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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report results of follow-up by PAP smears and colposcopy in 116 women treated since 1981 by conization for cervical intraepithelial neoplasia with human papillomavirus infection (HPV-CIN). The mean follow-up time was 31.9 (SD 19) months. Preoperative diagnosis was HPV-CIN II (with extension into the endocervix) in 11 cases and HPV-CIN III in 103 cases; two diagnostic conizations were performed. The histological examination of the cone biopsies showed complete excision of CIN in 109 cases (94%). Three patients underwent hysterectomy after conization; one had microinvasion in the cone biopsy, one had suspicion of microinvasion and one had non-radical conization. Three patients (2.6%) were lost to follow-up. After excluding these six patients the primary cure rate of HPV lesions (normal cytological and colposcopical finding after conization) was 82.7%. Four patients (4.6%) had residual CIN after conization. During the follow-up 15 patients had recurrence of HPV infection, only one had HPV-CIN I. HPV 16 was the most common HPV type (56/116, 48.2%) in the conization group and also in the recurrent cases (9/15, 60%). The results support the role of HPV 16 in cervical carcinogenesis.
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PMID:Conization for CIN associated with human papillomavirus infection. 171 44

Oncogenic potential of herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) which are both associated with occurrence of cervical cancer and the mechanism of oncogenesis by these viruses were investigated by transformation experiments in vitro. The results were obtained as follows. 1) HSV-2 induced neoplastic transformation of normal diploid cells is a multistep process. Cervical cancer associated antigen AG-4 is encoded within the specific region of HSV-2 DNA which converts immortalized cells to tumorigenic lines. 2) Tumor cells express cellular oncogene at a final stage of neoplastic transformation induced by HSV-2 and "hit and run" theory is applicable to oncogenesis of this virus. 3) Complete carcinogenesis can be mediated by HPV-16 or HPV-18 DNA under collaboration with other cofactors such as HSV-2. 4) It is suggested that neoplastic transformation induced by HPV-18 DNA is based on "hit and run" oncogenesis. 5) HPV-16 or HPV-18 DNA can immortalize primary diploid cells and convert them to fully tumorigenic phenotype by repeating cell passage. 6) It has been experimentally proved that the difference in transforming potential exists between HPV 6/11 and HPV 16/18. 7) Amplification and overexpression of c-myc oncogene was detected in transformed cells obtained by HPV-16 transfection. While overexpression of c-myc was detected in transformed cells induced by HPV-18 DNA, but no amplification was observed. On the other hand, detection of HPV, DNA and amplification or overexpression of protooncogenes was performed in cervical intraepithelial neoplasias (CIN) and invasive cervical carcinomas. The results were summarized as follows. 1) HPV DNA was detected in approximately 70% of a population with CIN by in situ hybridization. CIN II showed the highest incidence of positive HPV DNA (91%), and the positive ratio decreased in CIN III (56%). 2) Immunohistochemical study of paraffin-embedded specimens with monoclonal antibodies to oncogene products revealed that only some of cervical invasive carcinomas expressed c-myc protein, ras p21 or EGFR. 3) HPV DNA was detected in 46% of invasive cervical carcinomas by Southern blot hybridization. The percentage of patients with positive results for HPV 16/18 was 29%. However, it increased up to 58% by use of polymerase chain reaction (PCR), suggesting that there are many cervical cancer tissues in which a number of cells lack viral DNA. 4) Northern blot hybridization analysis revealed overexpression of c-myc mRNA in 30% of cervical invasive carcinomas although amplification of c-myc oncogene was detected in only one of invasive carcinomas.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[The possibility of viral etiology in cervical carcinogenesis]. 217 17

To examine the correlations between ras oncogene expression and the development of cervical cancer, the authors studied the reactivity of cervical intraepithelial neoplasia (CIN) and microinvasive lesions of the human uterine cervix by using anti-ras p21 mouse monoclonal antibody rp35. The frequency of positive p21 staining increased with increased grades of malignancy from 17.9% in CIN 1 to 28.9% in CIN 2 and 53.9% in CIN 3, whereas in microinvasive carcinoma it was 50.0%. Furthermore, ten cases of lesions that regressed during a 1-year follow-up period were positive for ras p21 in 20% of cases, but 14 cases of lesions that progressed and developed into higher graded lesions during the 2- to 5-year follow-up period had a 50.0% rate of positive p21 staining. It was concluded that ras oncogene product p21 correlates with the early phase of carcinogenesis of squamous cells of the uterine cervix.
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PMID:Ras oncogene expression and progression in intraepithelial neoplasia of the uterine cervix. 219 11

