Higher Risk Of Cervical Cancer Research Articles

POLYMORPHISM ARG72PRO OF THE P53 GENE AND THE RISK OF HUMAN PAPILLOMAVIRUS ASSOCIATED CERVICAL CANCER IN WOMEN FROM KYRGYZ REPUBLIC

Aim. Allele frequency and genotype distribution in the cervical cancer group were compared with those of the control group to determine whether polymorphism Arg72Pro of Р53 gene elevates the susceptibility of Kyrgyz women to cervical cancer (CC). Materials and Methods. A total of 102 women (mean age 53,5±10 years) of Kyrgyz nationality with cervical cancer were recruited into the study and 102 healthy women were used as the control group (mean age 46,5±8,5 years). The diagnosis of cervical cancer was confirmed histologically. 88 % (90/102) of women with cervical cancer were human papillomavirus (HPV) positive. 17 % (15/90) specimens were positive for HPV type 16, 48 % (43/90) were positive for HPV type 18 and 35 % (32/90) were positive both HPV - 16/18. Presence of human papillomavirus DNA types 16 and 18 was analyzed by polymerase chain reaction with hybridization-fluorescence detection. The Arg72Pro polymorphisms of the P53 gene were determined by the PCR-RFLP method. Results. No significant difference was found between genotype distributions in the cervical cancer patients and the control group (χ2=1,24; р=0,54). However, the Arg72Arg genotype and Arg72 allele was significantly more frequent in women with cervical cancers infected with HPV than in the control group (χ2=7,25; р=0,027 for для genotype, χ2=6,83; р=0,009 for allele). Women who are HIV positive and having the Arg72 allele had 1,94 fold (OR=1,94 [1,20-3,15]; р=0,009) higher risk of developing CC compared with subjects carrying neither of these alleles. HPV positive women carrying the genotype Arg72Arg had 1,85 fold (OR=1,85 [1,03-3,32]; р=0,027) higher risk of CC. Conclusion. The Arg72Arg genotype of р53 gene in HIV positive women from Kyrgyz Republic may represent a potential risk factor for the development of cervical cancer.

Cervical Papanicolaou Smears in Hematopoietic Stem Cell Transplant Recipients: High Prevalence of Therapy-Related Atypia during the Acute Phase

Hematopoietic stem cell transplant (HSCT) recipients have a higher risk of cervical cancer. Papanicolaou (Pap) smear is the standard tool for screening cervical cancer, but there is limited research about the cervical cytology in HSCT recipients. Here, we retrospectively included adult female patients who underwent allogeneic or autologous HSCT at National Taiwan University Hospital during 2009 to 2015 and reviewed their Pap smears before and after HSCT. There were 248 allogeneic and 131 autologous HSCT recipients in our study. In allogeneic HSCT recipients, 38.7% (96 of 248) had pre-HSCT Pap smears and 17.1% (44 of 248) had post-HSCT Pap smears. In the autologous HSCT recipients, 35.1% (46 of 131) had pre-HSCT Pap smears and 13.7% (18 of 131) had post-HSCT Pap smears. Compared with allogeneic HSCT recipients without post-HSCT Pap smears, more recipients with post-HSCT Pap smears received bone marrow–derived stem cells (18.2% versus 4.9% respectively; P = .0077) and had longer overall survival (median overall survival, not reached versus 22.1 months; P < .0001). The abnormal rates of post-HSCT Pap smear were 13% (6 of 44) and 11% (2 of 18) in allogeneic and autologous recipients respectively, higher than in the general Taiwanese population (1.22%). Infections were rare in post-HSCT Pap smears. Of note, 11% (5 of 44) of post-HSCT Pap smears from allogeneic recipients showed therapy-related atypia, manifesting as enlarged hyperchromatic nuclei, vacuolated cytoplasm, and occasional tadpole-like cells. These atypical cytological features mimic precancerous lesions, but cervical biopsies and human papilloma virus tests were negative. The atypical cytological features resolved spontaneously in the subsequent follow-up Pap smears. On average, Pap smears with therapy-related atypia were sampled at day +77, significantly earlier than those without therapy-related atypia (P = .016). Therapy-related atypia was more frequent in post-HSCT Pap smears sampled within 100 days after HSCT (before day +100, 4 of 5, 80%, versus after day +100, 1 of 39, 2.56%; P = .0002). The strong temporal relationship suggests these atypical cytological changes resulted from conditioning regimen, most likely busulfan-containing chemotherapy. No therapy-related atypia were observed after total body irradiation or nonbusulfan-containing chemotherapy. In conclusion, therapy-related atypia was common in post-HSCT Pap smears sampled within 100 days after HSCT. Clinical information is critical for correct cytological diagnosis.

