RELATIONSHIP BETWEEN CYCLIN G1 AND HUMAN PAPILLOMA VIRUS INFECTION IN CERVICAL INTRAEPITHELIAL NEOPLASIA AND CERVICAL CARCINOMA

Objective To evaluate the overexpression of cyclin G1 in cervical intraepithelial neoplasia （CIN） and cervical carcinoma, and the correlation between cyclin G1 and high-risk human papilloma virus （HPV） infection. Methods All of the specimens were obtained from the Department of Pathology of China-Japan Friendship Hospital from January 2000 to August 2004. We detected the expression of cyclin G1 with immunohistochemistry, HPV16/18 infection with in situ hybridization, and high-risk HPV infection with Hybrid capture system Ⅱ （HC-Ⅱ） in normal group （25 cases）, CIN Ⅰ （48 cases）, CIN Ⅱ （56 cases）, CIN Ⅲ（54 cases）, and invasive cervical squamous-cell carcinoma （SCC, 31 cases）. Results The positive rates of cyclin G1 expression in CIN（77.85% ）and SCC cervical tissues （87. 10% ） were significantly higher than normal （ 8.00%, P 〈 0. 01 ）, and the intensities of cyclin G1 expression in CIN（40. 60% ） and SCC cervical tissues （61.51%） were significantly higher than normal （2. 72%, P 〈0.05）. The positive rates and intensities of cyclin G1 expression increased gradually with the grade of cervical lesions. High-risk HPV infection rates were higher in CIN and SCC than normal groups （P 〈 0.05 ）. There was a positive correlation between cyclin G1 expression and high-risk HPV infection detected with HC-Ⅱ （Kendall＇s tau-b =0. 316, 0. 269, 0. 352, and 0. 474 in CIN Ⅰ, CIN Ⅱ, CIN Ⅲ, and SCC, respectively, P 〈 0. 05 ）. Conclusions Cyclin G1 is overexpressed in CIN and SCC. Cyclin G1 may be a biomarker for detecting CIN and SCC. Cyclin G1 may play an important role in the oncogenesis of CIN and SCC by high-risk HPV infection.

The Prevalence of High Grade Cervical Intraepithelial Neoplasia (CIN) in a Primary Human Papillomavirus (HPV) Cervical Screening Programme Population with HPV Positive and Cytology Negative Smear Results

High-risk HPV is found in 99.7% of cervical cancers. The causative role of HPV in cervical cancer has led to the inclusion of HPV testing as part of cervical screening. A pilot of HPV testing as primary screening was commenced in 2013 at six pilot sites in England. North Cumbria Integrated Care (NCIC) NHS Foundation Trust took part in the pilot, in which women with an HPV-positive/cytology-negative result were recalled at 12 months. Women with HPV type 16/18 found at initial screening and persisting at 12 months in spite of negative cytology were referred to Colposcopy services at 12 months. Women with smear positive for hrHPV other than 16/18 types were recalled twice at 12 and 24 months before referral to colposcopy. Persistent hrHPV positive/cytology negative smear at 12 and 24 months initiated a colposcopy referral. Objective: To assess the prevalence of high grade CIN and invasive cancer in patients referred to colposcopy services at NCIC NHS Foundation Trust with hrHPV positive/cytology negative smears. Method: The study was conducted at NCIC NHS Foundation Trust between January 2015 and December 2017. Data was collected retrospectively from the colposcopy data base (INFOFLEX). All patients with HPV positive/cytology negative smears seen in colposcopy clinic during the study period were included. Patients with high grade CIN, cervical glandular intraepithelial neoplasia (CGIN) or invasive cancer were recorded. Results: 763 women were included in the study. A total of 50 (6.6%) women had high grade CIN, CGIN or invasive cancer. 40 of these 50 women (80%) were treated by large loop excision of the transformation zone (LLETZ). Conclusion: HPV primary screening is more effective than cytology-based screening. A high grade HPV positive result with negative cytology, persisting for one year in type 16/18 and for two years in other high-risk HPV types, warrants referral for colposcopy, as 6.6% of women in this study had high grade or invasive pathology.

