Higher Risk Of Cervical Cancer Research Articles

Human Papillomavirus Infection in HIV-1 Infected Women in Catalonia (Spain): Implications for Prevention of Cervical Cancer

BackgroundHigh-risk human Papillomavirus infection is a necessary factor for cervical squamous intraepithelial lesions and invasive cervical cancer. In HIV-1-infected women, HPV infection is more prevalent and a higher risk of cervical cancer has been identified. We aimed to calculate the prevalence of infection by HR-HPV, determine the factors associated with this infection and abnormal cytology findings and to describe the history of cervical cancer screening in HIV-1-infected women.MethodsWe enrolled 479 HIV-1–infected women from the PISCIS cohort. Each patient underwent a gynecological check-up, PAP smear, HPV AND Hybrid capture, HPV genotyping, and colposcopy and biopsy, if necessary. We applied questionnaires to obtain information on sociodemographic, behavioral, clinical, and cervical screening variables. We present a cross-sectional analysis.ResultsMedian age was 42 years. The prevalence of HR-HPV infection was 33.2% and that of high-grade squamous intraepithelial lesions (HSIL) was 3.8%. The most common genotypes were 16(23%), 53(20.3%), and 52(16.2%). The factor associated with HR-HPV infection was age <30 years (odds ratio[OR],2.5; 95%confidence interval[CI],1.1–5.6). The factors associated with the presence of HSIL or low-grade squamous intraepithelial lesions (LSIL) were CD4T-lymphocyte count <200cells/mm3 versus >500cells/mm3 (OR,8.4; 95%CI,3.7–19.2), HIV-1 viral load >10,000copies/mL versus <400copies/mL (OR,2.1; 95%CI,1.0–4.4), and use of oral contraceptives (OR,2.0; 95%CI,1.0–3.9). Sixty percent of HIV-1–infected women had had one Pap smear within the last 2 years.ConclusionsThe high prevalence of HPV infection and cervical lesions in the HIV-1–infected population in Catalonia, as well as the low coverage and frequency of screening in this group, means that better preventive efforts are necessary and should include vaccination against HPV, better accessibility to screening programs, training of health care professionals, and specific health education for HIV-1–infected women.

The Challenge of Follow-Up in a Low-Income Colposcopy Clinic

The study aimed to identify sociodemographic and disease-specific factors associated with follow-up in an inner-city multiethnic colposcopy clinic. All charts of patients referred to colposcopy clinic for abnormal cervical cytology and/or high-risk human papillomavirus infections to the University of California, Irvine, Colposcopy Clinic in Santa Ana from November 2006 to December 2007 were reviewed. Compliance was defined as at least 1 follow-up evaluation within 3 to 14 months from initial colposcopy appointment. To determine compliance, the following factors were evaluated in a multivariate analysis: race, age, spoken language, insurance status, annual income, marital status, referral cytology, histology, and pregnancy status. Among the 1,046 scheduled appointments, 50% were attended. Of the patients, 458 with a minimum of 14 months of follow-up were included. The mean (SD) age of these patients was 31.0 (10.7) years. 58% were white and 55% spoke Spanish. A total of 248 patients (54%) had appropriately timed repeat testing, whereas 210 (46%) failed to return within 14 months. In univariate analysis, women who were referred from outside the clinic, single, younger than 40 years, and with self-pay or government-funded insurance were more likely to be noncompliant although this was not statistically significant. In multivariate analysis, referral from outside the clinic, self-pay, or government-funded insurance, Spanish-speaking, and single marital status were all significantly associated with noncompliance. Although cervical intraepithelial neoplasia 2 or 3 was not associated with noncompliance, 45% of women with cervical intraepithelial neoplasia 2 or 3 still did not comply with recommendations. This inner-city clinic is perhaps successful at maintaining compliance for women at highest risk for cervical cancer when the triage originates from within the clinic and when the patient is married, English-speaking, and privately insured. However, reasons for those patients at highest risk for noncompliance in this clinic may need to be better characterized.

