한국 여성의 자궁경부암에서 분리된 인유두종 바이러스 16 형의 E7 유전자 다형성에 관한 연구

안치석(CS Ahn),이효표(HP Lee) 대한산부인과학회 1998 Obstetrics & Gynecology Science Vol.41 No.1

Human papillomavirus(HPV)infection are now generally accepted as the most important factor for development of uterine cervical cancer and its precursor lesions. With increasing evidences that the HPV E7 encodes for oncoproteins critical for viral replication, host cell immortalization and transformation. Based on the previous reports that the high risk HPV type 16 DNA is frequently detected in specimens from Korean women with cervical cancer and that there is the sequence variation and geographical dependence of HPV 16 E7 gene in preinvasive and invasive cervical lesions, it is crucial to determine the prevalence of HPV 16 variants in uterine cervical lesions of Korean women. This study was performed to identify sequence variations of HPV 16 E7 gene and an association between HPV 16 E7 variants and uterine cervical cancer. The author has determined nucleotide sequences of the E7 gene of HPV 16 isolated from uterine cervical tissues in Korean women. HPV 16 DNAs were detected by the nested PCR in 112(24.5%) of a total of 457 samples. By direct sequencing of PCR-HPV 16 E7 positive cases, 79 samples(70.5%) showed variant sequences, while the prototype sequence was found in only 33 samples(29.5%). Twenty-three cases(57.5%) of 40 normal cervical samples showed sequence variation. Forty-eight(77.4%) of 62 cervical cancer cases showed sequence diversity from prototype HPV 16 E7 gene. There were four types of sequence variations. A single nucleotide change at position 647(A→G) was found in 52 cases(65.8%) of 79 HPV 16 E7 variants. Predicted amino acid change(Asn →Ser) was found in the HPV 16 E7 oncoproteins at amino acid position at 29. And this KE7-1 variant was commonly detected in the uterine cervical cancer compared to the normal cervix. The second most common variant, detected in 16 cases(20.3%), had three silent mutations at nucleotide positions 732(T→C), 789(T→C) and 795(T→G). The third variant had a single nucleotide change at position 666(G→A), and the fourth had a change at position 796(T→C). Furthermore, PCR-SSCP clearly showed distinct bands compatible with HPV 16 E7 variants as with the direct-sequencing method. PCR-SSCP was also an effective and reliable tool in detecting HPV 16 E7 variants. This study showed that there were four variant types of HPV 16 E7 in uterine cervical tissues and KE7-1 with corresponding amino acid change was the most commonly detected type in E7 variants of HPV 16 isolated from uterine cervical cancer in Korean women.

한국 여성 자궁경부 조직에서 분리된 인유두종 바이러스 16형의 상류전사 조절 부위 유전자 서열 변이 분석

전혜원(HW Jeon),이효표(HP Lee) 대한산부인과학회 1998 Obstetrics & Gynecology Science Vol.41 No.4

