Untold story of human cervical cancers: HPV-negative cervical cancer

Jae-Eun Lee,Yein Chung,Siyeon Rhee,Tae-Hyung Kim 생화학분자생물학회 2022 BMB Reports Vol.55 No.9

Cervical cancer is the fourth most common malignancy in womenworldwide. Although infection from human papillomavirus (HPV)has been the leading cause of cervical cancer, HPV-negativecervical cancer accounts for approximately 3-8% of all cases. Previous research studies on cervical cancer have focused onHPV-positive cervical cancer due to its prevalence, resulting inHPV-negative cervical cancer receiving considerably less attention. As a result, HPV-negative cervical cancer is poorly understood. Its etiology remains elusive mainly due to limitations inresearch methodology such as lack of defined markers and modelsystems. Moreover, false HPV negativity can arise from inaccuratediagnostic methods, which also hinders the progress of researchon HPV-negative cervical cancer. Since HPV-negativecervical cancer is associated with worse clinical features, greaterattention is required to understand HPV-negative carcinoma. Inthis review, we provide a summary of knowledge gaps andcurrent limitations of HPV-negative cervical cancer research basedon current clinical statistics. We also discuss future directionsfor understanding the pathogenesis of HPV-independent cervicalcancer. [

ANXA3, associated with YAP1 regulation, participates in the proliferation and chemoresistance of cervical cancer cells

Huang Jiazhen,Wei Wei,Kang Fuli,Tan Shuang,Li Yibing,Lu Xiaohang,Wang Ning 한국유전학회 2023 Genes & Genomics Vol.45 No.12

Background Cervical cancer, as one of the most common cancers in women, remains a major health threat worldwide. Annexin A3 (ANXA3), a component of the annexin family, is upregulated in numerous cancers, with no explicit role in cervical cancer. Objective This study aims to investigate the function of ANXA3 in cervical cancer. Methods Differential expression genes between the cervical cancer tissues of patients and the controls were analyzed in The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA) database. Using transfection approaches to either upregulate or downregulate ANXA3, its role in cell proliferation and chemosensitivity of human cervical cancer cell lines (HeLa and C33A) was evaluated. Furthermore, the binding activity between YAP1 and ANXA3 was also explored. Results Genomics analysis indicated that differential genes were mostly associated with cell cycle progression and DNA replication. ANXA3 was highly expressed in the cervical cancer tissues and closely linked to malignancy degree. Knockdown of ANXA3 in cervical cancer cells inhibited cell cycle progression. A similar result was observed in the reduction of cyclin D, CDK4, cyclin E, and CDK2 in cervical cancer cells with ANXA3 silencing. Cervical cancer cells obtained high sensitivity to cisplatin (DDP) when ANXA3 was downregulated. Conversely, these capabilities were the opposite in cervical cancer cells overexpressing ANXA3. Furthermore, the expression levels of ANXA3 and YAP1 were positively correlated. YAP1 upregulation was positively connected with malignant behaviors, which were reversed by ANXA3 downregulation. Conclusion In light of our findings, targeting ANXA3 expressed in cervical cancer might contribute to more potential therapeutic strategies.

자궁경부 상피내종양 및 자궁경부암 조직에서 bcl-2 및 c-myc 암유전자 발현과 세포증식 및 apoptosis와의 상관관계에 관한 연구

김병기(Byoung Gie Kim),이효표(Hyo Pyo Lee) 대한산부인과학회 1999 Obstetrics & Gynecology Science Vol.42 No.8