Human papillomavirus infection and the risk of cervical cancer in Japan

Infection with a high-risk human papillomavirus (HPV) is established as a major risk factor for cervical cancer. In Japan, eight HPV genotypes (16, 18, 31, 33, 35, 45, 52 and 58) confer a much higher risk of cervical cancer and its immediate premalignant lesions (cervical intraepithelial neoplasia grade 3 [CIN 3]) than do other high-risk and the low-risk HPV types. However, only a small fraction of infected women develop CIN 3 or invasive cervical cancer, suggesting the involvement of additional cofactors in cervical carcinogenesis. A multicenter prospective cohort study of Japanese women with low-grade cervical abnormalities has demonstrated that tobacco smoking is significantly associated with an increased risk of persistent low-grade cervical lesions, while the presence of human leukocyte antigen Class II DRB1*1302 protects against progression to CIN 3. Understanding the epidemiology of HPV infections and cervical cancer may improve prevention and lead to novel clinical management strategies for cervical precursor lesions. Viral and host factors that affect the risk of cervical cancer are discussed in this review.

Screening for Cervical Cancer: U.S. Preventive Services Task Force Recommendation Statement

Update of the 2003 U.S. Preventive Services Task Force (USPSTF) recommendation statement on screening for cervical cancer. The USPSTF reviewed new evidence on the comparative test performance of liquid-based cytology and the benefits and harms of human papillomavirus (HPV) testing as a stand-alone test or in combination with cytology. In addition to the systematic evidence review, the USPSTF commissioned a decision analysis to help clarify the age at which to begin and end screening, the optimal interval for screening, and the relative benefits and harms of different strategies for screening (such as cytology and co-testing). This recommendation statement applies to women who have a cervix, regardless of sexual history. This recommendation statement does not apply to women who have received a diagnosis of a high-grade precancerous cervical lesion or cervical cancer, women with in utero exposure to diethylstilbestrol, or women who are immunocompromised (such as those who are HIV positive).The USPSTF recommends screening for cervical cancer in women aged 21 to 65 years with cytology (Papanicolaou smear) every 3 years or, for women aged 30 to 65 years who want to lengthen the screening interval, screening with a combination of cytology and HPV testing every 5 years. See the Clinical Considerations for discussion of cytology method, HPV testing, and screening interval (A recommendation).The USPSTF recommends against screening for cervical cancer in women younger than age 21 years (D recommendation).The USPSTF recommends against screening for cervical cancer in women older than age 65 years who have had adequate prior screening and are not otherwise at high risk for cervical cancer. See the Clinical Considerations for discussion of adequacy of prior screening and risk factors (D recommendation).The USPSTF recommends against screening for cervical cancer in women who have had a hysterectomy with removal of the cervix and who do not have a history of a high-grade precancerous lesion (cervical intraepithelial neoplasia grade 2 or 3) or cervical cancer (D recommendation).The USPSTF recommends against screening for cervical cancer with HPV testing, alone or in combination with cytology, in women younger than age 30 years (D recommendation).

Cervical Cancer Screening: Primum Non Nocere

This issue includes the updated Task Force recommendations on screening for cervical cancer. The editorialists discuss this recommendation as well as the joint guideline from the American Cancer So...

Meta-analysis of association between GSTM1 gene polymorphism and cervical cancer

ObjectiveTo investigate association between glutathione S-transferases (GSTs) and cervical cancer. MethodsPublished literature from PubMed, EMBASE, and other databases were retrieved. All studies evaluating the association between GSTM1/GSTT1 polymorphisms and cervical were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using fixed- or random-effects model. ResultsA total of 15 case-control studies were included in the meta-analysis of GSTM1 genotypes (1 825 cases and 2 104 controls). The overall result showed that the association between GSTM1 null genotype and risk for cervical cancer was statistically significant (OR=1.53, 95%CI=1.18–2.00). Great heterogeneity was found between studies. Subgroup analysises were performed based on smoking and ethnicity. Our results showed that smokers with null GSTM1 genotype had higher risk of cervical cancer (OR=1.56, 95%CI=1.01–2.41). For the ethnicity stratification, significant increased risk of null GSTM1 genotype was found in Chinese and Indian population, but no increased risk in other population. ConclusionsThis meta-analysis provides strong evidence that the GSTM1 null genotype is associated with the development of cervical cancer, and especially in Chinese and Indian population, and smoking shows a modification on the association between GSTM1 null genotype and cervical cancer.

