-0.9771; P=0.0414). The CC genotype of hWAPL gene promoter polymorphism may be associated with cervical carcinogenesis.

FAS-670 gene polymorphism and cervical carcinogenesis risk: A meta-analysis

FAS is a cell surface receptor that plays an important role in the etiology of cancer. Previous studies on the association between FAS-670 polymorphism and cervical carcinogenesis failed to reach a consensus; therefore, this meta-analysis was conducted to estimate the association of FAS-670 polymorphism and the risk of cervical cancer. This meta-analysis included 10 studies on FAS-670 genotyping, including a total of 2,901 cases and 2,831 controls. The complete overdominant model was applied in our meta-analysis [AB vs. AA: odds ratio (OR)=0.879, 95% confidence interval (CI): 0.775-0.998, P=0.046; BB vs. AA: OR=0.903, 95% CI: 0.775-1.052, P=0.190]. The random effects OR was 1.13 (95% CI: 0.95-1.34, I2=52.7%, Pheterogeneity=0.03). An ethnic subgroup analysis was subsequently performed. The OR for Asians was 1.25 (6 comparisons, 95% CI: 1.05-1.48, I2=23.5%, Pheterogeneity=0.03), whereas for Caucasians, no significant association was observed between FAS-670 polymorphism and cervical carcinogenesis (4 comparisons, OR=0.96, 95% CI: 0.75-1.24, I2=45.9%, Pheterogeneity=0.14).

An interleukin-10 gene polymorphism associated with the development of cervical lesions in women infected with Human Papillomavirus and using oral contraceptives

Human Papillomavirus (HPV) infection plays a crucial role in the development of cervical lesions and tumors, however most lesions containing high-risk HPVs do not progress to cervical tumors. Some studies suggest that the use of oral contraceptives may increase the risk of cervical carcinogenesis, but this has not been confirmed by all the studies. Cytokines are important molecules that act in the defense of an organism against viral infections. Several genetic studies have attempted to correlate cytokine polymorphisms with human diseases, including cancer. The significance of IL10 polymorphisms for cancer is that they have both immunosuppressive and antiangiogenic properties. We aimed to investigate the role of promoter polymorphisms in the IL10 gene in women with cervical lesions associated with HPV infection, in the presence of the use of oral contraceptives. Using High Resolution Melt analysis (HRM), we analyzed an SNP -1082A/G and -819C/T in interleukin-10 promoter region in 364 Brazilian women: 171 with cervical lesions and HPV infection, and 193 with normal cytological results and HPV-negative. We observed no significant differences in genotype and allele frequencies in the two loci between patients and healthy controls. Furthermore, in the haplotype analysis of IL10, we found that CA haplotype was significantly more frequent in patients infected with HPV than in the control group (p=0.0188). We did not find any genotype and allelic association of the IL10 gene polymorphisms between cases and controls. However, in this study, when the HPV-positive patients were stratified according to their use of contraceptives, we found a significant association between the -1082G allele (p=0.0162) and -1082GG genotype (p=0.0332) among HPV-infected patients who used oral contraceptives. Our findings suggest that -1082A/G gene polymorphism represents a greater susceptibility to progressive cervical lesions in HPV- infected women who use oral contraceptives.

Functional polymorphism in manganese superoxide dismutase and antioxidant status: Their interactions on the risk of cervical intraepithelial neoplasia and cervical cancer

Objective Manganese superoxide dismutase (MnSOD), the primary antioxidant enzyme in mitochondria, plays a key role in protecting cells from oxidative stress. Furthermore, the MnSOD rs4880 polymorphism is associated with enzyme activity. The authors evaluated the interaction between MnSOD genotypes and cervical carcinogenesis risk and the modulating effects of serum antioxidant nutrient status (β-carotene, lycopene, zeaxanthin/lutein, retinol, α-tocopherol and γ-tocopherol). Methods Cases and controls for this study were recruited between June 2006 and July 2007 (263 controls, 84 cervical intraepithelial neoplasia (CIN), 94 CIN 2/3, and 99 cases of cervical cancer). The MnSOD polymorphism at rs4880T/C was examined using SNaPshot assays. Serum antioxidant vitamin concentrations were measured by reverse-phase gradient high-pressure liquid chromatography. Odds ratios (OR) and 95% confidence intervals (95%CI) were estimated after adjusting for age, menopause, parity, oral contraceptive use, smoking and alcohol consumption. Results No association was found between the MnSOD rs4880 polymorphism and cervical cancer. However, genotypes significantly modified the risk of cervical cancer in association with the serum statuses of micronutrients ( P interaction < 0.05 for β-carotene, lycopene, zeaxanthin/lutein, α-tocopherol, and γ-tocopherol). Decreased CIN1 risk in association with the MnSOD rs4880 variant genotype was also observed particularly for subjects with higher β-carotene and γ-tocopherol levels. Similar results were observed for lycopene and α-tocopherol in relation to the risk of CIN2/3. Conclusion Our findings suggest that a higher antioxidant micronutrients status may decrease the risk of CIN and cervical cancer and modify the effect of the MnSOD polymorphism on disease risk.

Impact of methylenetetrahydrofolate reductase (MTHFR) codon (677) and methionine synthase (MS) codon (2756) on risk of cervical carcinogenesis in North Indian population

Cervical cancer continues to be the most common cause of death among women in developing countries. Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) are critical enzymes of folate metabolic pathways. In this work, we have conducted a case-control study to assess the role of these two polymorphisms in cervical cancer development. We obtained blood samples from 200 women with cervical cancer and from equal matched controls and analysed using PCR-RFLP method. We found that the methylenetetrahydrofolate reductase variant CT and CT+TT genotypes decreased cervix cancer risk, statistically significant (OR:0.30, 95% CI: 0.18-0.51, P<0.001 for CT and OR:0.29, 95% CI: 0.18-0.49, P=0.0000006 for CT+TT). Similarly in those patients who used oral contraceptive with variant CT genotype, there was statistically highly significant reduced risk of cervix cancer (OR:0.25, 95% CI: -0.12-0.49, P<0.001) of methylenetetrahydrofolate reductase gene. For the methionine synthase, 2756 variant AG and AG+GG genotypes were similarly associated with highly significant reduced risk of cervix cancer (OR: 0.13, 95% CI: 0.07-0.26, P<0.001 for AG, and OR: 0.15, 95% CI: 0.08-0.27, P<0.001 for AG+GG) genotypes. In conclusion, our study suggested that methylenetetrahydrofolate reductase and methionine synthase polymorphisms might have protective effect on the risk of cervical cancer in the North Indian women.

Relationship between steroid hormone contraceptives and HPV, cervical intraepithelial neoplasia and cervical carcinoma.

Available data demonstrate an increase in the transcription of high-risk papillomaviruses by the 16alpha-hydroxylation of estrogens, which is in line with the epidemiologic data showing an increased cervical carcinogenesis risk for long-term contraceptive-using, HPV-infected women. No evidence exists for an increase in HPV-negative contraceptive users.