bcl-2 암유전자는 여러 가지 자극에 의한 apoptosis를 차단함으로써 유전자 이상을 가진 세포가 계속 생존하면서 유전자 변이가 누적되는 결과를 초래한다고 알려져 있다. 한편 c-myc 암유전자는 세포증식과 apoptosis를 유도하는 이중적 기능을 가지고 있으며 생존 신호가 결여될 경우에는 오히려 세포의 apoptosis를 유발한다고 알려져 있다. 그러나 c-myc과 bcl-2가 동시에 발현되면 bcl-2는 c-myc의 세포증식 작용은 영향을 주지 않고 apoptosis만을 선택적으로 차단함으로써 유전자 변이 세포의 생존 뿐만 아니라 증식을 촉진하는 것으로 관찰되었다. 자궁경부암에서 c-myc과 bcl-2 발현에 관한 개별적 보고는 있었으나 이들 두 유전자의 동시발현 및 이들 유전자들이 실제 암조직상에서 세포증식 및 apoptosis에 어떠한 영향을 미치는가에 관한 연구는 보고된 것이 없다. 따라서 본 연구에서는 자궁경부암 발생 과정중에서 bcl-2 및 c-myc 발현과 세포증식, apoptosis와의 상관관계를 알아보고자 하였다. 본 연구에서는 10개의 정상 자궁경부조직, 30개의 자궁경부 상피내종양 조직, 20개의 자궁경부암조직에서 bcl-2와 c-myc에 대한 면역조직화학 검사를 시행하였으며 세포증식과 apoptosis는 각각 Ki-67 면역조직화학적 방법과 TUNEL 방법으로 확인하였다. 또한 환자의 임상병리학적 인자들과의 상관관계도 알아보았다. 정상 자궁경부, 자궁경부 상피내종양, 자궁경부암조직 중 자궁경부암조직에서만 bcl-2와 c-myc 단백이 각각 35%와 50%에서 관찰되었으며, 또한 bcl-2와 c-myc의 동시발현이 25%에서 관찰되었다. 세포증식 지수(상피세포 100개중 Ki-67양성 세포수)는 정상 자궁경부, 상피내종양, 자궁경부암으로 진행되면서 10.2, 24.1, 59.7, 71.2로 유의하게 증가하는 양상을 보였으며(p<0.01), apoptosis 지수(상피세포 100개중 apoptosis 세포수)도 0, 0.33, 1.85, 3.89로 점차 증가하는 양상을 보였다(p<0.01). 또한 세포증식 지수와 apoptosis 지수와는 높은 상관관계(r=0.7451, p=0.0002)를 나타내었다. 그러나 자궁경부암 조직중 bcl-2 발현군과 비발현군간에 apoptosis지수에는 차이가 없었으며(p=0.4765), c-myc 발현군과 비발현군간에도 세포증식 지수에는 차이가 없었다(p=0.6891). 또한 bcl-2와 c-myc의 동시 발현군과 나머지 군간에도 증식지수와 apoptosis 지수에 차이가 없었다(각각 p=0.6311 및 p=0.7600). 한편 bcl-2와 c-myc의 동시 발현과 잘 알려져 있는 자궁경부암의 임상병리학적 예후인자들(종양 크기, FIGO 임상병기, 림프절 전이등)과는 유의한 상관관계가 없었다. 이상과 같은 결과에서 자궁경부암발생 과정에서 세포증식과 apoptosis는 병변의 등급과 비례하여 증가하고 apoptosis는 세포증식과 관련된 변화로 사료되었다. 한편 bcl-2와 c-myc과 발현은 자궁경부암에서만 관찰되는 유전자 변이로서 자궁경부 상피내종양의 발생과 진행과정에는 영향을 미치지 않으며, 또한 자궁경부암 조직에서도 암조직 전체의 세포증식 및 apoptosis와는 관련이 없을 것으로 사료되었다. bcl-2 prevents cell death from a wide variety of stimuli and provides survival of cells with accumulated genetic alterations and c-myc can promote both cell proliferation and cell death through the transcriptional regulation of target genes. Although several studies have been reported on the expression of bcl-2 or c-myc separately, little has been known about the role of coexpression of bcl-2 and c-myc to cell proliferation and apoptosis, as well as the frequency of these coexpression in cervical cancer specimens. In this study, we have examined the expression of bcl-2 and c-myc in cervical cancer specimens and cervical intraepithelial neoplasia(CIN) to determine the role of coexpression of bcl-2 and c-myc during progression into cervical cancer. Proteins and transcripts of bcl-2 and c-myc were evaluated by immunohistochemistry in 60 clinical specimens(20 cervical cancer, 30 CIN, and 10 normal cervix). In addtion, we evaluated kinetic indices of cell proliferation and apoptosis simultaneously. The cell proliferation index was determined by detection of the Ki- 67 in immunohistochemistry. Apoptotic index was determined by the detection of apoptotic cells with TUNEL staining. Medical records including pathologic reports were reviewed. Overexpression of bcl-2 and c-myc was identified in 7(35%) and 10(50%) of 20 cervical cancer specimens respectively, but none in normal cervix and CIN samples. In addition, coexpression of bcl-2 and c-myc was found in 5(25%) of 20 cervical cancer specimens. The cell proliferation index increased with progression from normal to CIN and invasive cancer(normal cervix, 10.2; CIN 1, 24.1; CIN 2/3 59.7; cervical cancer, 71.2; p <0.01). The apoptotic index also increased with grade of lesions(normal cervix, 0; CIN 1, 0.33; CIN 2/3, 1.85; cervical cancer, 3.89; p <0.01) and showed a significant correlation with proliferation index(r=0.7451, p=0.0002). However, there was no significant difference in apoptotic index between bcl-2 positive and bcl-2 negative group in cervical cancer(p=0.4765). In addition, there was also no significant difference in cell proliferation between c-myc positive and c-myc negative group(p=0.6891). Furthermore, there was no significant difference in cell proliferation and apoptosis between bcl-2 and c-myc positive group and others in cervical cancer(p=0.6311 and p=0.7600 respectively). The well-known clinicopathologic parameters, including tumor diameter, FIGO clinical stage, lymph node metastasis, did not correlate with simultanuos positive immunoreactivity for bcl-2 and c-myc proteins in cervical cancer. In conclusion, the cell proliferation and apoptosis increase with increasing lesion grade of cervical neoplasia and apoptosis correlates with cell proliferation. In addition, overexpression of bcl-2 and/or c-myc may be genetic alteration found only in cervical cancer and may not play a role in the development and progression of CIN. However, neither bcl-2 nor c-myc immunoreactivity correlated with the proliferation index or apoptotic index. These results suggest that other factors may also play a role in controlling the cell proliferation and apoptosis of cervical cancer.