It is widely accepted that human papillomaviruses (HPV), especially type 16 and type 18 are the primary causal agent for the development of invasive cervical cancer and its precursor lesions. Although the mechanisms by which HPV acts to transform cells are still not completely understood, complex interactions between virus and host cell seem to determine the biologic course of cervical cancer. In Korea, 50∼60% of the patients with cervical cancer have been associated with HPV 16. Recently phylogenetically distinct HPV 16 variants that differ from the prototype HPV 16 sequence have been identified and the significance of them in carcinogenesis is being studied. The upstream regulatory region (URR) does not encode for proteins, but it contains a complex array of overlapping binding sites for many different transcriptional factors and their genomic sequences usually diverge more than coding regions. We were analyzed to detect HPV 16 URR enhancer region variants in Korean women and to determine whether risk of cancerous lesion was associated with HPV 16 variants. Cervical tissues were taken from the women with cervical cancerous (N=125) and normal cervical biopsies (N=307). Of the HPV 16 infections detected in 70 cervical cancerous tissues and 43 normal cervical tissues, 56.0% and 14.0%. We amplified by nested-PCR and sequenced a 364-bp noncoding segment of the HPV 16 genome (nucleotide 7458∼7841). By direct sequencing of PCR product, a total of 11 point variations that differed from prototype HPV 16 sequence was detected in various combinations, giving rise to 8 distinct types of variants. Of the HPV 16 URR variants detected in 68 cervical cancerous tissues and 39 normal cervical tissues, 97.1% and 90.7%. In addition, four transcriptional factors binding sites (TEF-1, 2; YY1, 2) were found to be mutated; nucleotide 7797 variation was found in only cervical cancerous tissues. Variants of an YY1 binding site in cervical cancerous tissues were correlated to depth of invasion not to age, stage, tumor size, histologic type, and nodal metastasis. Variants of a TEF-1 binding site were not show any difference in the clinicopathologic factors. These results suggest that the URR variant is not a mutation that occurs during disease progression in susceptible individuals but is a distinct virus isolate of HPV type 16. The association with cervical cancer suggests that either the mutation may also influence the oncogenic properties of the HPV type 16 variant or that the base change is a marker of other mutations within the virus genome that may increase its oncogenicity. To trace the transmission route and natural history of HPV-associated disease, more than one gene segment` strategy using a highly variable one as a genetic marker will be necessary.

Human papilloma virus in oral cancer

Soung Min Kim 대한구강악안면외과학회 2016 대한구강악안면외과학회지 Vol.42 No.6

Cervical cancer is the second most prevalent cancer among women, and it arises from cells that originate in the cervix uteri. Among several causes of cervical malignancies, infection with some types of human papilloma virus (HPV) is well known to be the greatest cervical cancer risk factor. Over 150 subtypes of HPV have been identified; more than 40 types of HPVs are typically transmitted through sexual contact and infect the anogenital region and oral cavity. The recently introduced vaccine for HPV infection is effective against certain subtypes of HPV that are associated with cervical cancer, genital warts, and some less common cancers, including oropharyngeal cancer. Two HPV vaccines, quadrivalent and bivalent types that use virus-like particles (VLPs), are currently used in the medical commercial market. While the value of HPV vaccination for oral cancer prevention is still controversial, some evidence supports the possibility that HPV vaccination may be effective in reducing the incidence of oral cancer. This paper reviews HPV-related pathogenesis in cancer, covering HPV structure and classification, trends in worldwide applications of HPV vaccines, effectiveness and complications of HPV vaccination, and the relationship of HPV with oral cancer prevalence.