Perceptions of Cervical Cancer Risk among Ohio Appalachian Women

Abstract OBJECTIVE: To describe how Ohio Appalachian women are over- or under-estimating risk for cervical cancer by comparing an objective measure of cervical cancer risk to subjective interpretations of risk. METHODS: A cervical cancer risk index was computed for 530 female participants recruited from clinics in Ohio Appalachia (2006–2008). Risk factors for cervical cancer, including human papillomavirus infection, number of sexual partners, parity, age at first intercourse, age at first pregnancy, oral contraceptive use and cigarette smoking were used to create a cervical cancer risk index. This index was used to categorize participants into low, average or high risk for cervical cancer. Subjective risk was assessed by asking women to indicate whether they believe their risk of cervical cancer to be below, about average, or higher than other women. Objective risk categories were compared to subjective risk to determine if women were accurately perceiving risk, or over- or under-estimating risk. A multinomial logistic regression model was used to determine correlates of risk perception accuracy. The outcome was a categorical variable consisting of over-estimating risk, underestimating risk and accurate risk perception, with accurate risk perception serving as the reference level in the model. RESULTS: Out of 530 women, 33.6% (n = 178) over-estimated risk and 24.9% (n = 132) under-estimated risk. Women with household incomes of &amp;lt;$25 k were more likely to under-estimate cervical cancer risk, as opposed to being accurate in their risk perception, than women in households earning over $50 k [OR = 2.06, 95% CI (1.04–4.07)] as were women with less than a high-school education [OR = 2.52, 95% CI (1.06–5.96)] compared to women with a college education. Also, women who reported recent alcohol use were more likely to under-estimate risk [OR = 1.94, 95% CI (1.18–3.19)] compared to women with no self-reported recent alcohol use. No variables were found to be associated with risk over-estimation. CONCLUSIONS: Many women in Ohio Appalachia do not accurately perceive their cervical cancer risk. Low income and education are associated with under-estimating risk. Future studies should determine if risk misperceptions are associated with cervical cancer screening and other preventive behaviors.

Systematic Review and Meta-Analysis of Individual Patient Data to Assess the Sensitivity of Cervical Cytology for Diagnosis of Cervical Cancer in Low- and Middle-Income Countries.

PurposeTo assess the sensitivity of cervical cytology to cancer by pooling individual patient cytology results from cancers diagnosed in studies that assessed cervical screening in low- and middle-income countries.MethodsTwo authors reviewed studies identified through PubMed and Embase databases. We included studies that reported cervical cytology in which at least one woman was diagnosed with cervical cancer and in which abnormal cytology results were investigated at colposcopy and through a histologic sample (if appropriate). When cytology results were not reported in the manuscript, authors were contacted. Stratified analyses and meta-regression were performed to assess sources of heterogeneity between studies.ResultsWe included 717 cancers from 23 studies. The pooled sensitivity of cytology to cancer at a cutoff of a high-grade squamous intraepithelial lesion (HSIL) or worse was 79.4% (95% CI, 67.7% to 86.0%). Results from stratified analyses did not differ significantly, except among studies that recruited symptomatic women or women referred because of abnormal cytology, when the sensitivity of cytology was much higher (95.9%; 95% CI, 86.5% to 99.9%). The cutoff of an HSIL or worse detected 85% of the cancers that would have been detected at a cutoff of atypical squamous cells of undetermined significance or worse (relative sensitivity, 85.2%; 95% CI, 80.7% to 89.7%).ConclusionCytology at a high cutoff could be an excellent tool for targeted screening of populations at high risk of cervical cancer with a view to diagnose cancer at an earlier stage.

Comorbidity profiles among women with postcoital bleeding: a nationwide health insurance database.