Current status of cervical cancer and HPV infection in Korea

김영탁 대한부인종양학회 2009 Journal of Gynecologic Oncology Vol.20 No.1

Cervical cancer is an important cause of cancer-related deaths in women in developing countries. In Korea, cervical cancer is the third leading cancer among females and is fifth highest in mortality. The persistent oncogenic human papillomavirus (HPV) infections are the greatest risk of developing cervical intraepithelial neoplasia and invasive cancer. The overall prevalence of HPV was 10.4% in Korea and strong risk factors for HPV infection included a young age at sexual debut. The National Cancer Screening Program, which includes cervical cancer screening, has the following principles: the main screening tool is the Papanicolaou test conducted by gynecologists, which targets all women age 30 and over, and which is done every 2 years. HPV DNA tests have not yet been permitted as a screening test for cervical cancer in Korea; however, these are conducted along with a Pap test for screening cervical cancer in the clinic. The use of prophylactic HPV vaccine has been accepted in Korea; The Korean Society of Gynecologic Oncology and Colposcopy’s recommendation for routine vaccination is for females aged 15-17 years with a catch-up vaccination recommended for females aged 18-26 years who have not been previously vaccinated. However, many people in Korea are not familiar with the HPV vaccine. Therefore, it is necessary to improve awareness for the disease and HPV vaccination and to establish the effective strategies to obtain funding for HPV vaccination. In the future, cervical cancer is expected to disappear throughout the world, including the Asia Pacific region, through a combination of vaccination and qualified screening programs for cervical cancer. Cervical cancer is an important cause of cancer-related deaths in women in developing countries. In Korea, cervical cancer is the third leading cancer among females and is fifth highest in mortality. The persistent oncogenic human papillomavirus (HPV) infections are the greatest risk of developing cervical intraepithelial neoplasia and invasive cancer. The overall prevalence of HPV was 10.4% in Korea and strong risk factors for HPV infection included a young age at sexual debut. The National Cancer Screening Program, which includes cervical cancer screening, has the following principles: the main screening tool is the Papanicolaou test conducted by gynecologists, which targets all women age 30 and over, and which is done every 2 years. HPV DNA tests have not yet been permitted as a screening test for cervical cancer in Korea; however, these are conducted along with a Pap test for screening cervical cancer in the clinic. The use of prophylactic HPV vaccine has been accepted in Korea; The Korean Society of Gynecologic Oncology and Colposcopy’s recommendation for routine vaccination is for females aged 15-17 years with a catch-up vaccination recommended for females aged 18-26 years who have not been previously vaccinated. However, many people in Korea are not familiar with the HPV vaccine. Therefore, it is necessary to improve awareness for the disease and HPV vaccination and to establish the effective strategies to obtain funding for HPV vaccination. In the future, cervical cancer is expected to disappear throughout the world, including the Asia Pacific region, through a combination of vaccination and qualified screening programs for cervical cancer.