Provider perceptions of barriers and facilitators of HPV vaccination in a high-risk community

BackgroundMaximizing HPV vaccine uptake among those at highest risk for cervical cancer is critical. We explored healthcare provider perspectives on factors influencing HPV vaccination among adolescent girls in a community with high cervical cancer rates. MethodsFrom March to May 2009, we conducted in-depth interviews with 21 medical staff providing care to adolescent girls at two clinics in Los Angeles, CA, serving a predominantly Hispanic population with high cervical cancer rates. Interviews were recorded and transcribed data were reviewed for coding and thematic content related to potential barriers and facilitators of HPV vaccination. ResultsProviders and medical staff overwhelmingly focused on parental beliefs as barriers to HPV vaccination. Perceived parental misconceptions acting as barriers included the belief that adolescents do not need vaccinations and that no-cost vaccine programs like Vaccines for Children are only available for younger children. Perceived parental concerns that the vaccine will promote sexual activity were prevalent, which prompted providers to frame HPV vaccine as a “routine” vaccine. However, the medical staff felt mothers with a friend or relative supportive of HPV vaccination were more likely to request the vaccine. The staff also noted that for Hispanic parents the “preferred” source of information is peers; if the “right people” in the community were supportive of HPV vaccine, parents were more willing to vaccinate. Other barriers included lack of immunization records among immigrant parents and a difficult-to-reach, mobile clientele. ConclusionsProviders noted a number of barriers to HPV vaccination, including some perceived parental misconceptions that could be addressed with education about the need for adolescent vaccines and available free vaccine programs. Because community support appears particularly important to Hispanic parents, the use of promotoras – peer liaisons between health organizations and the community – may increase HPV vaccine uptake in this population.

Human Papillomavirus Vaccine Use Among Adolescent Girls and Young Adult Women: An Analysis of the 2007 California Health Interview Survey

Administration of the human papillomavirus (HPV) vaccine is recommended for adolescent girls and young adult women. Little is known about the factors associated with vaccination. This study examined prevalence and correlates of HPV vaccine initiation (≥1 dose) among a statewide representative sample of adolescent and young adult females living in California. HPV vaccination data on 3615 parents of adolescent girls aged 12-17 and 2068 young adult women aged 18-27 from the 2007 California Health Interview Survey (CHIS) were examined by sociodemographic, healthcare access, and health behavior factors using chi-square and multivariable logistic regression models. Nineteen percent of adolescent girls and 11% of young adult women had initiated the HPV vaccine series. In both groups, lower educational attainment (parental/own) was associated with lack of vaccine initiation. For adolescents, vaccine initiation was also significantly lower among those whose parents had low incomes or no usual source of care. For young adults, initiation was lower among the older group and those who spent less time in the United States, had public insurance, had no recent provider visit, or had fewer sexual partners. In a statewide representative sample, different correlates of early initiation of HPV vaccination emerged for Californian adolescent girls and young adult women. These different patterns may be due to differential access to programs that provide free or low-cost HPV vaccines. Because several of these factors are associated with disparities in use of Pap tests, disparities will persist or even worsen unless greater effort is placed on vaccinating populations at highest risk for cervical cancer.

Cost-effectiveness analysis of quadrivalent vaccine for prevention of cervical cancer in Serbia

Cervical cancer is second the most common cancer and the fourth cancer in relation to of mortality in women. As many as 85% of reported cases are found in developing countries, such as Serbia. The incidence of cervical cancer in Serbia is 24.3/100,000 women/year, and Serbia is among the countries with very high risk of cervical cancer. This study aims to show cost/effectiveness of quadrivalent vaccine for the prevention of cervical cancer in Serbia. Analysis was conducted using TreeAge software and Markov model was based on the literature data about effectiveness and on local Serbian cost calculation. The duration of one cycle was one year and the time horizon was set to 60 cycles i.e. 60 years. Monte Carlo simulation was done with 1000 virtual patients and sensitivity analysis (incoming variables varied ±50%) was presented by Tornado diagram. Application of quadrivalent vaccine for the prevention of cervical cancer proved to be very cost/effective method. This method was costeffective because costs were less than in the group that did not receive vaccine, and clinical efficacy in the vaccine group was slightly higher. After varying the incoming data for ±50%, the model remained stable, i.e. vaccine was still highly cost/effective. This study showed that use of vaccine for prevention of cervical cancer was very cost/effective. However, since the vaccine was recently marketed, and studies investigating its effectiveness longer than 5 years were not conducted, further studies are necessary to resolve question of long-term vaccine efficacy.

