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1.  Prophylactic vaccination against human papillomavirus infection and disease in women: a systematic review of randomized controlled trials 
Human papillomavirus (HPV) is now known to be a necessary cause of cervical cancer, and prophylactic HPV vaccines aimed at preventing genital warts, precancerous cervical lesions and cervical cancer are now available. To gauge the potential impact on disease burden, we performed a systematic review of the evidence from randomized controlled trials.
We conducted a systematic search of the literature to identify all randomized controlled trials of prophylactic HPV vaccination. Reports in 5 electronic databases covering 1950 to June 2007 (MEDLINE, MEDLINE in process, EMBASE, the Cochrane Central Registry of Controlled Trials and the Cochrane Library), bibliographies of all included studies and of narrative reviews (2006–2007), clinical trial registries, Google Scholar, public health announcements, selected conference proceedings (2004–2007) and manufacturers' information on unpublished data or ongoing trials were screened against predefined eligibility criteria by 2 independent reviewers. Vaccines had to contain coverage against at least 1 oncogenic HPV strain. The primary outcome of interest was the frequency of high-grade cervical lesions (high-grade squamous intraepithelial lesion, or grade 2 or 3 cervical intraepithelial neoplasia). The secondary outcomes were persistent HPV infection, low-grade cervical lesions (low-grade squamous intraepithelial lesion or grade 1 cervical intraepithelial neoplasia), external genital lesions, adverse events and death. Meta-analysis of the data was done in all cases where adequate clinical and methodological homogeneity existed.
Of 456 screened reports, 9 were included in the review (6 were reports of randomized controlled trials and 3 were follow-up reports of initial trials). Findings from the meta-analysis showed that prophylactic HPV vaccination was associated with a reduction in the frequency of high-grade cervical lesions caused by vaccine-type HPV strains compared with control groups: Peto odds ratio 0.14 (95% confidence interval [CI] 0.09–0.21) from combined per-protocol analyses, and 0.52 (95% CI 0.43–0.63) from modified intention-to-treat analyses. Vaccination was also highly efficacious in preventing other HPV-related infection and disease outcomes, including persistent HPV infection, low-grade lesions and genital warts. The majority of adverse events were minor. The incidence of serious adverse events and death were balanced between the vaccine and control groups.
Among women aged 15–25 years not previously infected with vaccine-type HPV strains, prophylactic HPV vaccination appears to be highly efficacious in preventing HPV infection and precancerous cervical disease. Long-term follow-up is needed to substantiate reductions in cervical cancer incidence and mortality.
PMCID: PMC1950172  PMID: 17671238
2.  Up regulation in gene expression of chromatin remodelling factors in cervical intraepithelial neoplasia 
BMC Genomics  2008;9:64.
The highest rates of cervical cancer are found in developing countries. Frontline monitoring has reduced these rates in developed countries and present day screening programs primarily identify precancerous lesions termed cervical intraepithelial neoplasias (CIN). CIN lesions described as mild dysplasia (CIN I) are likely to spontaneously regress while CIN III lesions (severe dysplasia) are likely to progress if untreated. Thoughtful consideration of gene expression changes paralleling the progressive pre invasive neoplastic development will yield insight into the key casual events involved in cervical cancer development.
In this study, we have identified gene expression changes across 16 cervical cases (CIN I, CIN II, CIN III and normal cervical epithelium) using the unbiased long serial analysis of gene expression (L-SAGE) method. The 16 L-SAGE libraries were sequenced to the level of 2,481,387 tags, creating the largest SAGE data collection for cervical tissue worldwide. We have identified 222 genes differentially expressed between normal cervical tissue and CIN III. Many of these genes influence biological functions characteristic of cancer, such as cell death, cell growth/proliferation and cellular movement. Evaluation of these genes through network interactions identified multiple candidates that influence regulation of cellular transcription through chromatin remodelling (SMARCC1, NCOR1, MRFAP1 and MORF4L2). Further, these expression events are focused at the critical junction in disease development of moderate dysplasia (CIN II) indicating a role for chromatin remodelling as part of cervical cancer development.
We have created a valuable publically available resource for the study of gene expression in precancerous cervical lesions. Our results indicate deregulation of the chromatin remodelling complex components and its influencing factors occur in the development of CIN lesions. The increase in SWI/SNF stabilizing molecule SMARCC1 and other novel genes has not been previously illustrated as events in the early stages of dysplasia development and thus not only provides novel candidate markers for screening but a biological function for targeting treatment.
PMCID: PMC2277413  PMID: 18248679
3.  Prevalence and predictors of Cervical Intraepithelial Neoplasia among HIV infected women at Bugando Medical Centre, Mwanza-Tanzania 
Cancer of the cervix rank the second most common cause of cancer related deaths among women in Sub-Saharan Africa. It is estimated that 529, 409 new cases are diagnosed annually with a mortality rate approaching 274,883 per year. Cervical Intraepithelial Neoplasia (CIN) precedes almost all cervical cancers. The incidence rate of CIN among HIV infected women is five times higher as compared to the rate in HIV negative women. The screening for cervical dysplasia and an appropriate management in women with CIN are effective methods for preventing cervical cancer. This study was done to determine the prevalence and predictors of CIN among a HIV infected women attending Care and Treatment centre (CTC) at Bugando Medical Centre (BMC).
A cross sectional survey was undertaken among HIV infected women aged 18 years and above attending at BMC CTC clinic between February and March 2013. Visual Inspection with Acetic acid (VIA) was used as the screening method for detection of CIN. Socio-demographic, reproductive and clinical information was obtained from participants and the blood was collected for CD4 lymphocyte count. Cervical punch biopsy for histological examination was performed for those who had VIA positive test. Data were entered and analyzed using STATA Version 12.0 soft ware.
A total number of 95 (26.8%) participants had positive VIA test among three hundred and fifty-five (355) HIV infected women. Histology results showed; 4(4.2%) were normal, 26 (27.4%) had an inflammatory lesion, 58(61.1%) had CIN and 7(7.3%) had invasive cervical cancer. CIN was found to be associated with a history of multiple sexual partners (P<0.001), a history of genital warts (P<0.001), and a history of STI (P = 0.010).
The Cervical Intraepithelial Neoplasia is a problem among HIV infected women. A history of multiple sexual partners, a history of genital warts, a history STI and a low baseline CD4 T lymphocyte were significant predictors for CIN. Screening for Cervical Intraepithelial Neoplasia is recommended for all women with HIV.
PMCID: PMC3833176  PMID: 24228805
Cervical intraepithelial Neoplasia; HIV; Mwanza
4.  Case–control study of HLA-G promoter methylation status, HPV infection and cervical neoplasia in Curitiba, Brazil: a pilot analysis 
BMC Cancer  2012;12:618.
The causal association between persistent human papillomavirus (HPV) infection and cervical cancer has been established, but the mechanisms that favor HPV persistence in cervical cells are still unknown. The diminished capability of the immune system to control and resolve HPV infection is one of several hypotheses. The tolerogenic protein HLA-G has shown aberrant expression in a variety of cancers, which has been suggested as a mechanism for tumor escape from immunosurveillance. In the present study we evaluate the role of epigenetic modification (promoter de-methylation) of the HLA-G gene on susceptibility to HPV infection and development of high-grade cervical lesions.