Cervical Cancer Screening in Korean American Women: Findings from Focus Group Interviews

Kim, Hoo-Ja,Lee, Kyung-Ja,Lee, Sun-Ock,Kim, Sung-Jae Korean Society of Nursing Science 2004 Journal of Korean Academy of Nursing Vol.34 No.4

Purpose. Korean American women have twice the rate of cervical cancer than white women and demonstrate low rates in participation in cervical cancer screening. This study was to describe the perceptions about cervical cancer and factors related to cervical cancer screening among Korean American women. Method. Focus group methods. Results. Five themes emerged. First, knowledge about cervical cancer; misconceptions about cervical cancer, its causes, reproductive anatomy and the treatment Second, perceived meanings of having cervical cancer; most of the women felt that cervical cancer represented a loss of femininity and existential value of woman-hood. Third, knowledge about cervical cancer screening; regular medical check-ups were necessary for early detection and prevention of cervical cancer. Forth, experiences and perceived meanings of cervical cancer screening; the participants expressed their feelings; embarrassment, fear, shame and shyness. Fifth, practices of cervical cancer screening; various intervals in participating in cervical cancer screening. But they mentioned several deterrents, language, insurance, time constraint, embarrassment, fear of the screening results, misbelief about susceptibility, lack of health prevention behavior, and lack of information written in Korean. Conclusion: Results emphasize the critical need for culturally appropriate health education to encourage participation of Korean American women in cervical cancer screening.

기혼여성의 자궁경부암 조기 검진행위와 관련요인

오은주,이영은,이선옥 한국모자보건학회 2010 한국모자보건학회지 Vol.14 No.1

Objectives: The purpose of this study was done to identify cervical cancer screening behavior and related factors among married women. Methods: This study's subjects were 225 married women who visited two laying-in women's hospitals located in P city in Korea. Data were collected from April 1, 2006 to April 20, 2006 by using a self-reported questionnaires and analyzed descriptive statistics, x2-test and logistic regression analysis using SPSS/WIN 12.0 program. Results: 1) Respondents attitude and the level of knowledge toward the cervical cancer (55.92±6.49, 10.98±4.47 respectively). 2) The screening behavior for the cervical cancer was 86.7% in a group who regularly checked for examination of cervical cancer and 13.3% in a group who occasionally checked for examination of cervical cancer. 3) The knowledge degree about the cervical cancer was significantly related to the screening behavior toward the cervical cancer (p=.000). 4) The attitude toward the cervical cancer was significantly related to the screening behavior toward the cervical cancer (p=.006). 5) The screening behavior for the cervical cancer was significantly related to the age (p=.003), the age at marriage (p=.025), average monthly income (p=.020), socioeconomic status (p=.045), acquisition of information about the cervical cancer (p=.000), experience of other cancer examination or medical checkup (p=.005). Conclution: Married women were found to have a higher level of knowledge about the cervical cancer, and their attitude is positive toward the cervical cancer, but they were found to have a lower level of cervical cancer screening behavior.

Epidemiology, prevention and treatment of cervical cancer in the Philippines

Efren J. Domingo,Ana Victoria V. Dy Echo 대한부인종양학회 2009 Journal of Gynecologic Oncology Vol.20 No.1