Most of the existing studies on postcoital bleeding (PCB) in Western countries. To date, no study has focused on the various PCB-related comorbidities in Taiwan women. This work aims to analyze and compare the presence or absence of PCB among Taiwanese women with gynecological comorbidity. This study is a population-based retrospective cohort investigation. Outpatients with PCB after the index date were considered. A total of 2377 female patients with PCB (ICD-9 626.7) were identified using a nationwide outpatient sample from 2001 to 2010. For comparison, 7131 cases were randomly matched with the study group in terms of gender and age. The PCB incidence rate was 39-59 cases/100,000 Taiwanese women, with mean age (±SD) of 36.74 ± 10.79 years, median age of 36 years, and mode age of 29 years. Women with PCB exhibited 1.47-fold risk of cervical dysplasia and 1.59-fold risk for malignant neoplasm of cervix. Young women with PCB showed high risk of cervical cancer. The most common benign diseases among PCB- related comorbidities were cervical erosion and ectropion (20.66%), followed by vaginitis and vulvovaginitis (19.18%). Comparison between PCB and non-PCB groups indicated several significant high-risk comorbidities including cervical polyps, cervical erosion, leukoplakia of cervix, intrauterine contraceptive device, cervicitis, vaginitis, menopause, dyspareunia, and vulvodynia. This study provides evidence that PCB-related comorbidities manifested benign diseases (51.58%), lower genital tract infection (46.11%), and cervical cancer (2.31%). Thus, healthcare providers must ensure that appropriate routine screening tests and counseling are given to women with PCB.

Trends in geographical disparities for cervical cancer mortality in China from 1973 to 2013: a subnational spatio-temporal study.

This study was designed to explore the time trends in geographical variations of cervical cancer mortality in mainland China over the period 1973 to 2013, to provide subnational spatio-temporal patterns for targeted promotion of human papillomavirus vaccine in China. Data were extracted from three national retrospective death surveys and cancer registry. The rate ratio (RR) was estimated for the aggregated data for seven geographical regions using generalized linear models to evaluate time trends in geographical disparities of cervical cancer mortality. There was a significant decrease in cervical cancer mortality in China from 1973-1975 to 2004-2005, but leveled off thereafter to 2011-2013. Compared to the period 1973-1975 the RR for the three last time periods were 0.33 [95% confidence interval (95% CI): 0.30-0.37] for 1990-1992, 0.21 (95% CI: 0.19-0.24) for 2004-2005 and 0.24 (95% CI: 0.22-0.26) for 2011-2013. Females living in the Northwest China and Central China have a high risk of mortality from cervical cancer compared to the nationwide, with the RR being 2.09 (95% CI: 1.83-2.38) and 1.26 (95% CI: 1.11-1.44) respectively, while the RRs for South China, Northeast China and Southwest China were below 1.00, indicating the lower death risk. Despite the mortality rate had increased slightly from 2004 to 2013, there was an encouraging sign that the geographical disparities in cervical cancer mortality had gradually narrowed over time across China. Although cervical cancer mortality in China has reduced to very low levels, the high risk of cervical cancer in Northwest China and Central China is still noteworthy. Public health policies including the promotion of vaccine should be targeted to further reduction of geographical disparities in cervical cancer mortality.

Adherencia al seguimiento y evolución de la lesión en mujeres con Neoplasia intra epitelial cervical escamosa grado 1

ObjectiveTo determine adherence to follow-up and outcome of lesions in women diagnosed with grade 1 cervical intraepithelial neoplasia (CIN 1). MethodologyThe study included non-pregnant women aged 18 or older, referred for colposcopy, with a colposcopy directed biopsy diagnosis of CIN 1, with no history of prior CIN, hysterectomy or cervical ablative therapy. Participants answered a questionnaire on risk factors, and the outcome of previous cytology and colposcopy was documented. All women should have been followed up for 1 year with cytology and colposcopy every six months. Those who did not have cytology and colposcopy / colposcopy assessments or documented treatments after 15 months were considered as non-adherent. ResultsA total of 40 patients with CIN 1 were included. The loss to follow-up rate of loss was 17/40 (42.5%). The demographic and clinical variables most frequently associated with non-adherence to follow-up were null parity and early initiation of sexual intercourse. The progression of low-grade to high-grade lesion was observed in 4.3%. 22.5% failed Conservative treatment failed conservative treatment and moved to invasive therapy. ConclusionThe rate of loss to follow-up was high, with a considerable referral from conservative to invasive therapy. A large percentage of patients had regression of CIN 1. This study should help clarify the optimal strategies for the treatment of women with low-grade cervical abnormalities in populations of low sociocultural conditions and high risk of cervical cancer.