A case–control study was carried out in Curitiba, Brazil, between February and June 2010. A total of 789 women aged 15–47 years were recruited: 510 controls with normal cervical cytology, and 279 cases with histologically confirmed cervical intraepithelial neoplasia grade 2 (CIN2, N = 150) or grade 3 (CIN3, N = 129). All women were administered a questionnaire by interview, which collected information on demographic and lifestyle factors, and a cervical sample was collected. HPV DNA detection was performed by GP5+/GP6+ primer-mediated PCR. HPV-positive samples were genotyped by multiplex PCR. A pilot analysis of HLA-G promoter methylation was carried out in a subset of the study population (96 cases and 76 controls) by pyrosequencing. HLA-G methylation and HPV infection status of cases and controls were compared, and confounding factors were computed by t Student and non-parametric Wilcoxon tests. Comparison of HLA-G methylation between cases and controls was assessed by the Bonferroni correction. The association of HLA-G methylation with CIN2/3 was evaluated by logistic regression.
HPV prevalence was 19.6% in controls and 94.3% in CIN2/3 cases. HPV16, 31, 33, 35 and 18 were the most prevalent types. Methylation analysis of seven CpGs in the HLA-G promoter did not reveal any spontaneous de-methylation events in CIN2/3 cases (mean proportion of methylation: 75.8%) with respect to controls (mean 73.7%; odds ratio 1.01, 95% confidence interval 0.96, 1.07).
This study did not support the hypothesis that spontaneous de-methylation events in the HLA-G promoter play a primary role in promoting escape from immunosurveillance in the development of precancerous cervical lesions.
PMCID: PMC3545901  PMID: 23265140
HPV; Cervical cancer; HLA-G; Methylation
5.  Association between bacterial vaginosis and cervical intraepithelial neoplasia 
The aim of this study was to determine whether the presence of bacterial vaginosis (BV) is associated with cervical intraepithelial neoplasia (CIN) and human papilloma virus (HPV) infection.
A total of 588 women who had abnormal Pap smears and had finally undergone loop electrosurgical excision procedure (LEEP) in our institute from September 2002 to May 2006 were selected. The screening tests for BV were done in 552 of the 588, and BV was diagnosed if three of the following four findings were satisfied: presence of abnormal discharge, vaginal pH>4.5, presence of clue cells, positive amine or whiff test. Five hundred and five patients had HPV typing tests by the HPV DNA chip. Forty two patients diagnosed with invasive cancer were excluded from this study. CIN was subdivided into low-grade CIN (CIN I) and high-grade CIN (CIN II/III) groups.
There was no statistically significant difference in patient characteristics between BV-present and BV-absent group. The incidence of CIN was significantly higher in the BV-present group (p=0.043), however, no statistical significance of BV on CIN was observed on multivariate analysis. HPV infection showed no significant relationship with BV. BV with or without HPV infection did not influence the incidence of CIN, regardless of the severity.
There was significant correlation between BV and the presence of CIN, regardless of the severity of CIN. In addition, there was no significant association between the presence of BV and HPV infection.
PMCID: PMC2676492  PMID: 19471662
Bacterial vaginosis; Cervical intraepithelial neoplasia; Human papilloma virus
6.  Functions of Paracrine PDGF Signaling in the Proangiogenic Tumor Stroma Revealed by Pharmacological Targeting  
PLoS Medicine  2008;5(1):e19.
Important support functions, including promotion of tumor growth, angiogenesis, and invasion, have been attributed to the different cell types populating the tumor stroma, i.e., endothelial cells, cancer-associated fibroblasts, pericytes, and infiltrating inflammatory cells. Fibroblasts have long been recognized inside carcinomas and are increasingly implicated as functional participants. The stroma is prominent in cervical carcinoma, and distinguishable from nonmalignant tissue, suggestive of altered (tumor-promoting) functions. We postulated that pharmacological targeting of putative stromal support functions, in particular those of cancer-associated fibroblasts, could have therapeutic utility, and sought to assess the possibility in a pre-clinical setting.
Methods and Findings
We used a genetically engineered mouse model of cervical carcinogenesis to investigate platelet-derived growth factor (PDGF) receptor signaling in cancer-associated fibroblasts and pericytes. Pharmacological blockade of PDGF receptor signaling with the clinically approved kinase inhibitor imatinib slowed progression of premalignant cervical lesions in this model, and impaired the growth of preexisting invasive carcinomas. Inhibition of stromal PDGF receptors reduced proliferation and angiogenesis in cervical lesions through a mechanism involving suppression of expression of the angiogenic factor fibroblast growth factor 2 (FGF-2) and the epithelial cell growth factor FGF-7 by cancer-associated fibroblasts. Treatment with neutralizing antibodies to the PDGF receptors recapitulated these effects. A ligand trap for the FGFs impaired the angiogenic phenotype similarly to imatinib. Thus PDGF ligands expressed by cancerous epithelia evidently stimulate PDGFR-expressing stroma to up-regulate FGFs, promoting angiogenesis and epithelial proliferation, elements of a multicellular signaling network that elicits functional capabilities in the tumor microenvironment.
This study illustrates the therapeutic benefits in a mouse model of human cervical cancer of mechanism-based targeting of the stroma, in particular cancer-associated fibroblasts. Drugs aimed at stromal fibroblast signals and effector functions may prove complementary to conventional treatments targeting the overt cancer cells for a range of solid tumors, possibly including cervical carcinoma, the second most common lethal malignancy in women worldwide, for which management remains poor.
Douglas Hanahan and colleagues investigate a paracrine regulatory circuit centered upon PDGF receptor signaling in cancer-associated fibroblasts and pericytes of a mouse model of cervical carcinogenesis.
Editors' Summary
Cancers—disorganized, life-threatening masses of cells—develop when cells acquire genetic changes that allow them to divide uncontrollably and to move into (invade) other tissues. Interactions with ostensibly normal cells in the tissue surrounding the tumor (the stroma) support the growth of these abnormal cells. The stroma contains endothelial cells and pericytes (which line the inside and coat the outside, respectively, of blood vessels), cancer-associated fibroblasts, and some immune system cells. Together, these cells support angiogenesis (the formation of a blood supply, which feeds the tumor), produce factors that stimulate tumor cell growth, and facilitate tumor cell invasion into surrounding tissues. One type of tumor with a prominent stromal compartment is cervical cancer. Precancerous changes in the epithelial cells lining the cervix (the structure that connects the womb to the vagina) are usually triggered by infection with human papillomavirus. Some of these early lesions, which are known as cervical intraepithelial neoplasias (CINs), develop into invasive cervical cancer, which is treated by surgery followed by chemotherapy or radiotherapy.
Why Was This Study Done?