자궁경부암과 인유두종바이러스 백신

김선영,곽정임,송윤미 대한가정의학회 2008 Korean Journal of Family Medicine Vol.29 No.11

The necessary role of genital infection by specific types of human papillomavirus (HPV) in cervical cancer development provides an opportunity to reduce the risk of cervical cancer, a second leading cancer in women, through prophylactic vaccination. Two types of vaccines targeting HPV 16 and 18 which are responsible for about 70% of all cervical cancer worldwide have been developed: a quadrivalent vaccine (GardasilⓇ) and a bivalent vaccine (CervarixⓇ). Gardasil also targets HPV 6 and 11 causing 90% of genital wart. Both two vaccines contain virus-like particles composed of L1 protein of viral capsid and do not exert infectivity. HPV vaccines were highly effective in preventing persistent infection by vaccine specific type HPV in young women who have not been previously exposed to them. Randomized double- blind placebo-controlled clinical trials have provided evidence that HPV vaccines have high efficacy against cervical precancerous lesion in young women irrespective of baseline HPV infection status. However, HPV vaccines neither treat existing HPV infections nor provide protection against all types of HPV related with cervical cancer. Therefore, even vaccinated females should take cervical cancer screening as recommended. Gardasil has been tested mainly in 9∼26 years old females and Cervarix in 15∼25 years old. Current recommendation for vaccination age is 9∼26 years for Gardasil and 10∼25 years for Cervarix, considering sexual debut and previous clinical trials. There are plenty of remaining issues regarding HPV vaccination such as vaccine efficacy in older women and in males, cost-effectiveness, duration of protection, cross-protection, potential replacement infection, and vaccine compatibility. 자궁경부암은 자궁경부 세포진 검사가 도입된 이래 그 발생이 크게 줄어들었으나 아직도 전 세계적으로 여성 암 중 두 번째로 흔히 발생하는 암이다.1) 한국 중앙암등록자료에 의하면 자궁경부암은 1999~2002년 사이 한국 여성 암 발생의 9.5%를 차지하는 네 번째로 흔한 암이었다.2) 또한 발생률에 비한 사망률이 낮은 편이지만 최근인 2007년에도 한국 여성의 자궁경부암 사망률은 10만명 당 4.4명으로 여성 암 사망의 7위이었으며 총 1,005명의 여성이 자궁경부암으로 사망하였다.3) 자궁경부암 발생위험은 성 행태와의 연관성이 높아서 성관계를 시작한 나이가 어리거나 다수의 성상대자를 둔 경우 증가하며, 출산 횟수 증가, 면역저하, 흡연에 의해서도 위험이 증가한다고 알려져 왔다.4) 하지만 인유두종 바이러스(human papilloma virus, HPV) 감염에 대한 연구가 수행되면서 HPV 감염은 자궁경부암의 가장 중요한 위험요인이며 자궁경부암 발생의 필요조건으로 밝혀졌다.4) 생식기 HPV 감염은 대부분의 경우 증상이 없이 저절로 낫지만, 감염이 반복되거나 지속되면 여성과 남성 모두에게 항문생식기 암과 생식기 사마귀를 일으킬 수 있고, 여성에서 자궁경부암을 유발한다.5) 따라서 지속적인 HPV 감염을 예방할 수 있는 방법이 개발된다면 자궁경부암 질병 부담을 더욱 줄일 수 있을 것으로 기대되어 왔고, 이러한 기대에 부응하여 현재까지 두 종류의 HPV 백신이 개발되어 시판이 승인되었다.6) 이 글에서는 자궁경부암 발생과 관련된 HPV 특성과 HPV vaccine의 효능 및 사용권고사항을 정리하였다.

Cervical Cancer Screening after Perimenopause: How Is Human Papillomavirus Test Performed?

( Oo-ho Chung ) 대한폐경학회 2016 대한폐경학회지 Vol.22 No.2

Cervical cancer is the third most prevalent cancer in women around the world. Recently in Korea, the incidence of cervical cancer has decreased, but in all stages of cervical intraepithelial neoplasia (CIN), CIN has shown a 91% increase from 1999 to 2008. Persistent human papillomavirus (HPV) infection has been found to be the main cause of cervical cancer. HPV types 16 and 18 have been found in 70% of cervical cancer patients around the world. Cervical cancer screening such as cytology has limitations in terms of sensitivity and specificity. A discussion about the need for the HPV test is becoming active in order to compensate for the limitation of cytology. After the role of HPV in cervical cancer was identified, the importance of HPV detection test as a screening was emphasized. Several tests have been developed and each test has its own advantages and disadvantages, and new test method to overcome the disadvantages is still being developed. Today``s guidelines and tests are those you would choose from among the large number of cervical cancer screening guidelines and tests, based on the consideration that the selected guidelines and the test are effective. (J Menopausal Med 2016;22:65-70)