Pre-microRNA Gene Polymorphisms and Risk of Cervical Squamous Cell Carcinoma.

MicroRNAs (miRNAs) are short (~22 nucleotides) regulatory RNAs that can modulate gene expression and are aberrantly expressed in many diseases, including cancer. It has been suggested that, the presence of single nucleotide polymorphisms in precursor miRNAs (pre-miRNAs) can alter miRNA processing, expression and binding to target mRNA and represents another type of genetic variability, that can contribute to the susceptibility of human cancers. The present study investigated the genetic variants in pre-miRNAs (hsa-miRNA-196a2 rs11614913 C/T, hsa-miRNA-499 rs3746444 T/C and hsa-miRNA-146a rs2910164 G/C) for their role in cervical cancer susceptibility. The study comprised 164 controls and 184 patients of cervical cancer. The genotypic frequency of miRNA polymorphisms were determined by using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Logistic regression was used for statistical analysis using SPSS Software version 15.0. Hsa-miRNA-499 rs3746444 T/C polymorphism showed a statistically significant association with considerable risk for cervical cancer at genotypes (CC, p=0.001, OR=4.801) and variant allele (p<0.001, OR=2.307). MiRNA 146a and miRNA 196a2 polymorphisms showed no association with cervical cancer. However, interaction of miRNA polymorphisms with smoking habit showed higher risk of cervical cancer with miRNA 196a2 polymorphism in patients with smoking but no significant modification in the risk of cervical cancer was seen for other polymorphisms. The results of the present study demonstrate that, miRNA 499 T/C polymorphism is significantly associated with genetic susceptibility to cervical cancer and may have a role in its pathogenesis.

The temporal and age-dependent patterns of hysterectomy-corrected cervical cancer incidence rates in Denmark: a population-based cohort study.

Hysterectomy is a common gynecological procedure; however, the incidence of total and subtotal hysterectomy varies across countries, by age, and over time. As only women with an intact cervix are at risk of cervical cancer, failing to remove hysterectomized women from the denominator may underestimate the cervical cancer incidence. We aimed to describe the temporal and age-dependent patterns of cervical cancer incidence in Denmark before and after correction for hysterectomy. Using data from national registries we calculated uncorrected and hysterectomy-corrected cervical cancer incidence rates among women ≥20 years during 2000-11. Hysterectomy-corrected rates were calculated by subtracting post-hysterectomy person-years from the denominator. The overall uncorrected cervical cancer incidence rate was 17.8/100 000 person-years (95% CI 17.3-18.3). After correction for hysterectomy, the rate increased by 8.4% to 19.3/100 000 person-years (95% CI 18.8-19.9). The highest uncorrected incidence was seen in women aged 35-39 years, peaking at 24.4/100 000 person-years, whereas the highest hysterectomy-corrected cervical cancer incidence rate was observed in women aged 75-79 years (29.4/100 000 person-years). Over time, women ≥60 years had the highest hysterectomy-corrected cervical cancer incidence. Correcting for hysterectomy incidence resulted in a higher cervical cancer incidence and a shift in the peak incidence from age 35-39 years to age 75-79 years. Over time, women ≥60 years were at the highest risk of cervical cancer. Given the high incidence in women >60-65 years, when women are eligible to exit screening, a revision of the screening guidelines may be warranted.