Cervical cancer remains to be one of the leading malignancies among Filipino women. High-risk human papillomavirus (HPV) types, such as 16 and 18, are consistently identified in Filipino women with cervical cancer. Factors identified to increase the likelihood of HPV infection and subsequent development of cervical cancer include young age at first intercourse, low socioeconomic status, high parity, smoking, use of oral contraception and risky sexual behaviors. Cancer screening programs presently available in the Philippines include Pap smears, single visit approach utilizing visual inspection with acetic acid followed by cryotherapy, as well as colposcopy. However, the uptake of screening remains low and is further compounded by the lack of basic knowledge women have regarding screening as an opportunity for prevention of cervical cancer. Prophylactic HPV vaccination of both quadrivalent and bivalent vaccines has already been approved in the Philippines and is gaining popularity among the Filipinos. However, there has been no national or government vaccination policy implemented as of yet. The standard of treatment of cervical cancer is radiotherapy concurrent with chemotherapy. Current researches are directed towards improving availability of both preventive and curative measures of cervical cancer management. Cervical cancer remains to be one of the leading malignancies among Filipino women. High-risk human papillomavirus (HPV) types, such as 16 and 18, are consistently identified in Filipino women with cervical cancer. Factors identified to increase the likelihood of HPV infection and subsequent development of cervical cancer include young age at first intercourse, low socioeconomic status, high parity, smoking, use of oral contraception and risky sexual behaviors. Cancer screening programs presently available in the Philippines include Pap smears, single visit approach utilizing visual inspection with acetic acid followed by cryotherapy, as well as colposcopy. However, the uptake of screening remains low and is further compounded by the lack of basic knowledge women have regarding screening as an opportunity for prevention of cervical cancer. Prophylactic HPV vaccination of both quadrivalent and bivalent vaccines has already been approved in the Philippines and is gaining popularity among the Filipinos. However, there has been no national or government vaccination policy implemented as of yet. The standard of treatment of cervical cancer is radiotherapy concurrent with chemotherapy. Current researches are directed towards improving availability of both preventive and curative measures of cervical cancer management.

Hong Kong Chinese Women's Lay Beliefs about Cervical Cancer Causation and Prevention

Wang, Linda Dong-Ling,Lam, Wendy Wing Tak,Wu, Joseph,Fielding, Richard Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.18

Background: This study aimed to seek insights into Chinese women's lay beliefs about cervical cancer causal attributions and prevention. Materials and Methods: Twenty-three new immigrant adult women from Mainland China and thirty-five Hong Kong adult women underwent semi-structured in-depth interviews. Interviews were audio taped, transcribed and analyzed using a Grounded Theory approach. Results: This study generated three foci: causal beliefs about cervical cancer, perceived risk of cervical cancer, and beliefs about cervical cancer prevention. Personal risky practices, contaminated food and environment pollution were perceived as the primary causes of cervical cancer. New immigrant women more likely attributed cervical cancer to external factors. Most participants perceived cervical cancer as an important common fatal female cancer with increased risk/prevalence. Many participants, particularly new immigrant women participants, expressed helplessness about cervical cancer prevention due to lack of knowledge of prevention, it being perceived as beyond individual control. Many new immigrant participants had never undergone regular cervical screening while almost all Hong Kong participants had done so. Conclusions: Some Chinese women hold pessimistic beliefs about cervical cancer prevention with inadequate knowledge about risk factors. Future cervical cancer prevention programs should provide more information and include capacity building to increase Chinese women's knowledge and self-efficacy towards cervical cancer prevention.

The associations of tobacco use, sexually transmitted infections, HPV vaccination, and screening with the global incidence of cervical cancer: an ecological time series modeling study

Luyan Zheng,Yushi Lin,Jie Wu,Min Zheng 한국역학회 2022 Epidemiology and Health Vol.45 No.-

OBJECTIVES: We aimed to quantify the temporal associations between cervical cancer incidence and cervical cancer-related factors and to predict the number of new cervical cancer cases averted under counterfactual scenarios compared to the status quo scenario. METHODS: We described temporal trends in cervical cancer and associated factors globally from 1990 to 2019. We then used generalized linear mixed models to explore the impact of tobacco use, sexually transmitted infections (STIs), human papillomavirus (HPV) vaccination, and cervical screening on cervical cancer incidence. A counterfactual analysis was performed to simulate the most effective scenario for reducing cervical cancer incidence. RESULTS: The worldwide incidence of cervical cancer showed a downward trend over the past 3 decades (estimated annual percentage change, -0.72%), although the incidence remained high (>30 cases per 100,000 persons) in sub-Saharan Africa, Latin America, and the Caribbean. Higher smoking and STI prevalence showed significant direct associations with the incidence of cervical cancer, whereas HPV vaccination and screening coverage showed significant inverse associations. If the strategic goals for accelerating the elimination of cervical cancer and tobacco control programs had been achieved in 2019, the largest decrease in the number of new cervical cancer cases would have been observed, with 54,169 fewer new cases of cervical cancer in 2019. CONCLUSIONS: Our counterfactual analysis found that a comprehensive intervention program emphasizing scaled-up cervical screening coverage (70%), HPV vaccination coverage (90%), and tobacco control (30% relative reduction) would be the most effective program for reducing cervical cancer incidence.