자궁경부암과 인 유두종 바이러스 백신 개발

황지영,김도균 東國大學校醫學硏究所 2003 東國醫學 Vol.10 No.2

자궁경부암은 한국 여성에서 발생 빈도가 높으며, 증가 추세인 유방암과 함께 중요한 질환으로 인식되고 있으며, 과학의 발달로 자궁경부암의 원인이 인 유두종 바이러스(human papillomavirus)라는 것이 밝혀진 이래로 자궁경부암은 성병과 같은 감염성 질환(infectious disease)으로 여겨지고 있는데, 이는 한편으로 예방할 수 있는 질환이라고 볼 수 있는 근거가 된다. 자궁경부암을 감소시키기 위하여 원천적으로 자궁경부암의 원인인 HPV 감염을 차단한다는 개념으로 개발된 예방적 백신은 성 생활을 시작하기 전의 젊은 여성들에게 접종을 통해 HRV에 대한 중화 항체를 만들어 HPV가 감염되어도 세포 속으로 침투하기 전에 무력화 시키겠다는 전략이다. 현재, 가장 진전된 예방백신 후보 물질들로 미국 NIH-NCI가 개발 중인 HPV 16 L1-VLP, GSK사의 HPV 16/18 L1, Merck사의 HPV 6/11/16/18 L1, Medigene사의 HPV 16 L1-chymeric VLP, 그리고 NCI의 HPV 16 L1-L2-E2-E7 chymeric VLP등이 있다. 이들 백신 후보 물질들은 모두, 안전성이 높은 것으로 확인되고 높은 면역원성이 증명되었다. 최근 임상실험 중 자궁경부암 예방백신이 곧 현실화될 수 있음을 제시하는 매우 중요한 결과 보고가 2002 년 11월에 있었는데, Merck사가 개발한 백신후보물질의 임상실험으로 HPV 예방효과를 분석하는 것이었다. HPV 감염 검사결과 765명의 위약 그룹에서 41례의 바이러스 지속감염이 확인된 반면, 접종을 한 768명 중에는 단 한 례도 나타나지 않았다는 것이었다. HPV감염에 대한 치료적 백신의 전략은 HPV의 비구조단백질을 목표로 하여 즉, 자궁경부암을 발생시키고, 유지시키는 발암 단백질 유전자인 E6, E7 부분을 면역학적으로 인식하여 무력화 시키겠다는 이론을 바탕으로 하여 E6, E7에 대한 항체 형성과 CTL (cytotoxic T lymphocyte)반응을 유도시킬 수 있도록 하는 것이다. 개발에 성공하면 이미 감염된 사람을 대상으로 훨씬 빠른 공중보건 상의 이익을 가져올 것으로 기대된다. 연구 중인 백신의 모델은 암유전자 E6, E7 등을 목표로 한 재조합융합단백질이나, vaccinia virus, adenovirus, retrovirus등을 vector로 사용하여 제조하거나, DNA vaccine 상태로 직접 투여하는 방법이다. 현재, 연구가 가장 많이 진전된 치료백신 후보 물질들로 Xenova사의 FP L2-E7-E6와 Vaccinia E6-E7, Transgene사의 Vaccinia(MVA)-E6-E7, Stressgen사의 HSP-E7등이 있다. 이와 같은 개발 및 실험 현황으로 볼 때 예방과 치료 목적의 HPV vaccine이 사용될 수 있는 시기가 5년 이내에 도래할 것으로 예상되고 있으며, 향후 우리나라에서도 효과적인 HPV 예방 백신을 사용할 수 있다면 최소 20~30년 이후에는 자궁경부암의 발생은 크게 감소할 수 있을 것으로 생각된다. Uterine cervical cancer has high incidence in Korea along with breast cancer and is regarded as an infectious disease because the scientific advances have provided the evidence of human papillomavirus (HPV) infection as the cause of it, and this suggests that the cervical cancer is a preventable disease. In order to decrease the incidence of cervical cancer, prophylactic vaccine blocking the HPV was developed for young women before actual sexual activity and the aim of this prophylactic vaccine is to make the neutralizing antibodies by injecting the antigenic materials for HPV. Most advanced available prophylactic HPV vaccine candidates are the HPV 16 L1-VLP from NIH-NCI, HPV 16/18 L1 from GSK, HPV 6/11/16/18 L1 from Merck, HPV 16 L1-chymeric VLP from Medigene, and HPV 16 L1-L2-E2-E7 chymeric VLP from NCI, etc... These vaccines are safe, highly immunogenic and well tolerated. From the clinical HPV vaccine trial by Merck company, important result was reported on November of 2002. It was that the 41 cases of 765 women who were injected with placebo appeared to have persistent HPV infection in the HPV-DNA test, while 768 women who were injected with HPV 16 VLP vaccine have all appeared to be free from HPV infection. The aim of therapeutic HPV vaccine is an immunologic recognition of oncoprotein E6/E7 associated with carcinogenesis followed by the formation of antibodies for E6/E7 and inducing the CTL (cytotoxic T lymphocyte) responses. If successful therapeutic vaccine is made, we can expect beneficial effects on public health since there are many patients who have had HPV infection, CIN(cervical intraepithelial neoplasia) or cervical cancer. Models of therapeutic HPV vaccine that are currently in research are the type of recombinant oncoprotein E6/E7, and live viral vectors like vaccinia virus, adenovirus, retrovirus and DNA vaccines. Most advanced available therapeutic HPV vaccine candidates are the FP L2-E7-E6 and Vaccinia E6-E7 from Xenova, Vaccinia(MVA)-E6-E7 from Transgene, and HSP-E7 from Stressgen. Under these circumstances, current researches and trials are expected to bring about the routine usage of prophylactic vaccine for HPV within 5 years, as well as decreasing the incidence of uterine cervical cancer in Korea by using it effectively.