Distribution of High-Risk Human Papillomavirus Genotypes among Women with Colposcopic Diagnosis of Cervical Intraepithelial Neoplasia in Bangladesh

Background: The incidence of cervical cancer is high in Bangladesh and there is a high prevalence of preinvasive lower genital tract disease among women of reproductive age. Persistent high-risk Human Papilloma Virus (HPV) infection is the main underlying cause of cervical cancer and its precursor, cervical intraepithelial neoplasia (CIN). Objective: The aim of the study was to identify the subtypes of high-risk HPV infection among women with the colposcopic diagnosis of cervical intraepithelial neoplasia in Bangladesh. Methods: This cross-sectional observational study was conducted in the colposcopy clinic of Dhaka Medical College Hospital over a six-month period. A total of 100 participants were enrolled. Married women, between 30 - 60 years of age with colposcopically diagnosed cervical intra epithelial neoplasia were enrolled. Women with chronic illness, pregnancy, and women unable to consent were excluded from this study. After counselling, colposcopically directed punch biopsies were taken from each CIN case concurrently with high-risk HPV testing by polymerase chain reaction (PCR). Results: The mean age of the patients was 38.69 (SD ±7.76) years. CIN 1 was diagnosed in 57% of participants, while 24% had CIN II and 19% had CIN III lesions. High-risk HPV was present in 52 patients. HPV 16 was the most common identified in 28 (53.84%) and HPV 18 was the second most common with 20 (38.46%) either singly or in combination with other high-risk subtypes. The other HPV strains, HPV 31, 33, 35, 52, 56 and 58, were also detected either as mono or co-infections. Out of the 52 HPV positive cases, 29 (55.8%) had mono infection and 23 (44.2%) had co-infection with several subtypes. The highest incidence (50%) of oncogenic HPV infections was present among women aged 35 - 45 years. Risk factors associated with HPV positive cases were high parity (P 0.05), early age at marriage (P = 0.754) and early age of first child. Conclusion: This study identified a high prevalence of HPV 16 and 18 genotypes. HPV vaccination with the current 9-valent HPV vaccine, which contains HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. Will be an effective public health measure to eradicate cervical cancer in Bangladesh.

THE DETECTION OF P53 GENE IN HUMAN CERVICAL CARCINOMA WITH AND WITHOUT HUMAN PAPILLOMAVIRUS INFECTION

The special primers Of p53 exon 7 as wed as HPV16 E6 and E7 ORFs (Opening Rending Frame) were used with PCR, PCR-SSCP technique, and 35 specimens of cervical carcinoma were examined. The results were as follows: ① HPV16 E6, E7 DNA was found in 25/35 specimens (71. 4%),which proved again HPV16 Infection an important event in cervical carcinogenesis. However only 11/35 (31.42% ) bad E6 and E7 ORFs simultaneously, 3/35 (8. 57%) and 11/35 (31. 42% ) had only E6 or E7 respectively. ② No mutation and LOH (Loss of Heterozygote) of p53 exon 7 were found in allof 35 specimens. Additionally in the present study, we developed a non-isotopic PCR-SSCP method.

Detection of Human Papillomavirus Type 16 DNA in Cervical Carcinomas

Accurate typing of the different human papillomavirus types is csscntial in view of the differ-ent pathological potential of the common virus types of human papillomavirus （HPV） present in thecervix. We have developed hybridization, washing and autoradiography conditions that minimize thecross-hybridization among different specific types of HPV so as to allow clear - cut type assignmentthrough practical dot blot hybridization technique using nylon membrane and 35S - labeled HPV - 16DNA probe. Under these conditions seventeen of thirty （56.7%） of squamous cell carcinomas of thecervix uteri obtained from Tianjin women were detected in the presence of HPV - 16 DNA.