An in situ DNA hybridization technique was used to identify various types of Human papillomavirus (HPV) in paraffin sections of serial punch biopsies taken from 64 patients having colposcopy because of abnormal smears. There women were in fact 64 consecutive patients out of 505 attending our clinic (at 6-month intervals) since 1981 for HPV infections. HPV 6 DNA sequences were found in 20%, HPV 11 in 17%, HPV 16 in 8% and HPV 18 in 5% of the 64 biopsies analysed with this method so far. More than 60% of HPV 6-positive lesions belong to HPV-NCIN (HPV lesion without concomitant CIN) or HPV-CIN I categories, as contrasted with HPV 16-positive lesions, 80% of which belong to HPV-CIN II and III categories. None of the HPV 16- or HPV 18-infected lesions regressed, as contrasted with 23% and 45% in those infected with HPV 6 and HPV 11, respectively (P less than 0.01). The rate of progression (38.4% and 45.5%, respectively) was markedly lower in HPV 6- and HPV 11 lesions as compared with that (80%) of HPV 16 lesions. The present results while supporting the concept on HPV 16 and HPV 18 as the high risk HPV types in cervical carcinogenesis also emphasize the applicability of the in situ DNA hybridization as a powerful tool in analysis of the specific HPV DNA sequences in routinely progressed biopsies of these lesions.
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PMID:Human papillomavirus (HPV) DNA sequences demonstrated by in situ DNA hybridization in serial paraffin-embedded cervical biopsies. 301 43

We used newly established cervical dysplasia-derived cell lines to elucidate a molecular mechanism of the preventive action of beta-carotene in cervical multi-step carcinogenesis. Liposomal beta-carotene was added to the culture medium for human cervical dysplasia cell lines, CICCN-2 from cervical intraepithelial neoplasia grade I (CIN I), CICCN-3 from CIN II, and CICCN-4 from CIN III, and human cervical carcinoma-derived cell lines such as CICCN-6, CICCN-18, and HeLa cells. beta-Carotene (10 mumol/L) induced significant growth retardation in three cervical dysplasia cell lines but not in three cervical carcinoma-derived cell lines. Binding activities of epidermal growth factor (EGF) and cellular amounts of either messenger RNA for EGF receptor gene or EGF receptor protein were all highest in CICCN-4 cells. Cell surface binding, as well as internalization, of 125I-labeled EGF was rapidly reduced after beta-carotene treatment in dysplasia cell lines and 170-kD protein bands of EGF receptor disappeared from protein immunoblots at day 3 of the treatment. Cellular amounts of EGF receptor messenger RNA remained constant until day 3 of the treatment and were substantially reduced after day 7. Chromatin condensations, morphologic evidence for apoptotic cell death, were observed at day 1 by staining. From these results, we contend that prevention of cervical carcinogenesis by beta-carotene is due to induction of apoptosis in cervical dysplastic cells, which are premalignant cells in cervical multi-step carcinogenesis, via down-regulation of EGF receptor protein.
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PMID:Growth retardation in human cervical dysplasia-derived cell lines by beta-carotene through down-regulation of epidermal growth factor receptor. 749 56