Prognostic significance of neutropenia during adjuvant concurrent chemoradiotherapy in early cervical cancer

김윤환,정현훈,김재원,박노현,강순범,송용상 대한부인종양학회 2009 Journal of Gynecologic Oncology Vol.20 No.3

Objective: To evaluate the prognostic significance of adjuvant concurrent chemoradiotherapy-induced neutropenia with survival in patients with squamous cell carcinoma of the uterine cervix. Methods: Data from 107 patients with stage IB-IIB cervical cancer were retrospectively analyzed. The median follow-up was 37.5 (4.2-72.7) months. All patients had received radical surgery, including pelvic lymphadenectomy, followed by paclitaxel plus carboplatin-based concurrent chemoradiotherapy. Relative neutropenia, defined as an absolute neutrophil count <1,000/㎣ at the concurrent chemoradiotherapy cycle nadir, correlated to the pathologic findings and survival outcomes. Results: Sixty-six patients experienced neutropenia at least once during concurrent chemoradiotherapy, and demonstrated marginal improvement in disease-free survival (p=0.055), although not in overall survival. By subgroup analyses, the gain of disease free survival mainly originated from the node metastasis subgroup (p=0.033). Treatment-induced neutropenia proved to be the only significant independent factor for recurrence in cervical cancer (p=0.042) by multivariate analysis. Conclusion: Concurrent chemoradiotherapy-induced neutropenia may be a prognostic factor of recurrence in patients with cervical cancer. Individualized dose titration of the tolerable myelosuppression might be beneficial. Objective: To evaluate the prognostic significance of adjuvant concurrent chemoradiotherapy-induced neutropenia with survival in patients with squamous cell carcinoma of the uterine cervix. Methods: Data from 107 patients with stage IB-IIB cervical cancer were retrospectively analyzed. The median follow-up was 37.5 (4.2-72.7) months. All patients had received radical surgery, including pelvic lymphadenectomy, followed by paclitaxel plus carboplatin-based concurrent chemoradiotherapy. Relative neutropenia, defined as an absolute neutrophil count <1,000/㎣ at the concurrent chemoradiotherapy cycle nadir, correlated to the pathologic findings and survival outcomes. Results: Sixty-six patients experienced neutropenia at least once during concurrent chemoradiotherapy, and demonstrated marginal improvement in disease-free survival (p=0.055), although not in overall survival. By subgroup analyses, the gain of disease free survival mainly originated from the node metastasis subgroup (p=0.033). Treatment-induced neutropenia proved to be the only significant independent factor for recurrence in cervical cancer (p=0.042) by multivariate analysis. Conclusion: Concurrent chemoradiotherapy-induced neutropenia may be a prognostic factor of recurrence in patients with cervical cancer. Individualized dose titration of the tolerable myelosuppression might be beneficial.

Cervical Cancer Screening after Perimenopause: How Is Human Papillomavirus Test Performed?