Distribution of high-risk human papillomavirus genotype prevalence and attribution to cervical precancerous lesions in rural North China

Objective: Precise prevention is more desired for cervical cancer due to the huge population, high prevalence of human papillomavirus(HPV) infection in China and the vision of screen-and-treat strategies in low-and middleincome countries(LMICs). Considerations of combining type-specific prevalence and attribution proportion to high-grade cervical intraepithelial neoplasia are informative to more precise and effective region-specific cervical cancer prevention and control programs. The aim of the current study was to determine the genotype distribution of HPV and attribution to cervical precancerous lesions among women from rural areas in North China.Methods: A total of 9,526 women participated in the cervical cancer screening project in rural China. The samples of women who tested positive for HPV were retested with a polymerase chain reaction(PCR)-based HPV genotyping test. The attribution proportion of specific high-risk human papillomavirus(HR-HPV) types for different grades of cervical lesions was calculated by using the type contribution weighting method.Results: A total of 22.2%(2,112/9,526) of women were HR-HPV positive and HPV52(21.7%) was the most common HR-HPV genotype, followed by HPV58(18.2%), HPV53(18.2%) and HPV16(16.2%). The top three genotypes detected in HR-HPV-positive cervical intraepithelial neoplasia(CIN)1 were HPV16(36.7%), HPV58(20.4%), HPV56(15.3%). Among CIN2+, the most frequent genotypes were HPV16(75.6%), HPV52(17.8%),HPV58(16.7%). HPV16, 56, 58, 53, 52, 59, 68, and 18 combined were attributed to 84.17% of all CIN1 lesions,and HPV16, 58, and 52 combined were attributed to 86.98% of all CIN2+ lesions.Conclusions: The prevalence of HR-HPV infection among women from rural areas in North China was high and HPV16, HPV58, HPV52 had paramount attributable fraction in CIN2+. Type-specific HPV prevalence and attribution proportion to cervical precancerous lesions should be taken into consideration in the development of vaccines and strategy for screening in this population.

Prevalence of HPV Infection And Cervical Intraepithelial Neoplasia And Attitudes towards HPV Vaccination among Chinese Women Aged 18-25 in Jiangsu Province

Objective：Few data are available on the epidemiology of HPV and cervical cancer among Chinese women younger than 25 years old.This study aimed to estimate the HPV infection rate and the prevalence of cervical intraepithelial neoplasia（CIN） in women aged 18-25,as well as their knowledge of and attitudes towards HPV vaccination.Methods：A population-based cervical cancer screening study was conducted on women aged 18-25 in Jiangsu province in 2008.Participants provided socio-demographic,reproductive and behavioral information and completed a survey about their knowledge of and attitudes towards HPV vaccination.Women then underwent a gynecologic exam to provide two cervical exfoliated cell samples for high risk HPV DNA testing and liquid-based cytology（LBC） as well as visual inspection with acetic acid（VIA）.Women testing positive for any test were referred to colposcopy and biopsy.The gold standard for diagnosis of cervical lesions was directed or random biopsies.Results：Within the sample of 316 women,3.4% of them were diagnosed with CIN grade 2 or worse lesions and 17.1% were found to be positive for HPV DNA.Among these young women,extra-marital sexual behavior of them（OR=2.0,95%CI：1.1-3.8） or their husbands（OR=2.6,95%：1.4-4.7） were associated with an increased risk of HPV positivity.Although overall HPV awareness was low,after a brief educational intervention,98.4% reported they would electively receive HPV vaccination and would also recommend that their daughters be vaccinated.However,most urban and rural women reported their ideal maximum out-of-pocket contribution for HPV vaccination to be less than 500 RMB and 50-100 RMB,respectively.Conclusion：Our study indicates cervical disease burden is relatively high among sampled Chinese women aged 18-25.Appropriate educational interventions for female adolescents and strategies to subsidize vaccine costs are definitely needed to ensure the effectiveness of vaccination campaigns in China.