Impact of Pap Test Compliance and Cervical Cancer Screening Intervals on Human Papillomavirus Vaccine Acceptance

The objective of this study was to determine the impact of Pap test compliance and cervical cancer screening intervals on human papillomavirus (HPV) vaccination acceptance. A convenience sample of 499 women 21 to 65 years old completed a 37-question survey in Augusta and Savannah, GA. The survey assessed their knowledge about HPV, cervical cancer, and the HPV vaccine. The questionnaire also determined their Pap test compliance and how longer Pap test intervals would influence their willingness to receive the HPV vaccine. Differences between categorical variables and knowledge scores were examined using χ test and unequal-variance t tests, respectively. Pap test-noncompliant women were more likely to get the HPV vaccine if they only needed a Pap test every 10 years compared with Pap test-compliant women (27.6% vs 14.6%, p = .02). A greater number (83.5%) of Pap test-noncompliant women preferred the HPV vaccine plus every 10-year Pap test option compared with Pap test-compliant women (31.3%, p < .0001). Most women (87%) responded that they would likely get the HPV vaccine if it would safely reduce the frequency of Pap testing. Women are receptive to getting the HPV vaccine in exchange for longer cervical cancer screening intervals. Moreover, Pap test-noncompliant women are more likely to get the HPV vaccine if Pap testing was needed less frequently. Increasing the Pap testing interval may be an excellent method to improving HPV vaccine acceptance in women at highest risk for cervical cancer.

Factors Associated with Time to Colposcopy After Abnormal Pap Testing in HIV-Infected Women

HIV-infected women are at increased risk for cervical dysplasia and require timely follow-up after an abnormal Papanicolaou (Pap) test. This retrospective cohort study assessed the proportion of HIV-infected women with colposcopic evaluation after an abnormal Pap test. Time to colposcopy within 12 months after an abnormal Pap test was assessed with univariate and multivariate Cox proportional hazard modeling in a diverse cohort of HIV-infected women between October 1, 2003, and September 30, 2007. One hundred seventy-seven subjects had an abnormal Pap test: 22 high-grade intraepithelial lesion (HSIL; 12%), 120 low-grade squamous intraepithelial lesion (LSIL; 68%), and 35 atypical squamous cells of undetermined significance, human papillomavirus positive (20%). One hundred twenty (68%) had follow-up colposcopy by 1 year. Decreased time to follow-up was associated with being married (HR 3.5, 95% CI 1.9-6.2), high school graduate or higher education level (HR 1.7, CI 1.2-2.6), HSIL Pap results (HR 2.8, CI 1.3-6.2), Pap testing performed by HIV nurse practitioner versus gynecology clinic (HR 1.7, 1.1-2.7), and CD4 count ≥500 cells/mm(3) (HR 1.8, CI 1.2-2.8), after adjusting for age, race/ethnicity, and LSIL Pap result. Private insurance was associated with decreased time to colposcopy in unadjusted, but not multivariate analysis. Drug use was not associated with time to follow-up colposcopy. Almost one third of HIV-infected women did not have a follow-up colposcopy by 12 months after an abnormal Pap test. Since HIV-infected women are at particularly high risk for cervical cancer, these results are unacceptably poor. Identification of the barriers to appropriate follow-up and targeted interventions are necessary to improve timely follow-up for cytologic abnormalities in this high-risk population.