The outlook for women whose cervical cancer is detected early is good but only 15%–30% of women whose cancer has spread out of the cervix survive for five years. If, as researchers believe, the stromal compartment is important in the development and growth (neoplastic progression) of cervical cancer, it might be possible to help these women by specifically targeting the cells in the stroma. However, relatively little is known about the role that the stroma plays in the neoplastic progression of cervical cancer or how it is regulated other than that a protein called platelet-derived growth factor (PDGF), which is made by the tumor cells, might be involved in its formation. In this study, the researchers have used a mouse model of cervical cancer (HPV/E2 mice) to investigate PDGF signaling in the tumor stroma. HPV/E2 mice develop CINs before they are three months old; by five months of age, 90% of them have invasive cervical cancer.
What Did the Researchers Do and Find?
The researchers report that PDGF was expressed in the cervixes of normal and HPV/E2 mice, mainly by epithelial cells, and that PDGF receptors (cell-surface proteins that bind PDGF and send a message into the cell that alters the expression of other proteins) were expressed on cells within normal stroma and in fibroblasts and pericytes in the stroma surrounding CINs and tumors (but not on the cancer cells). The expression of PDGF and its receptors increased slightly during tumor progression. Treatment of the HPV/E2 mice with imatinib, an inhibitor of PDGF signaling, slowed the progression of precancerous lesions, impaired the growth of invasive cancers, and reduced the number of blood vessels formed in the tumors and the coverage of these vessels with pericytes. Other experiments indicate that imatinib had these effects because its inhibition of stromal PDGF receptors suppressed the expression of FGF-7 (a factor that encourages epithelial cell division) and FGF-2 (a proangiogenic factor) by cancer-associated fibroblasts. Finally, as in HPV/E2 mice, FGF-2 and PDGF receptors were expressed in the stroma of human cervical cancers whereas PDGF was expressed in the cancer cells.
What Do These Findings Mean?
These findings suggest that PDGF receptor signaling in the stromal cells associated with cervical tumors in mice has a functional role during tumor progression. More specifically, they suggest that PDGF released by the tumor cells triggers PDGF signaling in the stromal cells, which increases the expression of factors that both directly and indirectly stimulate the growth of the tumor cells. Confirmation of this scheme will require additional experiments in mouse models of cervical cancer and the careful examination of more human material. Importantly, although approaches that work in mice do not always work in people, the current findings suggest that targeted therapeutics that prevent the stromal support of tumor growth (such as inhibitors of PDGF receptor signaling) might provide a complementary approach to conventional treatments that target the cancer cells themselves.
Additional Information.
Please access these Web sites via the online version of this summary at
The US National Cancer Institute provides information on all aspects of cancer, including information about cervical cancer (in English and Spanish)
The UK charity Cancerbackup also provides information on all aspects of cancer, including information on cervical cancer and on imatinib
Wikipedia has pages on platelet-derived growth factor, on PDGF receptors, and on imatinib (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC2214790  PMID: 18232728
7.  Association between Methylenetetrahydrofolate Reductase C677T Polymorphism and Susceptibility to Cervical Cancer: A Meta-Analysis 
PLoS ONE  2013;8(2):e55835.
To assess the association between MTHFR polymorphism and cervical cancer risk, a meta-analysis was performed.
Based on comprehensive searches of the PubMed, Embase, and Web of Science databases, we identified outcome data from all articles estimating the association between MTHFR polymorphism and cervical cancer risk. The pooled odds ratio (OR) with 95% confidence intervals (CIs) were calculated.
A total of 12 studies with 2,924 cases (331 cervical intraepithelial neoplasia (CIN) I, 742 CIN II/III, 1851 invasive cervical cancer) and 2,581 controls were identified. There was no significant association between MTHFR C677T polymorphism and CIN I risk (T vs. C, OR = 1.10, 95% CI = 0.92–1.31; TT vs. CC, OR = 1.14, 95% CI = 0.78–1.68; TT+CT vs. CC, OR = 1.22, 95% CI = 0.94–1.58; TT vs. CT+CC, OR = 0.99, 95% CI = 0.70–1.40). For the CIN II/III, lack of an association was also found (T vs. C, OR = 1.08, 95% CI = 0.95–1.23; TT vs. CC, OR = 1.15, 95% CI = 0.87–1.52; TT+CT vs. CC, OR = 1.13, 95% CI = 0.94–1.35; TT vs. CT+CC, OR = 1.07, 95% CI = 0.83–1.38). The T allele had significant association to susceptibility of invasive cervical cancer in recessive model (TT vs. CT+CC, OR = 1.23, 95% CI = 1.02–1.49). On subgroup analysis by ethnicity, similarly significant differences in T vs. C, TT vs. CC, and recessive model were found in Asians.
The present meta-analysis suggested that MTHFR C677T polymorphism were to substantially contribute to invasive cervical cancer in recessive model.
PMCID: PMC3576378  PMID: 23431363
8.  Association between HLA DQB1 * 03 and cervical intra-epithelial neoplasia. 
Molecular Medicine  1995;1(2):161-171.
BACKGROUND: Cervical intraepithelial neoplasia (CIN) and cervical cancer have been shown to be strongly associated with infection by human papillomavirus (HPV). However, other factors may be contributory in the progression from normal epithelium to CIN and cervical cancer, since not all women with HPV infection develop disease. Recently, it was demonstrated that there is a high risk for cervical cancer and CIN in women with HLA DQB1 * 03 (RR = 7.1, p < 0.0009) (1). Subsequent reports have been conflicting, due to sample size, genetic heterogeneity and differences in the techniques employed for the detection of HLA DQB1 * 03. MATERIALS AND METHODS: DNA from cervical smears of 178 women with CIN and 420 controls with normal cervical cytology was analyzed by polymerase chain reaction (PCR) with type-specific primers for HPV 16, 18, 31, and 33. The DNA from test and control samples were also analyzed by a novel PCR technique, which mutates the first base of codon 40 (DQ alleles) from T to G to create an artificial restriction site for an enzyme Mlu I that distinguish DQB1 * 03 from other alleles and are confirmed by digestion of amplified DNA with Mlu I. Further analysis of individual DQB1 * 03 alleles was performed using PCR and allele-specific primers. RESULTS: One hundred forty-four (34%) out of 420 controls (all HPV 16, 18, 31, or 33 negative and normal cytology), 37/66 (56%) of CIN I and 72/112 (64%) of CIN III were positive for DQB1 * 03 (trend test, p < 0.001, chi 2 = 37.3). A significant association was observed between DQB1 * 03 and CIN (odds ratio 3.03; 95% CI 2.11-3.45). Of women with CIN, 131/178 (73.5%) had HPV (types 16, 18, 31, or 33) infection. There was a significant association between DQB1 * 03 and presence of HPV (odds ratio 3.43; 95% CI 2.25-5.10). Homozygosity for DQB1 * 03 was more strongly associated with CIN than heterozygosity (odds ratios 4.0 and 2.63, respectively); and for the presence of HPV (odds ratio 4.47; 95% CI 2.58-7.77). HLA DQB1 * 0301 was the most strongly associated allele with CIN and HPV (odds ratios 2.53 and 2.63, respectively). CONCLUSIONS: HLA DQB1 * 03 is associated significantly with CIN and may be permissive for HPV infection. Further analysis of class II HLA typing in CIN is necessary to evaluate this association.
PMCID: PMC2229948  PMID: 8529095
9.  Genomic amplification of the human telomerase gene (hTERC) associated with human papillomavirus is related to the progression of uterine cervical dysplasia to invasive cancer 
Diagnostic Pathology  2012;7:147.