Expression and Significance of SHP-2 in Human Papillomavirus Infected Cervical Cancer

This study investigated the expression and prognostic value of SHP-2 in cervical cancer caused by human papillomavirus (HPV) infection. Forty-five specimens from patients with cervical cancer (stageⅠ-Ⅲ), 32 specimens from patients with cervical intraepithelial neoplasia (CIN) (Ⅰ, Ⅱ) and 20 normal cervical samples from patients with hysteromyoma were collected in Department of Pathology for comparison. The expression levels of SHP-2 and IFN-β proteins were detected by using immunohistochemistry. The mRNA expression level of SHP-2 was detected by using quantitative real-time polymerase chain reaction (PCR). HPVs were detected by HPV GenoArray Test. The Spearman correlation was used to compare the expression level of SHP-2 in HPV infected cervical cancer vs non-HPV infected normal cervix. The level of SHP-2 protein expression in the cancer tissues (88.8%) was significantly higher than in CIN tissues (62.5%) and normal cervixes (45%) (P<0.05 and P<0.05, respectively). The SHP-2 mRNA levels in the cancer tissues were upregulated as compared with those in the normal cervixes (P<0.05). Twenty-one (46.7%) cervical cancers, 25 (78.1%) CINs and 17 (85%) normal cervixes showed IFN-β positive staining in cytoplasm. There was statistically significant difference in the expression rate of IFN-β between cervical cancer and normal cervix (χ2=8.378, P<0.05) as well as between cervical cancer and CIN (χ2=7.695, P<0.05). HPV16/18 infections could be found in normal cervixs (15%), CINs (68.7%) and cervical cancers (84.4%). There was a correlation between HPV infection and SHP-2 expression in cervical cancer (rs=0.653, P<0.05). SHP-2 may be a useful prognostic and diagnostic indicator for HPV infected cervical cancer. In cervical cancers, SHP-2 mRNA and protein overexpression was associated with IFN-β lower-expression.

Clinical Observation of rhIL-2 Combined with Zhenqi Fuzheng and BaofuKang Suppository in the Treatment of Cervical Intraepithelial Neoplasia II with HPV Infection

Objective: To investigate the clinical effects of recombinant human interleukin-2 (rhIL-2) combined with Zhenqi Fuzheng and Baofukang on cervical intraepithelial neoplasia II (CINII) combined with human papilloma virus infection. Methods: There were 593 patients diagnosed with CINII with HPV infection, including 296 in the control group and 297 in the experimental group. The control group was given only Zhenqi Fuzheng oral and Baofukang suppository vaginal medicine. The experimental group was treated with rhIL-2 injection in addition to Zhenqi Fuzheng oral and Baofukang suppository vaginal medicine which is treated for 3 months. After 3 months, Thinprep cytologic test (TCT), human papilloma virus (HPV) quantitative examination and colposcopy biopsy were reviewed. Results: After 3 months of treatment, the negative conversion rate and total effective rate of HPV in the control group were 58.11% and 70.95% respectively, and the negative conversion rate and total effective rate of the experimental group were 79.46% and 90.57% respectively. There was significant difference between the two groups (p = 0.000). The curative rate of cervical lesions was significantly higher in the test group than in the control group, 89.56%, 68.91%, respectively. The statistical difference between the two groups is significant (p = 0.000). Conclusion: It has an essential clinical value that HPV infection patients and cervical intraepithelial neoplasia II associated with HPV infection patients are treated by rhIL-2 combined with Zhenqifuzheng and Baofukang, which is safe, effective, non-invasive, reusable advantages. However, the long-term efficacy and side effects need to be further studied.