Association between high risk human papillomavirus infection and co-infection with Candida spp. and Trichomonas vaginalis in women with cervical premalignant and malignant lesions

BackgroundHuman papillomavirus (HPV) is the necessary cause of cervical cancer. Cervico-vaginal infection with pathogens like Chlamydia is a likely cofactor. The interactions between HPV, Trichomonas vaginalis (TV) and Candida spp. are less understood, though inflammation induced by these pathogens has been demonstrated to facilitate oncogenesis. ObjectiveOur study aimed to evaluate the association between Candida spp. and TV co-infection with HPV in cervical oncogenesis. Study designWomen with normal cervix who were high-risk HPV-negative (N=104) and HPV-positive (N=105); women with CIN 1 (N=106) and CIN 2/CIN 3 (N=62) were recruited from a community based cervical cancer screening program. Cervical cancer patients (N=106) were recruited from a tertiary care oncology clinic. High-risk HPV was detected by Hybrid Capture II technique; Candida spp. and TV were detected by culturing the high vaginal swabs followed by microscopic examination in all. The disease status was established by histopathology in all the women. ResultHPV-positive women had significantly higher risk of having precursor lesions (of any grade) and cancer compared to HPV-negative women. Candida spp. or TV infection did not alter the risk of low grade or high grade lesions among HPV- positive women. HPV positive women co-infected with TV had higher risk of cervical cancer but not those co-infected with Candida spp. ConclusionThe higher risk of cancer observed in the women co-infected with HPV and TV without any enhanced risk of CIN 3 suggests secondary infection of the malignant growth by TV rather than any causal role. Co-infection with Candida spp. and/or TV infection did not increase the carcinogenic effect of HPV on cervix.

Characteristics Associated with HPV Diagnosis and Perceived Risk for Cervical Cancer Among Unmarried, Sexually Active College Women.

Human papillomavirus (HPV) has been identified as the leading cause of cervical cancer. While HPV risk factors have been well studied, less is known about those with HPV and their perceptions about health ramifications. The purposes of this study were to examine unmarried college student women's (1) HPV diagnosis status and (2) perceived risk of getting cervical cancer in the next 5years. Data were analyzed from 1106 unmarried, sexually active college women aged 18 to 26. Binary logistic regression compared HPV-related knowledge, vaccination-related perceptions, mandate support, healthcare utilization, sexual behaviors, and personal characteristics. Multinomial logistic regression was performed to assess the degree to which these factors were associated with perceived risk of cervical cancer diagnosis. Relative to those not diagnosed with HPV, participants who had more lifetime sex partners (P<0.001), unprotected sex during last intercourse (P=0.003), Pap test in the past year (P<0.001), and perceived themselves to be at higher risk for cervical cancer (P<0.001) were significantly more likely to be diagnosed with HPV. Those with HPV were more likely to support HPV vaccination mandates (P=0.036) and have fewer friends vaccinated (P=0.002). Participants who were uninsured (P=0.011), diagnosed with HPV (P<0.001), and had a family member (P<0.001) or friend (P<0.001) with cervical cancer were more likely to perceive themselves at risk for developing cervical cancer in the next 5years. Findings indicate women with HPV, despite engaging in risky sexual behaviors, acknowledge their cervical cancer risk and may be strong advocates for HPV vaccination mandates to protect youth against this preventable virus.

Association Between the IL-6 rs1800795 Polymorphism and the Risk of Cervical Cancer: A Meta-Analysis of 1210 Cases and 1525 Controls.

Cervical cancer is the second most common cancer and the third leading cause of cancer-related death among females in less developed countries. Studies have shown that the single-nucleotide polymorphisms of interleukin 6 might be associated with cervical cancer risk. A total of 710 articles from EMBASE, EBSCO, Web of science, PubMed, Springer link, and Chinese National Knowledge Infrastructure databases were reviewed in our study. A meta-analysis on the associations between interleukin 6 rs1800795 polymorphism and cervical cancer risk was carried out by comparison using 5 genetic models. In this systematic review, 5 studies were analyzed. The pooled population included 2735 participants (1210 cases and 1525 controls). The overall odds ratio (G vs C alleles) using fixed-effects model was 0.85 (95% confidence interval 0.75-0.97), P = .02. Our results show that the C genotype of interleukin 6 rs1800795 is associated with higher cervical cancer risk. Our results indicate that interleukin 6 rs1800795 polymorphism might be associated with susceptibility to cervical cancer.

Association of human papillomavirus type 16 and its genetic variants with cervical lesion in Korea.