Human papillomavirus (HPV) infection plays an etiological role in the development of cervical dysplasia and cancer. Amplification of human telomerase gene (hTERC) and over expression of telomerase were found to be associated with cervical tumorigenesis. This study was performed to analyze genomic amplification of hTERC gene, telomerase activity in association with HPV infection in different stages of cervical intraepithelial neoplasia (CIN) and cervical cancer. We were studying the role of hTERC in the progression of uterine cervical dysplasia to invasive cancer, and proposed an adjunct method for cervical cancer screening.
Exfoliated cervical cells were collected from 114 patients with non neoplastic lesion (NNL, n=27), cervical intraepithelial neoplasia (CIN1, n=26, CIN2, n=16, CIN3, n=24) and cervical carcinoma (CA, n=21), and analyzed for amplification of hTERC with two-color fluorescence in situ hybridization (FISH) probe and HPV-DNA with Hybrid Capture 2.
From these patients, 53 were taken biopsy to analyze telomerase activity by telomeric repeat amplification protocol (TRAP) and expression of human telomerase reverse transcriptase (hTERT), with immunohistochemistry (IHC). All biopsies were clinically confirmed by phathologists.
Amplification of hTERC was significantly associated with the histologic diagnoses (p<0.05). The positive correlation was found between the level of hTERC amplification and histologic grading of dysplasia (CIN2/3 from CIN1 or normal, P=0.03). A profounding increase in the accumulation of HPV and hTERC positive cases was observed in the CIN3 subgroup compared with the CIN2 group, 25% versus 62.96%, respectively (p=0.007).
hTERC ampliffication can be detected with FISH technique on exfoliated cervical cells. Amplification of hTERC and HPV infection are associated with more progressive CIN3 and CA. The testing of hTERC amplification might be a supplementary to cytology screening and HPV test, especially high-risk patients.
Virtual slides
The virtual slide(s) for this article can be found here:
PMCID: PMC3488518  PMID: 23107094
Cervical cancer; Telomerase; hTERT; hTERC; HR-HPV
10.  Down‐regulated nucleoside diphosphate kinase nm23‐H1 expression is unrelated to high‐risk human papillomavirus but associated with progression of cervical intraepithelial neoplasia and unfavourable prognosis in cervical cancer 
Journal of Clinical Pathology  2006;59(10):1044-1051.
One of the factors leading to an invasive phenotype is the nm23 family of metastases‐associated genes. Of the six known members, nm23‐H1 is the most frequently studied potential anti‐metastatic gene in cervical cancer. However, the possible molecular links to oncogenic human papillomavirus (HPV) are completely unexplored as yet.
Materials and methods
As a part of the HPV‐Pathogen Istituto Superiore di Sanità study, a series of 150 squamous cell carcinomas (SCCs) and 152 cervical intraepithelial neoplasia (CIN) lesions were examined by immunohistochemical staining for nm23‐H1, and tested for HPV by polymerase chain reaction (PCR) with three sets of primers (MY09/11, GP5+/GP6+ and short PCR fragment). Follow‐up data were available on all patients with SCC, and 67 CIN lesions were monitored by serial PCR for clearance or persistence of HPV after cone treatment.
A linear decrease (p = 0.001) was observed in nm23‐H1 expression, starting from CIN1 (85% with normal expression), with the most dramatic down regulation on transition from CIN2 (70% normal) to CIN3 (39%) and further to SCC (25%). Reduced expression was associated with CIN3 or cancer at an odds ratio 8.72 (95% confidence interval 4.13 to 18.41). Nm23‐H1 was of no use as a marker of the high‐risk human papillomavirus (HR‐HPV) type, and it did not predict clearance or persistence of HR‐HPV after treatment of CIN. Importantly, nm23‐H1 expression was a significant prognostic factor in cervical cancer, reduced expression being associated with lower survival (p = 0.022) in univariate analysis. In the multivariate (Cox) regression model, however, only the International Federation of Gynecology and Obstetrics stage (p = 0.001) and age (p = 0.011) remained independent prognostic predictors.
Down‐regulated nm23‐H1 expression is markedly associated with progression from CIN2 to CIN3, and predicts poor prognosis in cervical cancer. Nm23‐H1 down regulation is probably orchestrated by mechanisms independent of HR‐HPV oncoproteins and is possibly related to the emergence of a proteolytic phenotype.
PMCID: PMC1861749  PMID: 16537673
11.  Prevalence of cervical neoplastic lesions and Human Papilloma Virus infection in Egypt: National Cervical Cancer Screening Project 
Data from Egyptian studies provide widely varying estimates on the prevalence of pre-malignant and malignant cervical abnormalities and human papilloma virus (HPVs) infection. To define the prevalence and risk factors of pre-invasive and invasive cervical cancer (cacx), a community based full-scale cross sectional, household survey including 5453 women aged between 35 and 60 years was conducted.
The study period was between February 2000 and December 2002. Initially, conventional Papanicolaou (Pap) smears were evaluated using the Bethesda system (TBS), followed by colposcopic guided biopsy (CGB) for all epithelial abnormalities (EA). In a third step, HPV was tested on all EA by in-situ hybridization (ISH) using first the broad spectrum HPV probe recognizing HPVs 6, 11, 16, 18, 30, 31, 35, 45, 51 and 52 followed by subtyping with probes 6/11, 16/18 and 31/33. Lastly, unequivocal cases were immunostained for herpes simplex type-2 (HSV-2), cytomegalovirus (CMV), and human immunodeficiency virus (HIV).
EA representing 7.8% (424/5453), were categorized into atypical squamous cell of undetermined significance (ASCUS) (34.4%), atypical glandular cell of undetermined significance (AGCUS) (15.3%), combined ASCUS and AGCUS (3.1%), low grade squamous intraepithelial lesions (SIL) (41.0%), high grade SIL (5.2%) and invasive lesions (1%). CGB of EA (n = 281) showed non neoplastic lesions (12.8%), atypical squamous metaplasia (ASM) (19.2%), cervical intraepithelial neoplasia I (CIN) (44.4%), CIN II (4.4%), CINIII (2.8%), endocervical lesions (5.2%), combined squamous and endocervical lesions (10.0%), invasive squamous cell carcinoma (SCC) (0.02%) and extranodal marginal zone B cell lymphoma (MZBCL) (0.02%). The overall predictive value of cytology was 87% while the predictive value for high grade lesions was 80%. On histological basis, HPVs were present in 94.3% of squamous lesions while it was difficult to be identified in endocervical ones. ISH revealed positivity for pan HPV in 65.9% of the studied biopsies (n = 217), with incorporation of the viral genome HPV 6/11, 16/18 and 31/33 in 11.1%, 33.3% and 17.1% respectively. Multiple HPVs infections were identified in 0.02%.
Pre-invasive high grade lesions and invasive cervical carcinoma represent 0.5% and 0.04% respectively in Egyptian women. HPV mostly 16/18 as a risk factor (p < 0.001), was frequently associated with mixed infections (p < 0.001) and bilharzial infestation (p < 0.001).