Clinical applicability of immunotherapy of cervical intraepithelial neoplasia

Immunotherapy for cervical intraepithelial neoplasia （CIN） has not yet reached clinical applicability, but seems sensible and shows promising preliminary results. One of the most promising forms of immunotherapy for CIN may currently be imiquimod, because of its established role in other human papillomavirus （HPV）-induced genital conditions, its promising treatment effcacy in high-grade CIN, and its off-label availability. Although imiquimod cannot yet replace the current gold standard treatment for CIN [ i.e. , large loop excision of the transformation zone （LLETZ）] in all patients, it may be considered in subgroups of patients; for example, young women who may wish to become pregnant in the future, or patients with recurrent CIN lesions in whom a second LLETZ is to be avoided. Immunotherapy of CIN could be extended to post-treatment vaccination, in order to prevent new HPV infections and disease recurrence.

Photodynamic Therapy for Low-grade Cervical Intraepithelial Neoplasia(CIN1):A Case Report

As a drug-mechanical combination technology,photodynamic(PDT)can achieve accurate and taurgeted therapy for maligmant tumors and benign diseases through the production of reactive oxygen species,oxygen free radicals or singlet oxygen by photosensitizers at specific wavelengths.Compared with traditional surgery,it has the advantages of selective killing.repeatable teatment,preserving target organ fiunction and so on.The purpose of this study was to explore the clinical value of photodynamic therapy in cervical precancerous lesions by taking the patients with low-grade cervical intaepithelial neoplasia(CIN1)with high-risk human papillomavinus(HR HPV)persistent infection diagnosed by"three-step diagnosis and teatment procedure"as an example.Using HiPorfn as a photosensitizer,photodynamic therapy was performed 48 hours after intavenous drip.Set laser wavelength 630nm,light dose density 137.58J/cm^2,ansmission efficiency 1.42,output power 2w.3cm columnar optical fber was placed around the 2cm in the cervical canal to cover all the lesions,and the inadiation time was 900s(600s in the cervical canal and 300s outside the cervical canal).The patients were given oxygen inhalation for 6 hours after operation,and the patients were observed for itching and other discomfort,and paid attention to avoid light.Photodynamic therapy was performed again in the same way on the second day.After two months of treatment,pathological biopsy showed chronic cervicitis,indicating that the disease had been effectively controlled.Theoretically,although the patient is not the absolhute indication of photodynamic therapy(hat is,meeting CIN Ⅱ or CIN Ⅲ,having fertility requirements and not undergoing surgery),this therapy can remove not only the superficial lesions inside and outside the cervix,but also the potential lesions not found under colposcopy.It can also block the persistent infection of HPV by.inhbting the expression of HPV18,E6 and E7mRNA in Hela cells.In combination with Baofukang suppository,it can block HPV infection.Increase the negative conversion rate of cervical HPV and reduce the probablity of recurence after CIN1 cure.For youmng female patients with persistent HR-HPV infection and fertility requirements,photodynamic therapy is an effective choice for clinical treatment of CIN1.

Nomograms based on HPV load for predicting survival in cervical squamous cell carcinoma: An observational study with a longterm follow-up

Objective: To investigate the prognostic value of pretreatment human papillomavirus(HPV) viral load for cervical cancer, and to develop nomograms based on HPV load and other clinicopathological factors for long-term survival.Methods: We conducted a prospective study on cervical squamous cell carcinoma(SCC) patients diagnosed between January 2003 and December 2008. Cervical samples were tested for HPV viral load by the Hybrid Capture II(HCII) assay before treatment and 6 months after treatment. Clinical characteristics and follow-up information were also collected. A multivariable Cox proportional hazards model was used to adjust covariates in both the radical hysterectomy(RH) treatment group and concurrent chemoradiotherapy(CCRT) treatment group to identify relevant covariates, and then nomograms were constructed and used for internal validation.Results: A total of 520 SCC patients enrolled in this study with a median follow-up of 127 months, 360 patients received RH, whereas 160 patients received CCRT. The median HPV viral load in RH and CCRT groups was356.10 and 294.29, respectively. Tumor size was positively correlated with high pretreatment HPV load in both groups. In CCRT group, the advanced International Federation of Gynecology and Obstetrics(FIGO) stage and enlarged retroperitoneal lymph node status determined by computed tomography(LNSCT) were correlated with low HPV load group. Initial HPV viral load, FIGO stage and lymph node metastasis were prognostic factors for RH group, whereas HPV viral load, squamous cell carcinoma antigen(SCC-Ag) level and LNSCT were identified as prognostic factors for CCRT group. Nomograms incorporating these predictors for 10-year progression-free survival(PFS) were constructed [concordance index(C-index): 0.756, 0.749].Conclusions: A low pretreatment HPV viral load is an independent prognostic factor for poor prognosis of cervical SCC and is related to other clinicopathological factors. The survival nomogram based on HPV viral load could predict the long-term prognosis.