Inhibition of the epidermal growth factor receptor by erlotinib prevents immortalization of human cervical cells by Human Papillomavirus type 16

The Human Papillomavirus type-16 (HPV-16) E6 and E7 oncogenes are selectively retained and expressed in cervical carcinomas, and expression of E6 and E7 is sufficient to immortalize human cervical epithelial cells. Expression of the epidermal growth factor receptor (EGFR) is often increased in cervical dysplasia and carcinoma, and HPV oncoproteins stimulate cell growth via the EGFR pathway. We found that erlotinib, a specific inhibitor of EGFR tyrosine kinase activity, prevented immortalization of cultured human cervical epithelial cells by the complete HPV-16 genome or the E6/E7 oncogenes. Erlotinib stimulated apoptosis in cells that expressed HPV-16 E6/E7 proteins and induced senescence in a subpopulation of cells that did not undergo apoptosis. Since immortalization by HPV E6/E7 is an important early event in cervical carcinogenesis, the EGFR is a potential target for chemoprevention or therapy in women who have a high risk for cervical cancer.

Correlation of macrophage migration inhibitory factor gene polymorphism with the risk of early-stage cervical cancer and lymphatic metastasis

Associations of functional single nucleotide polymorphisms in MIF-173G/C with early stage cervical cancer were investigated in a hospital-based case-control study on 250 patients with cervical cancer prior to surgery (including 49 cases with and 201 cases without lymphatic metastasis) and 147 healthy controls. The polymorphism was assessed using restriction fragment length polymorphism polymerase chain reaction, and the MIF serum concentration was examined using the enzyme-linked immunosorbent assay to analyze the correlation between the polymorphism and the MIF serum concentration. Carriers of the variant C allele in MIF-173 were at a significantly higher risk of cervical cancer compared to carriers of the wild-type allele (aOR=1.508; 95% CI, 1.128-2.016, p=0.05). The GC and CC genotypes may be the causative factors for cervical cancer (aOR=1.851; 95% CI, 1.132-3.027, p=0.013). Individuals with the GC+CC genotype and C allele at the MIF-173G/C site were at a significantly higher risk of cervical cancer and lymphatic metastasis. The risk of lymphatic metastasis in early stage cervical cancer was increased more than 1.6 times in patients with the CC and GC genotypes compared with those with the GG genotype. The genotype distribution and allele frequency of MIF-173G/C were statistically significant in the well-, moderately and poorly differentiated groups (P<0.05). Compared to the GG genotype and G allele, patients with GC and CC genotypes and C allele exhibited a lower degree of differentiation and a higher degree of malignancy. A significant difference was observed in MIF serum concentrations among the various subgroups (P<0.05). The early cervical cancer, lymphatic metastasis and poorly differentiated groups exhibited higher MIF levels in serum. Moreover, patients with the CC genotype exhibited higher MIF serum concentration, which could increase the risk of early stage cervical cancer and lymphatic metastasis. The results presented in this study provide the first evidence that the genetic polymorphism MIF-173 is associated with cervical cancer in humans. Detection of MIF serum concentration and genotyping may be used as biomarkers for early diagnosis and therapy for cervical cancer.

Association between CTLA-4 gene polymorphism and susceptibility to cervical cancer

To investigate the association between CTLA-4 +49A/G polymorphisms and the risk of susceptibility to cervical cancer. A hospital-based case-control study was conducted. 314 cases with primary cervical cancer and 320 healthy controls were collected and genotyped by PCR-based RFLP for +49A/G polymorphisms in the CTLA-4 gene. The A allele and AA genotype of CTLA-4 gene were 32.5% and 9.6% in the patients, and 25.8% and 5.6% in the controls, respectively. Subjects with CTLA-4 +49AA genotype conferred a higher risk of cervical cancer (OR = 2.06, 95%CI: 1.10 - 3.85; P = 0.024). However, the correlation between AA genotype in CTLA-4 polymorphisms and clinicopathological characteristics was not significant. The results of this study suggest that CTLA4 gene is associated with cervical cancer risk and may be a susceptible gene of cervical cancer.