PMCID: PMC1945019  PMID: 17610742
12.  Genome-wide methylation profiling identifies hypermethylated biomarkers in high-grade cervical intraepithelial neoplasia 
Epigenetics  2012;7(11):1268-1278.
Epigenetic modifications, such as aberrant DNA promoter methylation, are frequently observed in cervical cancer. Identification of hypermethylated regions allowing discrimination between normal cervical epithelium and high-grade cervical intraepithelial neoplasia (CIN2/3), or worse, may improve current cervical cancer population-based screening programs. In this study, the DNA methylome of high-grade CIN lesions was studied using genome-wide DNA methylation screening to identify potential biomarkers for early diagnosis of cervical neoplasia. Methylated DNA Immunoprecipitation (MeDIP) combined with DNA microarray was used to compare DNA methylation profiles of epithelial cells derived from high-grade CIN lesions with normal cervical epithelium. Hypermethylated differentially methylated regions (DMRs) were identified. Validation of nine selected DMRs using BSP and MSP in cervical tissue revealed methylation in 63.2–94.7% high-grade CIN and in 59.3–100% cervical carcinomas. QMSP for the two most significant high-grade CIN-specific methylation markers was conducted exploring test performance in a large series of cervical scrapings. Frequency and relative level of methylation were significantly different between normal and cancer samples. Clinical validation of both markers in cervical scrapings from patients with an abnormal cervical smear confirmed that frequency and relative level of methylation were related with increasing severity of the underlying CIN lesion and that ROC analysis was discriminative. These markers represent the COL25A1 and KATNAL2 and their observed increased methylation upon progression could intimate the regulatory role in carcinogenesis. In conclusion, our newly identified hypermethylated DMRs represent specific DNA methylation patterns in high-grade CIN lesions and are candidate biomarkers for early detection.
PMCID: PMC3499328  PMID: 23018867
cervical precancerous lesion; DNA methylation; MeDIP-chip; cervical scraping
13.  Performance of Human Papillomavirus DNA and mRNA Testing Strategies for Women with and without Cervical Neoplasia ▿  
Journal of Clinical Microbiology  2009;47(8):2458-2464.
In the present study we investigated the cross-sectional positivity for DNA and E6/E7 mRNA from high-risk human papillomavirus (HPV) types in 643 women with high-grade cervical neoplasia (135 cases of cervical intraepithelial neoplasia grade 2 [CIN2], 495 cases of CIN3/adenocarcinoma in situ [ACIS], and 13 cases of invasive carcinoma) and in 736 women with normal cytology by using the Amplicor and PreTect HPV-Proofer assays. In addition, genotyping was performed using Linear Array for women with normal cytology and a positive HPV test and in all women with histologically confirmed CIN2+. In women with normal cytology, 8.3% (61/736) were Amplicor positive and 3.3% (24/736) were PreTect HPV-Proofer positive (P < 0.001). Concordant results between the Amplicor and PreTect HPV-Proofer tests were present in 90.3% (665/736). In women with CIN2+ lesions 96.4% (620/643) were positive by Amplicor, 98.4% (633/643) by linear array, and 64.1% (412/643) by PreTect HPV-Proofer. Concordant results for the three HPV assays were present in 63.8%. The genotype profile detected by linear array and PreTect HPV-Proofer showed substantial agreement for HPV types 16, 18, 33, and 45. HPV type 16 and/or 18 was detected in 58.8% (378/643) of the women with high-grade neoplasia. Detection of E6/E7 mRNA by PreTect HPV-Proofer increased with severity of the cervical lesion. Detection of HPV DNA, however, was not associated with histology grade. In conclusion, the detection of HPV varied according to the assay used, and the concordance between the tests was poor. Our results indicate that mRNA testing may be a biomarker for progression of cervical neoplasia, but the optimal genotype mix remains to be determined.
PMCID: PMC2725639  PMID: 19535524
14.  Aetiology, pathogenesis, and pathology of cervical neoplasia. 
Journal of Clinical Pathology  1998;51(2):96-103.
Early epidemiological studies of cervical neoplasia suggested a causal relation with sexual activity and human papillomaviruses (HPVs) have emerged as prime suspects as venerally transmitted carcinogens. HPVs fall into two broad camps: low risk types, associated with cervical condylomas and CIN 1; and high risk types (mostly 16 and 18), found in 50-80% of CIN 2 and CIN 3 lesions, and 90% of cancers. This association with cancer is very strong, with odds ratios of > 15 (often much higher) in case-control studies that are methodologically sound. An infrequently detected third group of intermediate risk type HPVs is associated with all grades of CIN and occasionally with cancers. HPVs have also been detected in a wide range of asymptomatic controls, indicating that other events are required for development of neoplasia such as viral persistence and/or altered expression of viral genes, often following integration of the viral genome. This leaves the two major viral oncogenes, E6 and E7, directly coupled to viral enhancers and promoters, allowing their continued expression after integration. High risk HPV E7 proteins bind and inactivate the Rb protein, whereas E6 proteins bind p53 and direct its rapid degradation. A range of putative cofactors has been implicated in progression: HLA type, immunosuppression, sex steroid hormones, and smoking; most of these cofactors appear to influence progression to CIN 3. The natural history includes progression to CIN 3 in 10% of CIN 1 and 20% of CIN 2 cases, whereas at least 12% of CIN 3 cases progress to invasive carcinoma. Cervical glandular intraepithelial neoplasia (CGIN) often coexists with squamous CIN, and the premalignant potential of high grade CGIN is not in doubt, but the natural history of low grade CGIN remains uncertain. A high proportion of CGIN lesions and adenocarcinomas are HPV positive, and HPV18 has been implicated more in glandular than in squamous lesions. A strong clinical case for the application of HPV typing of cells recovered from cervical scrapes can be made; however, a rigorous cost-benefit analysis of introducing HPV typing into the cervical screening programme is required. Prophylactic and therapeutic HPV vaccines are under development. This article reviews the aetiology, pathogenesis, and pathology of cervical neoplasia, emphasising the role of HPVs.
PMCID: PMC500501  PMID: 9602680
15.  Prevalence and Predictors of Colposcopic-Histopathologically Confirmed Cervical Intraepithelial Neoplasia in HIV-Infected Women in India 
PLoS ONE  2010;5(1):e8634.
Prevalence estimates of cervical intraepithelial neoplasia (CIN) among HIV-infected women in India have been based on cervical cytology, which may have underestimated true disease burden. We sought to better establish prevalence estimates and evaluate risk factors of CIN among HIV-infected women in Pune, India using colposcopy and histopathology as diagnostic tools.
Previously unscreened, non-pregnant HIV-infected women underwent cervical cancer screening evaluation including standardized diagnostic colposcopy by a gynecologist. Histopathologic confirmation was conducted among consenting women with clinical suspicion of CIN. The prevalence of CIN was evaluated by a composite diagnosis based on colposcopy and histopathology results. Multivariable ordinal logistic regression analysis was conducted to determine independent predictors of increasing severity of CIN.