Persistent human papillomavirus type 16 (HPV16) is the major risk factor for cervical cancer. HPV16 intratypic variants differ in their geographical distribution and oncogenic potential. This study aimed to analyze the distribution of HPV16 variants and their association with cervical lesion histopathology in Korean women. In total, 133 HPV16-positive cervical samples from women admitted to Seoul National University Boramae Hospital were analyzed by sequencing E6, E7, and L1 genes and the long control region (LCR), and the variant distribution according to cervical lesion grade was determined. Isolates were grouped into a phylogenetic lineage, and A1-3, A4, C, and D sublineages were detected in 54.1, 37.8, 0.7, and 7.4% of samples, respectively. The most commonly observed LCR variations were 7521G>A (91.5%), 7730A>C (59.6%), and 7842G>A (59.6%). Furthermore, A4 or D sublineage-positive women had a higher risk for cervical cancer than women who were positive for A1-3. Among HPV phylogenetic clusters, A1-3 was the predominant sublineage, and within A1-3, the 350G polymorphism was highly frequent. These results differed from those of previous studies in Korea and other Asian countries. The findings suggest that cervical neoplasia incidence in HPV16-infected patients could be affected by the distribution of HPV16 variants in the population.

Follow-up of women with cervical cytological abnormalities showing atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion: a nationwide cohort study

Atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion in abnormal cervical cytology among young women in cervical cancer screening is an increasing health burden, and comparative effectiveness studies of different management options for such diagnoses are needed. The objective of the study was to compare the incidence of invasive cervical cancer, following different management options pursued after an atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion index smear. In this nationwide cohort study, we included all women aged 22-50 years and resident in Sweden 1989-2011 and with at least 1 cervical smear registered during the study period (n= 2,466,671). Follow-up of a first atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion cytological diagnosis within 25 months was classified as repeat cytology, colposcopy/biopsy, or without further assessment. Incidence rate ratios and 95% confidence intervals of subsequent cervical cancer within 6.5 years following atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion were estimated using Poisson regression by age group and management strategy. Women managed with repeat cytology within 6 months after atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion cytology had a similar risk of cervical cancer compared with colposcopy/biopsy (incidence rate ratio, 1.1, 95% confidence interval, 0.5-2.5, and incidence rate ratio, 2.0, 95% confidence interval, 0.6-6.5, respectively) among women aged 22-27 years. For women aged 28 years and older, women managed with repeat cytology had a higher risk for cervical cancer than women managed with colposcopy/biopsy. Our findings suggest that women with a first cytological diagnosis of atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion up to age 27 years may indeed be safely followed up with repeat cytology within 6 months. A large amount of colposcopies that are currently performed in this group, therefore, could safely be discontinued.

Abstract 3444: Analysis of human papillomavirus 16 variants and risk for cervical cancer in Chinese population

Abstract HPV16 is the most carcinogenic HPV type, but only a minority of HPV16 infections progress to cancer. Intratype genetic variants of HPV16 have been suggested to confer differential carcinogenicity. To investigate risk implications of HPV16 variants among Chinese women, a case-control study was conducted with 298 cervical cancer patients and 85 controls (all HPV16-positive). HPV16 isolates were predominantly of the A variant lineage, and variants of A4 (previously named “Asian”) sublineage were common. A4/Asian variants were significantly associated with increased risk of cervical cancer compared to A1-3 (OR = 1.72, 95% CI = 1.04-2.85). Furthermore, a meta-analysis including 703 cases and 323 controls from East Asia confirmed the association (OR = 2.82, 95% CI = 1.44-5.52). In conclusion, A4 variants appear to predict higher risk of cervical cancer among HPV16-positive women, which may provide clues to the genetic basis of differences in the carcinogenicity of HPV16 variants. Citation Format: Dong Hang, Yin Yin, Jing Han, Jie Jiang, Hongxia Ma, Shuanghua Xie, Xiaoshuang Feng, Kai Zhang, Zhibin Hu, Shen Hongbing, Gary M. Clifford, Min Dai, Ni Li. Analysis of human papillomavirus 16 variants and risk for cervical cancer in Chinese population. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3444.