Relationship between Microsatellite Alterations of RASSF1A Gene and Development of Cervical Carcinoma

Objective： To explore the relationship between microsatellite alterations of RASSFIA gene and the development of cervical carcinoma, and its relationship with HPV16 infection. Methods： Two sites of microsatellite polymorphism of RASSFIA gene were selected. Polymerase chain reaction （PCR） technique was used to detect LOH and MSI in 50 cases of cervical carcinoma and 40 cases of cervical intraepithelial neoplasia （CIN）, and to detect the infection state of HPV16. Results： At D3S1478 and D3S4604, the LOH rates of cervical carcinomas were 32.6% （14/43） and 48.9% （23/47）, the MSI rates were 14% （6/43） and 19.1% （9/47）, respectively. The LOH rates of CINs were 31.4% （11/35） and 39.5% （15/38）, the MSI rates were 11.4% （4/35） and 15.8% （6/38）, respectively. There were no significant differences between cervical carcinomas and CINs in respect to their positive rates of LOH and MSI at D3S1478 and D3S4604 （P〉0.05）. There were significant differences in LOH rates at D3S1478 and D3S4604 between the stage Ⅰ-Ⅱ and Ⅲ-Ⅳ cervical carcinomas and between the well/moderately differentiated cervical carcinomas and the poorly differentiated cervical carcinomas （P〈0.05）. The positive rates of LOH and MSI for CIN Ⅲ and noninvasive cervical carcinomas were higher than those in CIN Ⅰ-Ⅱ. The rates of infection of HPV16 in cervical cancer was obviously higher than that in CIN and in normal cervical tissues （P〈0.05）, and the incidence of LOH of RASSFIA gene was higher in HPV16（＋） than that in HPV16（-） （P〈0.05）. Conclusion： The RASSFIA gene change is a relatively late event in cervical carcinomas. The detection of LOH and MSI of RASSFIA gene might be helpful to the early diagnosis and the screening of cervical carcinoma. It might also be useful for predicting the prognosis of cervical carcinoma.

Risk Factors of Cervical Carcinoma and Countermeasures against Them in Mountainous Area of Wufeng County, China

Cases (n=44) with squamous cell cervical cancer (SCCA) and age-matched healthy controls (n=176) were analyzed. Significant difference due to human papillomavirus (HPV) infection, ages at the first marriage, ages at the first sexual intercourse, ages at the first birth given to baby, number of gravidities, number of deliveries, Body Mass Index (BMI), education level of women and their husbands (p<0.05) was observed. According to multivariate logistic regression analysis, four factors have entered the model (p<0.05), including HPV infection [OR (odds ratio)=26.13, 95%CI (confidence interval)=9.40?72.60], education level of women (OR=0.41, 95%CI=0.21?0.79), education level of spouses (OR=0.45, 95%CI=0.22?0.94), BMI (OR=0.73, 95%CI=0.57?0.93). Moreover, HPV infection is relative to education level of women (r=?0.14), and their spouses (r=?0.21), age at the first marriage (r=?0.20), age at the first birth given to baby (r=?0.20) and BMI (r=?0.15).