The evidence implicating specific HPV types in the aetiology of cervical cancer is now strong enough to establish a causative role. HPV infection of the cervix affects the developing immature metaplastic cells of the transformation zone. Cervical neoplasia can be viewed as the interaction of high risk papillomavirus and immature metaplastic epithelium. Once maturity is reached, there is minimal risk of subsequent development of cervical squamous neoplasia. Exposure to HPV is an extremely common event, especially in young sexually active women. Yet, despite frequent HPV exposure at that phase of life in which the cervical transformation zone is at its most vulnerable, established expressed disease is relatively uncommon. Most studies in which the natural history of CIN is not altered by cervical biopsy reveal a progression rate from low to high grade CIN of less than one third. Where viral type is taken into account, however, the progression rate from normal but high risk HPV-infected cervical epithelium to CIN 2 or 3 is higher. Despite this, most cervical abnormalities will not transform into invasive cancer, even if left untreated. The variance between the high rate of HPV infection, the intermediate rate of CIN and the relatively low rate of cervical cancer establishes a stepwise gradient of disease of increasing severity with decreasing prevalence. In an immunocompetent host, HPV infection alone does not appear to be sufficient to induce the step from high grade CIN to invasion. Epidemiological studies indicating that HPV infection with oncogenic viral types is far more common than cervical neoplasia suggest the necessity of cofactors in cervical carcinogenesis. The long time-lag between initial infection and eventual malignant conversion suggests that random events may be necessary for such conversion, and the spontaneous regression of many primary lesions suggests that most patients are not exposed to these random events. Potential cofactors include cigarette smoking, hormonal effects of oral contraceptives and pregnancy, dietary deficiencies, immunosuppression and chronic inflammation. In those women who develop cervical cancer, malignant progression is rarely rapid, more commonly taking many years or decades. Malignant progression has been documented in patients who presented initially with only low grade HPV-induced atypia. On the other hand, progression may be a misnomer, as 'apparent' progression may really represent adjacent 'de novo' development of higher grade CIN. Although most cervical cancers contain high risk HPV types, up to 15% of such cancers test negative for HPV, raising the possibility that a few, usually more aggressive, cervical cancers may arise from from a non-viral source.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Epidemiology of cervical intraepithelial neoplasia: the role of human papillomavirus. 760 Jul 20

Studies using cervical carcinoma cell lines usually show mutated p53 in cases without detectable HPV, and wild-type p53 in cases with detectable HPV. These findings suggest that loss of p53 function, either by mutation or by binding to HPV E6, is required for cervical carcinogenesis. Because mutated p53 is usually detectable immunohistochemically, one would predict an inverse relationship between the presence of HPV and detectable p53. In this study we examined 88 formalin-fixed paraffin-embedded clinical specimens of cervix for the presence of HPV and p53 expression. All cases were studied for the presence of p53 using immunohistochemical methods. The antibody used was mouse monoclonal PAb1801 (Biogenex). The presence of HPV was detected by PCR. Twenty-six specimens showed foci of p53 expression (0/7 normal, 1/8 (13%) condylomas, 1/6 (17%) CIN I, 3/7 (43%) CIN II, 6/20 (30%) CIN III, 13/22 (59%) SCC, 2/5 (40%) adenosquamous carcinomas, and 0/13 adenocarcinomas). p53 expression was more frequent in SCC than with CIN (P = 0.026). HPV was present in 15 of 24 cases with detectable p53 and 22 of 48 cases without detectable p53. No correlation was seen between HPV status and detection of p53. With the exception of one case, p53 expression was seen in less than 10% of cells. p53 expression was not detected in any of the 13 adenocarcinomas examined (P = 0.0016 vs SCC). Our results show that alterations of p53 may play a role in the pathogenesis of cervical squamous carcinoma. However, p53 expression was neither sufficient nor required for cervical carcinogenesis, irrespective of HPV status.
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PMID:Cervical squamous dysplasias and carcinomas with immunodetectable p53 frequently contain HPV. 767 94

A mutation in codon 12 of the H-ras oncogene has been implicated in the pathogenesis of cervical cancer. To determine if mutational activation of H-ras is an early event in carcinogenesis, we looked for the presence of codon 12 H-ras mutation in precancerous cervical dysplasia. We analyzed cervical DNA from 63 normal patients and 72 patients with biopsy-proven cervical dysplasia [CIN I (48), CIN II (9), CIN III (15)]. HPV typing was performed on these samples by Viratype and analysis and polymerase chain reaction (PCR). To detect H-ras codon 12 mutation, DNA was isolated and amplified by PCR with primers for H-ras. A unique restriction site for MspI contained within the wild-type ras PCR product allows discrimination between unmutated and mutated sequences. Restriction enzyme analysis with MspI was performed on PCR products to distinguish between wild-type and mutated sequences. HPV 16 or 18 was present in 33% of CIN I, 56% of CIN II, and all CIN III samples. No codon 12 mutations were detected in any sample. We conclude that while HPV is associated with cervical dysplasia and its prevalence increases in more advanced lesions, it is unlikely that H-ras codon 12 mutations are an early occurrence in the progression of precancerous lesions to cervical carcinoma.
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PMID:H-ras codon 12 mutation in cervical dysplasia. 838 12