Analysis of the association of HOTAIR single nucleotide polymorphism (rs920778) and risk of cervical cancer

We recently demonstrated that overexpression of HOTAIR (Hox transcript antisense intergenic RNA) was associated with tumor progression and radio-resistance in human cervical cancer. Considering the single nucleotide polymorphism (SNP) rs920778 (C>T) could influence HOTAIR expression and cancer predisposition in other malignancies, we herein investigated the association between rs920778 status and cervical cancer susceptibility in a Chinese population. Using the specific TaqMan PCR assay, we genotyped rs920778 in 215 cervical cancer patients and 430 age-matched healthy controls. As shown in our data, TT genotype of rs920778 was significantly correlated with the upregulation of HOTAIR (p=0.008). Compared with the healthy control, TT genotype and T allele notably indicated a much higher risk of cervical cancer [TT genotype: odds ratio (OR)=2.186, 95% confidence interval (CI)=1.378-3.466, p=0.003; T allele: OR=1.556, 95% CI=1.221-1.981]. In addition, we also found that the TT genotype of rs920778 was correlated with advanced tumor stage (p=0.039), highly histological grade (p=0.013), lympho node metastasis (p<0.001) and positive infection of high risk HPV (p<0.001). Among the patients who underwent concurrent chemo-radiotherapy, TT genotype carriers present notably resistance to the combination of EBRT+ICBT+cisplatin (p=0.023). In conclusion, we firstly reported that TT genotype of HOTAIR rs920778 was significantly associated with the cervical cancer susceptibility. Moreover, the TT genotype of rs920778 might be a potent prognostic marker in cervical cancer patients.

Electrochemical chip-based genomagnetic assay for detection of high-risk human papillomavirus DNA

Cervical cancer, being the fourth leading cause of cancer death in women worldwide, predominantly originates from a persistent infection with a high-risk human papillomavirus (HPV). Detection of DNA sequences from these high-risk strains, mostly HPV-16 and HPV-18, represents promising strategy for early screening, which would help to identify women with higher risk of cervical cancer. In developing countries, inadequate screening options lead to disproportionately high mortality rates, making a fast and inexpensive detection schemes highly important. Electrochemical sensors and assays offer an alternative to current methods of detection. We developed an electrochemical-chip based assay, in which target HPV DNA is captured via magnetic bead-modified DNA probes, followed by an antidigoxigenin-peroxidase detection system at screen-printed carbon electrode chips, enabling parallel measurements of eight samples simultaneously. We show sensitive detection in attomoles of HPV DNA, selective discrimination between HPV-16 and HPV-18 and good reproducibility. Most importantly, we show application of the assay into both cancer cell lines and cervical smears from patients. The electrochemical results correlated well with standard methods, making this assay potentially applicable in clinical practice.

A Randomized Trial of Human Papillomavirus Self-Sampling as an Intervention to Promote Cervical Cancer Screening Among Women With HIV

Women living with HIV experience higher risk of cervical cancer, but screening rates in the United States are lower than recommended. The purpose of this study was to examine whether an intervention using self-sampling of cervicovaginal cells for human papillomavirus (HPV) with results counseling would increase cervical cytology ("Pap") testing among women with HIV. This was a randomized controlled trial to test the effectiveness of an intervention of self-sampling for HPV and results counseling. Participants were 94 women older than 18 years, with HIV infection, attending an HIV clinic for a primary care visit, whose last cervical cancer screening was 18 months or more before baseline. Women were assigned to the intervention or information-only group. The primary outcome was completion of cervical cytology testing within 6 months of baseline. The secondary outcome was the women's perceived threat of developing cervical cancer. A total of 94 women were enrolled and analyzed in the study. The cytology completion rate overall was 35% by 6 months from baseline. There were no differences in comparing HPV-positive with HPV-negative women nor comparing them with the information-only group. In the intervention group, a positive HPV test increased perceived threat of cervical cancer. The intervention did not improve cytology test attendance, although education about HPV and cervical cancer risk as part of study procedures was associated with testing for 35% of this group of women whose previous cytology occurred an average of 3.6 years before the baseline appointment. Self-sampling for HPV testing was feasible.

Effects of Twelve Germline Missense Variations on DNA Lesion and G-Quadruplex Bypass Activities of Human DNA Polymerase REV1.