Risk assessment and triage strategy of cervical cancer primary screening on HPV integration status:5-year follow-up of a prospective cohort study

Objective:We investigated the relation between man papillomavirus(HPV)integration status and the immediate risk of cervical intraepithelial neoplasia(CIN),as well as the triage strategy based on HPV integration test.Methods:4086 women aged 20 to 65 years in China were enrolled in 2015 for a prospective,population-based,clinical observational study to evaluate the triage performance of HPV integration.Cervical exfoliated cells were collected for HPV testing and cytologic test.If high-risk HPV was positive,HPV integration test was performed at baseline,2-year and 5-year follow-up.Results:At baseline,HPV integration was positively correlated with the severity of cervical pathology,ranging from 5.0%(15/301)in normal diagnosis,6.9%(4/58)in CIN1,31.0%(9/29)in CIN2,70%(14/20)in CIN3,and 100%(2/2)in cervical cancer(P<0.001).Compared with cytology,HPV integration exhibits comparable sensitivity and negative predictive value for the diagnosis of CIN3+,higher specificity(92.8%[90.2%-95.4%]vs.75.5%[71.2%-79.8%],P<0.001)and higher positive predictive value(36.4%[22.1%-50.6%]vs.15.2%[8.5%-21.8%],P<0.001).HPV integration testing strategy yielded a significantly lower colposcopy referral rate than cytology strategy(10.7%[44/410]vs.27.3%[112/410],P<0.001).The HPV integration-negative group exhibited the lowest immediate risk for CIN3+(1.6%)and accounted for the largest proportion of the total population(89.3%),when compared with the normal cytology group(risk,1.7%;proportion,72.7%).Conclusion:As a key molecular basis for the development of cervical cancer,HPV integration might be a promising triage strategy for HPV-positive patients.

GENETIC INSTABILITY IN CERVICAL CARCINOMA

Objective: The role of human papillomavirus (HPV) in the development of cervical carcinoma has been clearly established but other factors could be involved in cervical tumorigenesis such as loss of heterozygosity (LOH) and microsatellite instability (MI). The aim of the present study was to investigate the genetic instability in cervical carcinoma tissues and provide evidence for discovering new tumor suppressor genes and screening diagnostic molecular marker of cervical carcinoma. Methods: Fifty primary cervical carcinoma samples from high-incidence area were analyzed by PCR for HPV16 infection, LOH and microsatellite instability. Results: HPV16 was detected in 88% of the cases. Sixty-six percent of total cases showed LOH with no more than 3 different loci per case. The highest frequency of the allelic loss was found in D18S474 (18q21, 40.5%). MI was detected in 4 cases (8%) only. Conclusion: Different percentages of LOH on specific chromosomal regions were found and MI was very infrequent in cervical carcinoma. The putative suppressor gene(s) could be located on specific chromosome regions such as 18q, and genetic instability could be involved in cervical tumorigenesis.

Polymorphism in the upstream regulatory region of human papilloma virus type 16 from the cervical cancer biopsies in Xinjiang Uygur women

To investigate the mutations in the upstream regulatory region (URR) of human papillomavirus type 16 (HPV-16) from the cervical cancer biopsies in Xinjiang Uygur women and its relationship to the high incidence of cervical cancer in the southern Xinjiang, the tissue DNA was extracted from the cervical cancer biopsies, and the URR segment of HPV-16 DNA was amplified, sequenced and analyzed. Thereafter, the polymorphism of URR in HPV-16 was then analyzed. It was demonstrated that the positive rate detected for the presence of URR in HPV-16 was 89.47% (17/19). Compared with the previously published sequence in URR of prototype HPV-16, some mutations were detected in the sequence of URR. The mutations in 17 URR fragments of HPV-16 could be divided into 11 patterns (XJU-1 to XJU-11) at nucleic acid level, in which each of XJU-1 and XJU-4 accounted for 23.53% (4/17), and other patterns of mutation accounted for 5.88% (1/17) . In comparison with the URR of prototype HPV-16, the DNA identity of these patterns was 98.50%-99.68% . In these 17 URR fragments, two point mutations occurred at position 7192 (G to T) and position 7520 (G to A) and they appeared to be constant in Xinjiang area. These two mutations were ubiquitous in the Asia-American type and conferred strong infection activity and carcinogenicity of this virus. In addition, the mutations at position 7729 (A to C), position 7843 (A to G) and position 7792 (C to T) could enhance its transcription activity considerably. It is concluded that some mutations occur in URR gene of HPV-16 in the cervical cancer biopsies taken from Uygur women in Xinjiang area, suggesting that certain relationship exists among the mutations in URR of HPV-16, the phylogeny of HPV-16 and the high incidence of cervical cancer in southern part of Xinjiang area.