The median age of the n = 303 enrolled HIV-infected women was 30 years (interquartile range, 27–34). A majority of the participants were widowed or separated (187/303, 61.7%), more than one-third (114/302, 37.7%) were not educated beyond primary school, and nearly two-thirds (196/301, 64.7%) had a family per capita income of <1,000 Indian Rupees (∼US$22) per month. Cervical high-risk HPV-DNA was detected in 41.7% (124/297) of participants. The composite colposcopic-histopathologic diagnoses revealed no evidence of CIN in 220 out of 303 (72.6%) women, CIN1 in 33/303 (10.9%), CIN2 in 31/303 (10.2%), CIN3 in 18/303 (5.9%) and 1 (0.3%) woman was diagnosed with ICC. Thus, over a quarter of the participants [83/303: 27.7% (95% CI: 22.7–33.1)] had ≥CIN1 lesions and a sixth [50/303: 16.5% (95% CI: 12.2–21.9)] had evidence of advanced (≥CIN2) neoplastic disease. The independent predictors of increasing severity of CIN as revealed by a proportional odds model using multivariable ordinal logistic regression included (i) currently receiving antiretroviral therapy [adjusted odds ratios (aOR): 2.24 (1.17, 4.26), p = 0.01] and (ii) presence of cervical high-risk HPV-DNA [aOR: 1.93 (1.13, 3.28), p = 0.02].
HIV-infected women in Pune, India have a substantial burden of cervical precancerous lesions, which may progress to invasive cervical cancer unless appropriately detected and treated. Increased attention should focus on recognizing and addressing this entirely preventable cancer among HIV-infected women, especially in the context of increasing longevity due to antiretroviral therapy.
PMCID: PMC2798747  PMID: 20072610
16.  Hybrid capture II for high-risk human papillomavirus DNA testing to detect cervical precancerous lesions: A qualitative and quantitative study 
Hybrid capture II (HC-II) is the only technique that can be used in clinical human papillomavirus (HPV) DNA detection. However, there is controversy in regards to how to analyze and assess the viral load of high-risk (HR)-HPV by use of HC-II and the relation between viral load and cervical lesions. In this study, we analyzed the results of a sequential screening of outpatients at the Department of Obstetrics and Gynecology of the China-Japan Friendship Hospital, and we aimed to explore the relationship between HR-HPV viral load and the severity of cervical lesions, and to clarify the clinical significance of the titer of HR-HPV DNA determined by HC-II. Using HC-II, 2,761 women were screened for HR-HPV DNA combined with cytological testing using liquid-based cytology. All women with HR-HPV-positive results or abnormalities in cytology underwent a cervical biopsy through colposcopy. Cervical biopsies were taken in 1,051 women. The HR-HPV infection rate was 78.35% (76/97) in HPV-associated lesions, 87.33% (193/221) in cervical intraepithelial neoplasia (CIN) I, 94.74% (144/152) in CIN II, 100% (178/178) in CIN III and 100% (20/20) in invasive cervical cancer (ICC), respectively (P<0.05). Based on the criteria of histopathology, the sensitivity of HR-HPV DNA testing by HC-II for detecting high-grade cervical lesions was 97.71%, the specificity was 79.64%, the positive-predictive value was 41.06% and the negative-predictive value was 99.59%. The viral loads of HR-HPV DNA were 512.15±764.19 in HPV-associated lesions, 753.95±978.27 in CIN I, 871.08±1003.52 in CIN II, 603.40±740.25 in CIN III and 466.44±673.05 in ICC, respectively. In conclusion, the positive rate of HR-HPV increased significantly in accordance with the severity of cervical lesions. The viral loads of cervical inflammatory lesions were markedly lower than CINs and ICC. The viral loads of HR-HPV DNA tested by HC-II had no correlation with the grade of cervical lesions.
PMCID: PMC3490331  PMID: 23136614
human papillomavirus; cervical intraepithelial neoplasia; viral load
17.  Differences in serological IgA responses to recombinant baculovirus-derived human papillomavirus E2 protein in the natural history of cervical neoplasia. 
British Journal of Cancer  1997;75(8):1144-1150.
Infection with certain types of human papillomavirus (HPV) presents a high risk for the subsequent development of cervical intraepithelial neoplasia (CIN) and cervical carcinoma. Immunological mechanisms are likely to play a role in control of cervical HPV lesions. The HPV E2 protein has roles in virus replication and transcription, and loss of E2 functions may be associated with progression of cervical neoplasia. Accordingly, it is of interest to monitor immune responses to the E2 protein, and previous studies have reported associations between serological reactivity to E2 peptide antigens and cervical neoplasia. In order to investigate serological responses to native, full-length E2 protein, we expressed HPV-16 E2 proteins with and without an N-terminal polyhistidine tag using the baculovirus system. Purified HPV-16 E2 protein was used to develop enzyme-linked immunosorbent assays to detect serological IgG and IgA responses in cervical neoplasia patients and controls. We found that serum IgA levels against the E2 protein were elevated in CIN patients relative to normal control subjects but were not elevated in cervical cancer patients. Moreover, there appeared to be a gradient of response within cervical neoplasia such that the highest antibody levels were seen in lower grades of neoplasia up to CIN 2, whereas lower levels were observed in CIN 3 and still lower levels in cervical carcinoma. These findings suggest that the IgA antibody response to E2 may associate with stage and progression in cervical neoplasia.
PMCID: PMC2222781  PMID: 9099962
18.  The Clinical Meaning of a Cervical Intraepithelial Neoplasia Grade 1 Biopsy 
Obstetrics and gynecology  2011;118(6):1222-1229.
To determine whether the diagnosis of cervical intraepithelial neoplasia grade 1 (CIN1) increases the risk of cervical intraepithelial neoplasia grade 3 (CIN3) above what is observed for human papillomavirus (HPV) infection.
Using data from the atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) triage study (ALTS), we compared the 2-year cumulative risk of CIN3 for women with an enrollment diagnosis of CIN1 (n = 594) (median age = 23 years) compared with those with negative histology or no biopsy taken at colposcopy (“no CIN1,” n = 570) (median age = 24 years). Baseline cervical specimens were tested for carcinogenic HPV by a clinical HPV test and HPV genotypes by polymerase chain reaction. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) as a measure of association of enrollment status, including CIN1 compared with no CIN1 diagnosis, with 2-year worst outcomes of CIN3.
The two-year risks of CIN3 were 10.3% (95%CI: 7.9%–13.0%) for women with CIN1, 7.3% (95%CI: 4.6%–10.9%) for negative histology, and 6.4% (95%CI: 3.8%–9.9%) for women referred to colposcopy and no biopsies were taken (p = 0.1). The 2-year risk of CIN3 for women positive for HPV16, HPV18, or other carcinogenic HPV genotypes was 19.1%, 13.9%, and 5.7%, respectively, and did not differ significantly by the baseline cytology interpretation (ASCUS or LSIL). Taking HPV genotypes into account, having a CIN1 (compared with no CIN1) was not a risk factor for developing CIN3 (OR = 0.99, 95%CI: 0.54–1.8).
A CIN1 diagnosis does not represent a significant risk factor for CIN3 above the risk attributed to its molecular cause, genotype-specific HPV infection.
PMCID: PMC3229199  PMID: 22105250
19.  Tubal Ligation Frequency in Oklahoma Women with Cervical Cancer 
Gynecologic oncology  2012;127(2):278-282.