Cofactors in human papillomavirus infection and cervical carcinogenesis

This study aimed to identify the effect of various risk factors as the promoters of HPV infection, and to identify which HPV-positive women may have an increased risk of developing cervical cancer. Smear preparations were examined and classified according to the Bethesda system. HPV-DNA detection and genotyping was carried out using polymerase chain reaction combined with reverse hybridization line-probe assays. Age, smoking habit, age at first sexual intercourse, number of sexual partners, number of term births, contraceptive method, progesterone therapy, history of sexually transmitted diseases, history or existence of warts and existence of cervical infection were recorded. 642 women (96 women with abnormal cervical cytology and 546 women with normal cytology) provided cervical samples. Smoking habit, number of sexual partners, number of term births, history of sexually transmitted diseases, history or existence of warts and existence of cervical infection were identified as the promoters of HPV infection. History of sexually transmitted diseases, history or existence of warts and existence of cervical infection were identified as cofactors affecting progression from HPV infection to cervical cancer. Neither of contraceptive methods studied was related to HPV infection or coexistence with malign transformation to cervical cancer. Information gathered from this study could be used to prioritize limited screening and treatment services to woman who have specific characteristics that may put them at an increased risk of HPV infection. Additionally, by identifying which women have a higher risk of cervical cancer; it may be possible to reduce the number of unnecessary colposcopies.

Do Health Beliefs, Health Care System Distrust, and Racial Pride Influence HPV Vaccine Acceptability among African American College Females?

The promise of human papillomavirus (HPV) vaccines rests with the ability to promote widespread uptake especially among populations at high risk of cervical cancer and other associated disease outcomes. The purpose of this study was to examine health beliefs and culturally specific influences of HPV vaccine acceptability among African American college females. Approximately 76 percent of participants reported HPV vaccine acceptability. Predictors of acceptability included: higher perceived benefit and lower racial pride. Findings can be used to inform development of campus-based HPV educational approaches to promote widespread HPV vaccine acceptability and safer sex practices among African American college females.

P5-S6.14 Qualitative assessment of facilitators and barriers to HPV vaccination among providers serving a high-risk community

BackgroundMaximising HPV vaccine uptake among those at highest risk for cervical cancer is critical. We explored healthcare provider perspectives on factors influencing HPV vaccination among adolescent girls in a community...

Cigarette smoke condensate-induced oxidative DNA damage and its removal in human cervical cancer cells

Exposure to cigarette smoke is well documented to increase oxidative stress and could account for higher risk of cervical cancer in smokers. Cervical pre-cancerous lesions that are initiated by human papillomavirus (HPV) infection generally regress in the absence of known risk factors such as smoking. 8-oxodeoxyguanosine (8-oxodG) is a highly mutagenic oxidative DNA lesion that is formed by the oxidation of deoxyguanosine. In the present study, we examined: a) the effect of cigarette smoke condensate (CSC) on 8-oxodG formation in and its removal from HPV-transfected (ECT1/E6 E7), HPV-positive (CaSki) and HPV-negative (C33A) human cervical cancer cells, and b) the cell cycle progression and apoptosis in CSC-treated ECT1/E6 E7 cells. CSC induced 8-oxodG in a dose- (p=0.03) and time (p=0.002)-dependent fashion in ECT1/E6 E7 cells as determined by flow cytometry. A 2.4-fold higher level of 8-oxodG was observed in HPV-positive compared with HPV-negative cells. However, 8-oxodG lesions were almost completely removed 72 h post-exposure in all cell lines as determined by ImageStream analysis. This observation correlates with the 2- and 5-fold increase in the p53 levels in ECT1/E6 E7 and CaSki cells with no significant change in C33A cells. We conclude that: a) cigarette smoke constituents induce oxidative stress with higher burden in HPV-positive cervical cancer cells and b) the significant increase observed in p53 levels in wild-type cervical cells (ECT1/E6 E7 and CaSki) may be attributed to the p53-dependent DNA repair pathway while a p53-independent pathway in C33A cells cannot be ruled out.

Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice

Concurrent testing for human papillomavirus (HPV) and cervical cytology (co-testing) is an approved alternative to cytology alone in women aged 30 years and older. We aimed to assess the safety in routine clinical practice of 3-year screening intervals for women testing negative for HPV with normal cytology and to assess if co-testing can identify women at high risk of cervical cancer or cervical intraepithelial neoplasia grade 3 (CIN3) or worse over 5 years. We assessed the 5-year cumulative incidence, starting in 2003-05, of cervical cancer and CIN3 or worse for 331,818 women aged 30 years and older who enrolled in co-testing at Kaiser Permanente Northern California (Berkeley, CA, USA) and had adequate enrolment co-test results. Follow-up continued until Dec 31, 2009. We defined cumulative incidence to include prevalence at enrolment and incidence after enrolment. Prevalence at enrolment was defined as the ratio of women diagnosed with each outcome on the biopsy visit immediately after their enrolment screening visit to the total enrolled women. At screening visits only HPV test and Pap smear samples were collected, and at biopsy visits colposcopically directed biopsies were taken. To estimate post-enrolment incidence, we used Weibull survival models. In 315,061 women negative by HPV testing, the 5-year cumulative incidence of cancer was 3.8 per 100,000 women per year, slightly higher than for the 306,969 who were both negative by HPV and Pap testing (3.2 per 100,000), and half the cancer risk of the 319,177 who were negative by Pap testing (7.5 per 100,000). 313,465 (99.5%) women negative by HPV testing had either normal cytology or equivocal abnormalities. Abnormal cytology greatly increased cumulative incidence of CIN3 or worse over 5 years for the 16,757 positive by HPV testing (12.1%vs 5.9%; p<0.0001). By contrast, although statistically significant, abnormal cytology did not increase 5-year risk of CIN3 or worse for women negative by HPV testing to a substantial level (0.86%vs 0.16%; p=0.004). 12,208 (73%) of the women positive by HPV testing had no cytological abnormality, and these women had 258 (35%) of 747 CIN3 or adenocarcinoma in situ, [corrected] 25 (29%) of 87 cancers, and 17 (63%) of 27 adenocarcinomas. For women aged 30 years and older in routine clinical practice who are negative by co-testing (both HPV and cytology), 3-year screening intervals were safe because a single negative test for HPV was sufficient to reassure against cervical cancer over 5 years. Incorporating HPV testing with cytology also resulted in earlier identification of women at high risk of cervical cancer, especially adenocarcinoma. Testing for HPV without adjunctive cytology might be sufficiently sensitive for primary screening for cervical cancer. Intramural Research Program of the US National Cancer Institute/NIH/DHHS, and the American Cancer Society.

Effect of folic acid and DNA methyltransferase 1 on cervical cancer and its precancerous lesion

To explore the effect of folic acid and DNA methyltransferase 1 (DNMT1) on cervical cancer and cervix precancerous lesion. 100 patients with cervix squamous cell carcinoma (SCC), 101 patients with cervical intraepithelial neoplasm (CIN) and 109 patients with cervix inflammation (CI) diagnosed by histology were included in this study. Radioimmunoassay (RIA), polymerase chain reaction (PCR) and Western blot were used to detect the levels of serum folate, HPV16 infection and the expression of DNMT1 protein, respectively. The average levels of serum folate were (2.60 ± 1.61) ng/ml, (3.14 ± 2.08) ng/ml and (3.32 ± 1.74) ng/ml, and the expression of DNMT1 protein were 2.40 ± 0.99, 1.88 ± 0.33 and 0.89 ± 0.29 in the group of SCC, CIN and CI, respectively. The relationship of folate levels and DNMT1 protein expression showed inverse correlation (r = -0.186, P = 0.001). The results in our study indicated that there was an additive interaction between low-level of serum folate and high-expression of DNMT1 protein related to the risk of CIN and SCC, with OR value as 2.50 (95%CI: 1.21 - 9.22) and 6.03 (95%CI: 2.79 - 21.72) respectively. The relative excess risk of interaction (RERI), attributable proportion of interaction (API) and synergy index (S) were 0.92, 0.36 and 2.59 in the CIN group while 2.47, 0.41 and 1.96 in the SCC group. The low level of serum folate and high expression of DNMT1 protein seemed to be associated with high risk of cervical cancer and its precancerous lesion. It suggested that there might be a synergistic action between serum folate and DNMT1 in the progression of cervix carcinogenesis.