Thedual pathogenesisofpenileneoplasia: The heterogeneous morphology of human papillomavirus-relatedtumors

Objective:Penile neoplasia,usually of squamous histogenesis,is currently classfied into human papillomavirus(HPV)-related or-dependent and non-HPV-related or-indepen dent.There are distinct morphological differences among the two groups.New research studies on penile cancer from Northern countries showed that the presence of HPV is corre lated with a better prognosis than virus negative people,while studies in Southern countries had not confirmed,perhaps due to differences in staging or treatment.Methods:We focused on the description of the HPV.related carcinomas of the penis.The approach was to describe common clinical features followed by the pathological features of each entity or subtype stressing the characteristics for differential diagnosis,HPV genotypes,and prognostic features of the invasive carcinomas.Similar structure was followed for penile intraepithelial neoplasia,except for prognosis because of the scant evidence available.Results:Most of HPV-related lesions can be straightforwardly recognized by routine hematoxylin and eosin stains,but in some cases surrogate p16 immunohistochemical staining or molecular methods such as in situ hybridization or polymerase chain reaction can be utilized.Currently,there are eight tumor invasive variants associated with HPV,as follows:basaloid,warty,warty-basaloid,papillary basaloid,clear cell,medullary,lymphoepithelioma-like,and giant condylomas with malignant transformation.Conclusion:This review presents and describes the heterogeneous clinical,morphological,and genatypic features of the HPV-related subtypes of invasive and non-invasive penile neoplasia.

Aberrant DNA methylation in cervical carcinogenesis

Persistent infection wit h high-risk types of human papillomavirus(HPV) is known to cause cervical cancer;however,additional genetic and epigenetic alterations are required for progression from precancerous disease to invasive cancer.DNA methylation is an early and frequent molecular alteration in cervical carcinogenesis.In this review,we summarize DNA methylation within the HPV genome and human genome and identify its clinical implications.Methylation of the HPV long control region(LCR) and L1 gene is common during cervical carcinogenesis and increases with the severity of the cervical neoplasm.The L1 gene of HPV16 and HPV18 is consistently hypermethylated in invasive cervical cancers and can potentially be used as a clinical marker of cancer progression.Moreover,promoters of tumor suppressor genes(TSGs) involved in many cellular pathways are methylated in cervical precursors and invasive cancers.Some are associated with squamous cell carcinomas,and others are associated with adenocarcinomas.Identification of methylated TSGs in Pap smear could be an adjuvant test in cervical cancer screening for triage of women with high-risk HPV,atypical squamous cells of undetermined significance,or low grade squamous intraepithelial lesion(LSIL).However,consistent panels must be validated for this approach to be translated to the clinic.Furthermore,reversion of methylated TSGs using demethylating drugs may be an alternative anticancer treatment,but demethylating drugs without toxic carcinogenic and mutagenic properties must be identified and validated.

Co-infection of Epstein-Barr virus and human papillomavirus in human tumorigenesis

Viral infections contribute to approximately 12%of cancers worldwide,with the vast majority occurring in developing countries and areas.Two DNA viruses,Epstein-Barr virus(EBV) and human papillomavirus(HPV),are associated with38%of all virus-associated cancers.The probability of one patient infected with these two distinct types of viruses is increasing.Here,we summarize the co-infection of EBV and HPV in human malignancies and address the possible mechanisms for the co-infection of EBV and HPV during tumorigenesis.