Infrequent Pap screening is an important risk factor for cervical cancer. We studied the association between contraceptive methods, screening frequency, and cancer.
Women (n=2,004) enrolled in the cross-sectional Study to Understand Cervical Cancer Endpoints and Determinants(SUCCEED) underwent colposcopy to evaluate an abnormal Pap test. Questionnaire data were compared between those with cervical intraepithelial neoplasia(CIN)3/adenocarcinoma in situ(AIS) and those with invasive cancer to identify factors associated with cancer. Logistic regression was used to calculate age-stratified measures of association between contraceptive method and Pap frequency as well as tubal ligation(TL) and cancer risk.
In all age groups, women with TL were more likely to have had no Pap screening in the previous 5 years compared to women using other contraception: 26-35 years (OR 4.6, 95%CI 2.4 −8.6; p<0.001), 36-45 years (OR 3.8, 95%CI 2.1-7.0; p<0.001), and 46-55 years (OR 2.2, 95%CI 1.0-4.9; p=0.050). Subjects with cancer (n=163) were more likely to have had a TL (41% vs. 21%, p<0.001) than those with CIN3/AIS (n=370). Age-stratified analyses showed an increased odds of tubal ligation in women with cancer versus those with CIN3/AIS between 25 and 45 years, with a significant increase in women 26 to 35 years old (OR 3.3, 95%CI 1.4-8.1; p=0.009). Adjusting for Pap frequency changed the effect only slightly, suggesting increased risk was not fully mediated by lack of screening.
Contraceptive type is associated with Pap screening. Women with TLs obtain less frequent Pap testing and may be at increased risk for cervical cancer.
PMCID: PMC3472093  PMID: 22858904
20.  Systematic Review and Meta-Analysis of L1-VLP-Based Human Papillomavirus Vaccine Efficacy against Anogenital Pre-Cancer in Women with Evidence of Prior HPV Exposure 
PLoS ONE  2014;9(3):e90348.
It is unclear whether L1-VLP-based human papillomavirus (HPV) vaccines are efficacious in reducing the likelihood of anogenital pre-cancer in women with evidence of prior vaccine-type HPV exposure. This study aims to determine whether the combined results of the vaccine trials published to date provide evidence of efficacy compared with control (hepatitis A vaccine/placebo).
A systematic review and meta-analysis was conducted. Randomized-controlled trials (RCTs) were identified from MEDLINE, Embase, Web of Science, PubMed, Cochrane Central Register of Controlled Trials and references of identified studies. The bivalent vaccine containing HPV-16 and 18 VLPs from GlaxoSmithKline Biologicals (Rixenstart, Belgium), the quadrivalent vaccine containing HPV-6, 11, 16, and 18 VLPs from Merck & Co., Inc., (Whitehouse Station, NJ USA), and the HPV-16 monovalent vaccine from Merck Research Laboratories (West Point, PA USA) were evaluated.
Three RCT reports and two post-trial cohort studies were eligible, comprising data from 13,482 women who were included in the vaccine studies but had evidence of HPV infection at study entry. Data on efficacy was synthesized using the Mantel-Haenszel weighted fixed-effect approach, or where there was heterogeneity between studies, the DerSimonian and Laird weighted random-effect approach. The mean odds ratio (OR) and 95% confidence interval (CI) for the association between Cervarix, Gardasil and HPV-16 monovalent vaccine and HPV-associated cervical intraepithelial neoplasia grade 3 or worse was 0·90 (95% CI: 0·56, 1·44). For the association between Gardasil and HPV-associated vulval/vaginal intraepithelial neoplasia grades 2–3, the overall OR and 95% CI was 2.25 (95% CI: 0·78, 6.50). Sample size and follow-up were limited.
There was no evidence that HPV vaccines are effective in preventing vaccine-type HPV associated pre-cancer in women with evidence of prior HPV exposure. Small effects of vaccination however cannot be excluded and a longer-term benefit in preventing re-infection remains possible.
PMCID: PMC3940851  PMID: 24595046
21.  Cross-Sectional Comparison of an Automated Hybrid Capture 2 Assay and the Consensus GP5+/6+ PCR Method in a Population-Based Cervical Screening Program 
Journal of Clinical Microbiology  2006;44(10):3680-3685.
In this cross-sectional study, clinical performances of the hybrid capture 2 assay using an automated instrument (i.e., rapid capture system) (hc2-RCS) and the high-risk human papillomavirus GP5+/6+ PCR-enzyme immunoassay (EIA) test were compared using cervical scrape specimens from 8,132 women that participated in a population-based screening trial. The hc2-RCS test scored significantly more samples positive (6.8%) than the GP5+/6+ PCR-EIA (4.8%) (P < 0.0005). This could be attributed largely to a higher positivity rate by the hc2-RCS test for women with cytologically normal, borderline, or mild dyskaryosis. A receiver operator characteristics analysis of the semiquantitative hc2-RCS results in relation to different cytology categories revealed that these differences are owing to differences in assay thresholds. For women classified as having moderate dyskaryosis or worse who also had underlying histologically confirmed cervical intraepithelial neoplasia grade 3 or cervical cancer (≥CIN3), the hc2-RCS scored 97% (31/32) of samples positive, versus 91% (29/32) by GP5+/6+ PCR-EIA. However, this difference was not significant (P = 0.25). After increasing the hc2-RCS cutoff from 1.0 to 2.0 relative light units/cutoff value of the HPV16 calibrator (RLU/CO), no additional CIN3 lesions were missed by hc2-RCS, but the number of test-positive women with normal, borderline, or mild dyskaryosis was significantly decreased (P < 0.0005). However, at this RLU/CO, the difference in test positivity between hc2-RCS and the GP5+/6+ PCR-EIA was still significant (P = 0.02). The use of an RLU/CO value of 3.0 revealed no significant difference between hc2-RCS and GP5+/6+ PCR-EIA results, and equal numbers of smears classified as ≥CIN3 (i.e., 29/32) were detected by both methods. In summary, both assays perform very well for the detection of ≥CIN3 in a population-based cervical screening setting. However, adjustment of the hc2-RCS threshold to an RLU/CO value of 2.0 or 3.0 seems to produce an improved balance between the clinical sensitivity and specificity for ≥CIN3 in population-based cervical screening.
PMCID: PMC1594747  PMID: 17021097
22.  The association between MTHFR 677C>T polymorphism and cervical cancer: evidence from a meta-analysis 
BMC Cancer  2012;12:467.
MTHFR 677C>T polymorphism is a genetic alteration in an enzyme involved in folate metabolism, but its effect on host susceptibility to cervical cancer is still uncertain. The aim of this study was to investigate the association between MTHFR 677C>T polymorphism and cervical cancer by performing a meta-analysis.
Pubmed, Embase, Web of Science, and the Chinese Biomedical Database (CBM) databases were searched for case–control studies investigating the association between MTHFR 677C>T polymorphism and cervical cancer. Odds ratios (OR) and 95% confidence intervals (95%CI) were used to assess this possible association.