정수호 대한폐경학회 2016 대한폐경학회지 Vol.22 No.2

Cervical cancer is the third most prevalent cancer in women around the world. Recently in Korea, the incidence of cervical cancer has decreased, but in all stages of cervical intraepithelial neoplasia (CIN), CIN has shown a 91% increase from 1999 to 2008. Persistent human papillomavirus (HPV) infection has been found to be the main cause of cervical cancer. HPV types 16 and 18 have been found in 70% of cervical cancer patients around the world. Cervical cancer screening such as cytology has limitations in terms of sensitivity and specificity. A discussion about the need for the HPV test is becoming active in order to compensate for the limitation of cytology. After the role of HPV in cervical cancer was identified, the importance of HPV detection test as a screening was emphasized. Several tests have been developed and each test has its own advantages and disadvantages, and new test method to overcome the disadvantages is still being developed. Today's guidelines and tests are those you would choose from among the large number of cervical cancer screening guidelines and tests, based on the consideration that the selected guidelines and the test are effective. (J Menopausal Med 2016;22:65-70)

자궁 경부암종에서 Epstein-Barr Virus의 검출 - 중합효소연쇄반응법과 In Situ PCR을 이용한 연구 -

김인선(In Sun Kim),강재성(Jae Seong Kang),최안나(An Na Choi),김영식(Young Sik Kim) 대한산부인과학회 2000 Obstetrics & Gynecology Science Vol.43 No.2

Objective: Uterine cervical cancer is the most common malignant tumor in Korean women. Human papillomaviruses are associated in 85-90% of the cases. However, other cofactors are considered to be important in carcinogenesis. There is an evidence that the uterine cervix is the site of shedding of the Epstein-Barr viruses(EBV). Furthermore the virus has been detected in cervical intraepithelial neoplasia and invasive carcinoma of the uterine cervix. We studied to evaluate the role of EBV in cervical carcinogenesis. Methods: Non-neoplastic cervices(12), carcinoma in situ(32), microinvasive squamous cell carcinomas(9), invasive squamous cell carcinomas(37) and adenocarcinomas and adenosquamous carcinomas(14) were studied for EBV infection. PCR and in situ PCR for EBNA-1 were done and subtyping was done using PCR for EBNA 3C. Results: In non-neoplastic cervix, EBV was detected in 16.7% by PCR and found in normal epithelial cells and lymphocytes in in situ PCR. By PCR technique, EBV was detected in 65.6% of CIS, 66.3% and 51.4% of microinvasive and invasive squamous cell carcinomas, 57.1% of adenocarcinomas and adenosquamous carcinomas. EBV subtyping was done in EBV positive cases by PCR and all showed type 1. Conclusion: EBV was detected in higher frequency in cervical cancer than in non-neoplastic cervix. However the frequency was not correlated to the invasion depth and histologic types of cervical carcinomas. EBV was detected in tumor cells as well as normal epithelial cells and lymphocytes also. It was suggested that EBV may play a role in cervical cancers but the mechanism in carcinogenesis remains to be solved.

Innovations in HPV Vaccination and Roles of Nurses in Cervical Cancer Prevention

Yildirim, Julide Gulizar,Arabaci, Zeynep Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.23

The human papilloma virus (HPV) is the main aetiological agent for cervical cancer, one of the most frequent cancers observed in women throughout the world. There are effective programs for reducing the incidence of cervical cancer with HPV vaccination. The objective of this study was to discuss the applicability of the HPV vaccination and the role of nurses in prevention of cervical cancer. Use of bivalent and quadrivalent vaccines has been initiated against the types of HPV which are the primary cause of cancer. The quadrivalent HPV vaccination has entered into the routine vaccination schedule in many European countries for use in children and adolescents between 9-15 years of age and for women between 16-26 years of age, whereas it has been proposed that the bivalent vaccination should be given to girls between 9-18 years of age. While cervical cancer is among the cancers that can be prevented, it is essential to continue screening tests while introducing vaccination in a systematic manner for protection. On this subject, among the most important roles of nurses is to implement the screening programs by fulfilling the caregiving, training and consultancy roles for the society and especially, for high risk groups and to increase the awareness of the people.