The Y-family DNA polymerase REV1 is involved in replicative bypass of damaged DNA and G-quadruplex (G4) DNA. In addition to a scaffolding role in the replicative bypass, REV1 acts in a catalytic role as a deoxycytidyl transferase opposite some replication stall sites, e.g., apurinic/apyrimidinic (AP) sites, N(2)-guanyl lesions, and G4 sites. We characterized the biochemical properties of 12 reported germline missense variants of human REV1, including the N373S variant associated with high risk of cervical cancer, using the recombinant REV1 (residues 330-833) proteins and DNA templates containing a G, AP site, N(2)-CH2(2-naphthyl)G (N(2)-NaphG), or G4. In steady-state kinetic analyses, the F427L, R434Q, M656V, D700N, R704Q, and P831L variants displayed 2- to 8-fold decreases in kcat/Km for dCTP insertion opposite all four templates, compared to that of wild-type, while the N373S, M407L, and N497S showed 2- to 3-fold increases with all four and the former three or two templates, respectively. The F427L, R434Q, M656V, and R704Q variants also had 2- to 3-fold lower binding affinities to DNA substrates containing G, an AP site, and/or N(2)-NaphG than wild-type. Distinctively, the N373S variant had a 3-fold higher binding affinity to G4 DNA than the wild-type, as well as a 2-fold higher catalytic activity opposite the first tetrad G, suggesting a facilitating effect of this variation on replication of G4 DNA sequences in certain human papillomavirus genomes. Our results suggest that the catalytic function of REV1 is moderately or slightly altered by at least nine genetic variations, and the G4 DNA processing function of REV1 is slightly enhanced by the N373S variation, which might provide the possibility that certain germline missense REV1 variations affect the individual susceptibility to carcinogenesis by modifying the capability of REV1 for replicative bypass past DNA lesions and G4 motifs derived from chemical and viral carcinogens.

Chlamydia Trachomatis Infection-Associated Risk of Cervical Cancer: A Meta-Analysis.

As whether Chlamydia trachomatis infection increases the risk of cervical cancer is controversial in the literature, we performed a meta-analysis.Based on a comprehensive search of publications in the Medline, Cochrane, and EMBASE databases, we identified and extracted data from all relevant articles examining C. trachomatis infection and the risk of cervical cancer. The quality of each included study was assessed according to the 9-star Newcastle–Ottawa scale. The strength of association between the C. trachomatis and risk of cervical cancer was estimated by odds ratio (OR) and 95% confidence intervals (CIs). This review was registered at PROSPERO with registration No. CRD42014015672.A total of 22 studies with 4291 cervical cancer cases and 7628 controls were identified. Overall, C. trachomatis was significantly linked to increased cervical cancer risk in prospective studies (OR = 2.21, 95% CI: 1.88–2.61, P < 0.001), as well as in retrospective studies (OR = 2.19, 95% CI: 1.74–2.74, P < 0.001). Additionally, with a multivariate logistic regression analysis adjusted for HPV and age, C. trachomatis infection was identified as an independent predictor of cervical cancer in 11 studies (OR = 1.76, 95% CI: 1.03–3.01, P = 0.04). Coinfection of human papilloma virus and C. trachomatis has a higher risk of cervical cancer (OR = 4.03, 95% CI: 3.15–5.16, P < 0.001). A subgroup analysis based on histological type indicated an elevated risk for both squamous cell carcinoma (OR = 2.21, 95% CI: 2.00–2.45, P < 0.001), and adenocarcinoma (OR = 1.61, 95% CI: 1.21–2.15, P = 0.001), in associated with C. trachomatis. Subgroup analysis by where C. trachomatis infection was detected showed a significantly higher risk of cervical cancer associated with C. trachomatis infection detected in serum (OR = 2.20, 95% CI: 2.01–2.42, P < 0.001), cervical tissue blocks (OR = 2.88, 95% CI: 1.21–6.83, P = 0.02), and cervical secretion (OR = 2.71, 95% CI: 1.41–5.20, P = 0.003), especially in serum with no obvious heterogeneity.In conclusion, our novel data demonstrate that individuals infected with C. trachomatis have a higher risk of cervical cancer. Therefore, it is necessary to expand C. trachomatis infection screening and treat women with C. trachomatis promptly, particularly those with human papilloma virus infections. This approach will not only protect against pelvic inflammatory disease and infertility, but may also prevent cervical cancer.