11 studies with a total of 1898 cervical cancer cases and 2678 controls were included. Meta-analyses of a total 11 studies showed no association between MTHFR 677C>T polymorphism and cervical cancer using all five genetic models (All P values > 0.05). However, subgroup analyses showed the odds of the homozygous TT genotype were much less in cervical cancer cases than in controls in Europeans, which implied an association between the homozygous TT genotype and cervical cancer in Europeans (For TT versus CC, fixed-effects OR = 0.65, 95%CI 0.45-0.93, P = 0.020, I2 = 0.0%). The odds for the homozygous TT genotype were greater in cervical cancer cases than in controls in East Asians, which also implied an association between the homozygous TT genotype and cervical cancer in East Asians (For TT versus CC, random-effects OR = 1.66, 95%CI 1.05-2.62, P = 0.029, I2 = 52.6%; For TT versus CT/CC, random-effects OR = 1.55, 95%CI 1.09-2.22, P = 0.016, I2 = 42.4%). Both subgroup analyses and meta-regression analyses suggested ethnicity was the major source of heterogeneity. Publication bias was not evident.
This meta-analysis supports an association between MTHFR 677C>T polymorphism and cervical cancer, and the effect of this association may be race specific. Further studies with large sample sizes and careful design are needed to identify this association more comprehensively.
PMCID: PMC3583684  PMID: 23057736
MTHFR; Single nucleotide polymorphism; Cervical cancer; Meta-analysis
23.  Association of human ß-herpesviruses with the development of cervical cancer: bystanders or cofactors 
Journal of Clinical Pathology  2001;54(1):48-53.
Background/Aim—Human papillomaviruses (HPVs) are important, but not sufficient, for the development of cervical cancer. All three human ß-herpesviruses—cytomegalovirus (CMV) and human herpesviruses (HHV) types 6 and 7—have been detected in the cervix. In addition, CMV and HHV-6 can interact with HPVs in vivo. This study examined the possible role of ß-herpesviruses in cervical cancer development.
Methods—HPV, CMV, HHV-6, and HHV-7 were detected by the polymerase chain reaction using cervical scrapes taken at colposcopy from 388 women. HPV types were identified using restriction fragment length polymorphisms. Colposcopy guided biopsies were taken from abnormal areas, and the histological findings were regarded as the final diagnoses. The associations between herpesvirus infection and the degree of cervical lesion were analysed with respect to HPV status.
Results—Of the 388 women, 51.8% had a normal cervix, 14.4% had cervical intraepithelial neoplasia grade 1 (CIN1), 8.2% had CIN2, 19.3% had CIN3, and 6.2% had invasive carcinoma. Overall, the positive rates for high, intermediate, and low risk HPVs were 18.8%, 21.4%, and 5.2%, respectively. Fifteen patients harboured HPVs for which the genotype could not be identified. Positive rates for CMV, HHV-6, and HHV-7 were 9.5%, 3.6%, and 3.4%, respectively. HPV positive patients carried a higher risk for high grade lesions (CIN2/3 or carcinoma) (odds ratio (OR), 5.24; 95% confidence interval (CI), 3.19 to 8.62; χ2 = 51.79; p < 0.001), whereas those positive for CMV, HHV-6, or HHV-7 did not. Thirteen of 131 patients with high grade lesions had HPV/herpesvirus coinfections, but no association with the cervical lesion was noted. Furthermore, positive rates for herpesviruses among HPV negative, high/intermediate risk HPV negative, and high risk HPV negative subgroups were similarly low and without a significant association.
Conclusions—The ubiquitous nature of herpesviruses may pose difficulty in elucidating their pathogenic role. These results indicate that CMV, HHV-6, and HHV-7 are bystanders rather than cofactors in the oncogenesis of cervical cancer.
Key Words: human papillomavirus • human herpesvirus 6 • human herpesvirus 7
PMCID: PMC1731269  PMID: 11271789
24.  Aberrant expression of VEGF‐C is related to grade of cervical intraepithelial neoplasia (CIN) and high risk HPV, but does not predict virus clearance after treatment of CIN or prognosis of cervical cancer 
Journal of Clinical Pathology  2006;59(1):40-47.
Increased angiogenesis leads to invasion in cervical cancer. Vascular endothelial growth factors (VEGFs) are involved in angiogenesis, but molecular links to the most important aetiological agent, human papillomavirus (HPV), need clarifying.
Archival samples—150 squamous cell carcinomas (SCCs) and 152 cervical intraepithelial neoplasia (CIN) lesions—were examined immunohistochemically for anti‐VEGF‐C antibody and for HPV by polymerase chain reaction (PCR). Follow up data were available for all SCC cases, and 67 CIN lesions were monitored with serial PCR to assess HPV clearance/persistence after treatment.
High risk (HR) HPV types were closely associated with CIN (odds ratio, 19.12; 95% confidence interval, 2.31 to 157.81) and SCC (27.25; 3.28 to 226.09). There was a linear increase of VEGF‐C expression—weak in CIN1 and intense in CIN3 and SCC (20.49; 8.69 to 48.26). VEGF‐C upregulation was a sensitive (93.5%; 95% CI, 90.1% to 96.9%) marker of HR‐HPV type (4.70; 2.17 to 10.21), but lost its significance in multivariate regression—p16INK4a and survivin were equally strong independent predictors of HR‐HPV. Aberrant expression of VEGF‐C did not predict clearance/persistence of HR‐HPV after treatment of CIN. In cervical cancer, VEGF‐C had no prognostic value in univariate or multivariate survival analysis. After adjustment for HR‐HPV, FIGO stage, age, and tumour grade, only FIGO stage and age remained independent prognostic predictors.
VEGF‐C is an early marker of cervical carcinogenesis, with linearly increasing expression starting from low grade CIN. VEGF‐C expression is closely related to HR‐HPV in cervical lesions, probably because of its p53 independent upregulation by the E6 oncoprotein of HR‐HPV.
PMCID: PMC1860266  PMID: 16394279
vascular endothelial growth factor C; angiogenesis; human papillomavirus; cervical intraepithelial neoplasia; cervical cancer; prognosis; virus clearance; high risk human papillomavirus; conisation
25.  HPV Prevalence and Cervical Intraepithelial Neoplasia among HIV-infected Women in Yunnan Province, China: A Pilot Study 
To determine the prevalence of HPV and cervical neoplasia among HIV-infected women in southwestern China.
Cervical cytology, HPV detection by Hybrid Capture-2™ assay, and diagnostic colposcopy were followed by cervical biopsy if indicated. Logistic regression analysis was used to analyze associations between HPV co-infection and cervical intraepithelial neoplasia (CIN), and HIV-related clinical and laboratory parameters.
Colposcopic-histopathologically proven CIN2+ lesions were present in 7/83 (8.4%) HIV-infected women. Nearly half (41/83, 43%) were co-infected with carcinogenic HPV genotypes. HPV co-infection was higher in women with colposcopic-histopathologically proven CIN2+ lesions than women with
HIV/AIDS care and treatment programs should integrate effective cervical cancer prevention services to mitigate the risk of invasive cervical cancer among HIV-infected women in China.
PMCID: PMC3809115  PMID: 22502720
China; HIV/AIDS; HPV; cervical cancer; screening; prevention

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