Cervical cancer is the second most common malignancy in women worldwide and remains a significant health problem for women, especially minority and underserved women. Despite an understanding of the epidemiologic risks, the screening Papanicolaou smear, and morbid and costly treatment, overall survival remains 40%. New strategies, based on the clinical and molecular aspects of cervical carcinogenesis, are desperately needed. Chemoprevention refers to the use of chemical agents to prevent or delay the development of cancer in healthy populations. Chemoprevention studies have several unique features that distinguish them from classic chemotherapeutic trials; these features touch on several disciplines and weave knowledge of the biology of carcinogenesis into the trial design. In the design of chemoprevention trials, four factors are important: high risk cohorts must be identified; suitable medications must be selected; study designs should include Phases I, II, and III; and studies should include the use of surrogate end point biomarkers. Surrogate end point biomarkers are sought because the cancer develops over a long period of time, and studies of chemopreventives would require a huge number of subjects followed for many years. Surrogate end point biomarkers serve as alternative end points for examination of the efficacy of chemopreventives in tissue. High risk cohorts include women with cervical intraepithelial neoplasia (CIN) or squamous intraepithelial lesions (SIL). Nutritional studies have helped define micronutrients of interest (folate, carotenoids, vitamin C, vitamin E). Other medications of interest include retinoids (4-hydroxyphenylretinamide [4-HPR], retinyl acetate gel, topical all-trans-retinoic acid), polyamine synthesis inhibitors (alpha-difluoromethylornithine [DFMO]), and nonsteroidal anti-inflammatory drugs (ibuprofen). Phase I chemoprevention studies of the cervix have tested retinyl acetate gel and all-trans-retinoic acid. Phase II trials of all-trans-retinoic acid, beta-carotene, and folic acid have been and are being carried out, whereas Phase III trials of all-trans-retinoic acid have been completed and have shown significant regression of CIN 2 but not CIN 3. Phase I studies of DFMO and Phase II studies of DFMO and 4-HPR are underway. Surrogate end point biomarkers under study include (1) quantitative cytology and histopathology; (2) human papillomavirus type testing; (3) biologic measures of proliferation, regulation, differentiation, and genomic instability; and 4) fluorescence spectroscopic emission. Clinical trials with biologic end points will contribute to our understanding of the neoplastic process and hence aid us in developing new preventive and therapeutic strategies.
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PMID:Chemoprevention trials and surrogate end point biomarkers in the cervix. 863 87

In order to evaluate the association between seropositivity for herpes simplex virus (type 1 and type 2) and cervical intraepithelial neoplacia (CIN), we analysed data from a population-based case-control study of CIN grade II-III which included Norwegian women aged 20 to 44 years, 94 cases and 228 controls. Our objectives were to determine if HSV-1 and/or HSV-2 seropositivity were independent risk factors for CIN, taking human papillomavirus exposure into account, and to elucidate the combined effect of HPV positivity and seropositivity for HSV In logistic regression analyses, the association between HSV-2 or HSV-1 seropositivity and CIN II-III was not explained by HPV (adjusted OR 3.0; 95%, CI 1.3-7.2 and adjusted OR 3.3; 95% CI 1.3-8.4, respectively). In analyses restricted to HPV-16 DNA-positive individuals, seropositivity for HSV-2 increased the risk of CIN (OR 11.1; 95% CI 1.2-105.7), whereas HSV-1 seropositivity was not significantly associated with CIN. In women positive for other HPV types, only HSV-1 seropositivity was associated with CIN (OR 8.5; 95% CI 1.3-55.8). In analyses of the HPV-16-seropositive individuals, neither HSV-1 nor HSV-2 seropositivity was associated with CIN. Compared to the reference group of jointly unexposed subjects, the HPV-16 DNA-positive women who were anti-HSV-2 negative had an increased risk of CIN (OR 29; 95% CI 12-67), whereas the risk in women who were both HPV-16 DNA-positive and HSV-2 was OR=247 (95% CI 31-1996). The estimate of interaction was strong, but did not reach significance, and our findings may suggest that the combined effect of the two viruses is of aetiological importance in cervical carcinogenesis. Furthermore, the results indicate that HPV DNA positivity is not sufficient to explain the sexual behaviour-associated risk of cervical neoplasia and that further studies on the role of genital HSV (type 1 as well as type 2) and other STDs are warranted.
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PMID:Herpes simplex virus and human papillomavirus in a population-based case-control study of cervical intraepithelial neoplasia grade II-III. 954 32


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