The genomic state of HPVS and the antobody responst to HPV Proteins in patients with cervical cancer

Kim,Chan Joo,Lee,Joon Mo,Um,Soo Jong,Kim,Seung Jo,Park,Jong Sup,Namkoong,Sung Eun 가톨릭중앙의료원 가톨릭암센터 1997 암심포지움 Vol.- No.2

In contrast to the episomal state of HPV DNAs in most of low-grade cervical intraepithelial neoplasias (CINs), HPV DNAs are often found to be integrated into the chromosome in high-grade CINs as well as invasive cervical cancers. These integration events, commonly distrupted at the site of E2 DNA, have been hypothesized to cause the increased expression of the E6 and E7 genes, which were known to play critical roles in immortalization and transformation by inactivating the tumor suppressor genes. An aspect of the biology of HPV, which is still poorly understood, is the immune response to the virus. Investigation of the relationship between the genomic states of specific HPV genes and their antibody responses against the virus-like particles (VLPs) of HPV-16 L1/L2 proteins and the in vitro translated HPV-16 E6 and E7 proteins may help to illustrate the mechanism of HPV-related cervical carcinogenesis and host immune response. Cervical cancer tissues obtained from 41 patients with cervical cancer were studied for evaluation of genomic states of HPV genes by Southern blot hybridization, DNA-PCR and RT-PCR. The antibody response against the HPV-16 L1/L2 VLPs of serum specimens from the patients were tested by ELISA and the antibody response against the in vitro translated HPV-16 E6 and E7 proteins were tested by radioimmunoprecipitation assay (RIPA), respectively. Integrated forms of HPV-16 DNA were found in 23 of the 38 patients (60.5%) Episomal HPV DNAs were found in 15 of the 38 patients (39.5%); there were 2 cases of pure episomal form and the remaining 13 cases were mixed forms with episome and integration. The HPV-16 positive cervical cancer patients showed a significantly higher prevalence rate (36.8%; 14/38) of antibodies to HPV-16 L1/L2 VLPs than that of the control group (8.7% 2/28)(p<0.05). Antibodies to HPV-16 L1/L2 VLPs were more detectable in cervical cancer patients having episomal form of HPV-16 DNA (pure episomal and mixed forms)(53.3% 8/15) than those who having only integrated forms of HPV-16 DNA (26.1%; 6/23), but the difference was not statistically significant. HPV-16 L1/L2 genes were not detectable by RT-PCR in the patients of cervical cancer without episomal form of HPV DNA. Antibodies to E6 and E7 proteins were positive in 36.8% (14/38) and 50% (19/38) of the patients with HPV-16 positive cervical cancer, respectively and those were significantly higher than the positivities for the control (8.3% and 2.8%) (p<0.005). The differences between sero-reactivities to E6 and E7 proteins in the patients with episomal forms of HPV-16 DNA and those with integrated forms of HPV-16 DNA were not statistically significant. HPV-16 E6 and E7 transcripts were uniformly expressed and there was no difference of the positivities to the antibodies against the E6 and E7 proteins in spite of the different physical states of HPV DNAs. The positive rates of antibodies to the L1/L2 VLPs E6 and E7 proteins of HPV-16 were not associated with the clinico-pathologic indices which included FIGO stage, tumor size, pathologic type and presence of pelvic lymph node metastasis of cervical cancer. Integrated forms of HPV-16 DNA were prevalent in most patients with cervical cancer. Antibodies to HPV-16 L1/L2 VLPs. in vitro translated HPV-16 E6 and E7 proteins appeared positively in a significant proportion of the HPV-associated cervical cancer patients. Antibody positivity to HPV-16 L1/L2 VLPs may represent the immune response to whole virion of HPV-16 at the time of early infection. Antibody responses to HPV-16 E6 and E7 proteins were not influenced by the different states of viral gene. More number of studies would be neccessary to determine the genomic states of HPV and the immune responses to their proteins by the such genomic and serologic paramertes for application in adiunctive diagnosis in the patients of cervical cancer.