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

A case control design was used to investigate human papillomavirus (HPV) prevalence and risk factors associated with development of cervical squamous intraepithelial lesion (SIL) and cervical cancer (CC) in Japan. One hundred and twenty-three women with histologically confirmed SIL or CC were compared to a control group of 778 cytologically normal women. With the use of a polymerase chain reaction (PCR)-based method for detection of low-risk (types 6 and 11) and high-risk (types 16, 18, 31, 33, 35, 52 and 58) HPVs, a high prevalence of HPV infection was observed in smokers among the controls. Logistic regression analysis demonstrated that high-risk HPV infection was the most significant risk determinant for LSIL (OR=9.4, 95% CI=4.5-19), HSIL (OR=77, 95% CI=28-217) and CC (OR=97, 95% CI=35-269). It also showed that unmarried women, women married for 5 to 19 years and smokers represented high risk groups for SIL, while smokers and women with a history of many pregnancies/parities had increased risk for CC. Smoking was the only HPV infection-independent factor for CC, suggesting that smoking may have a carcinogenic effect on the cervix. Since neither history of other cancer nor family cancer history was associated with SIL or CC, genetic factors appear to play little role in cervical carcinogenesis. The risk for cervical neoplasia due to HPV infection increased after marriage in Japan, suggesting a role for husbands as carriers of HPV transmission. Protection from high-risk HPV infection may be of greatest importance for prevention of cervical cancer.
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PMID:Human papillomavirus infection and risk determinants for squamous intraepithelial lesion and cervical cancer in Japan. 919 29

Invasive squamous carcinoma of the uterine cervix (CC) arises from sequential progression of low-grade (L) and high-grade (H) squamous intraepithelial lesions (SILs). In clinical observations, these lesions are frequently found as synchronous multiple foci. The nature and evolutionary mechanism of these lesions are largely unknown. We have performed allelotyping of three 3p markers (at 3p14, 3p22-24, and 3p25) on 22 LSILs and 15 HSILs microdissected from patients with multiple (n = 21) or uniform (n = 6) cervical lesions. The results were analyzed together with our previous allelotyping of 57 deeply invasive CCs. Loss of heterozygosity at one of the three markers was observed in 23%, 27%, and 31 % of LSILs, HSILs, and CCs, respectively. Frequent and early allelic loss was noted (in 30% of LSILs and 50% of HSILs) at 3p14, which may harbor tumor suppressor genes involved in early stages of cervical carcinogenesis. A high frequency of microsatellite alteration (MA) was found in LSIL (41%) and HSIL (67%) but not in CC (5.3%). In particular, MA was more frequently found in low-grade lesions in association with invasive cancers (75%, 6/8) than in those associated with SILs (29%, 4/14) (P < 0.05). Together with the finding of a monoclonal origin of premalignant and malignant cervical lesions, the present results allow us to propose a model of local field effect of genomic instability that progressively affects the clonal evolution of SIL of uterine cervix.
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PMID:Monoclonality and surface lesion-specific microsatellite alterations in premalignant and malignant neoplasia of uterine cervix: a local field effect of genomic instability and clonal evolution. 988 79

In this study, the 8-hydroxy-2'-deoxyguanosine (8-OHdG) level was assessed in human cervical cells by an immunoperoxidase method and was related to the presence of human papillomavirus (HPV) infection and precancerous lesions. After optimizing the immunohistochemical method of detecting oxidative DNA damage in whole cells, we have used this technique to estimate the oxidative damage in cervical cells collected during a routine PAP test. The analysis of variance (ANOVA) of the data from human samples showed significant differences in the 8-OHdG content among normal, low-grade and high-grade squamous intraepithelial lesion (SIL, HGSIL and LGSIL, respectively; P < 0.001). In the comparison of the three groups, statistically significant differences were detected between normal SIL and HGSIL (P < 0.001) and between LGSIL and HGSIL (P = 0.003), whereas no statistically significant difference was found between normal SIL and LGSIL (P = 0.1). Grouping observations by HPV status, no significant difference was detected in 8-OHdG levels between HPV(+) and HPV(-) subjects (P = 0.8). The polytomous and proportional odds models, extensions of the logistic regression analysis, showed that the effect of 8-OHdG levels in rising the risk of dysplasia was roughly constant through SIL grades. In conclusion, the immunoperoxidase method, applied to single human cervical cells, provides clear evidence that significant differences exist in 8-OHdG content between normal and dysplastic cells and that oxidative DNA damage might play an important role in cervical carcinogenesis.
Carcinogenesis 2000 Jun
PMID:8-hydroxy-2'-deoxyguanosine in cervical cells: correlation with grade of dysplasia and human papillomavirus infection. 1083 2

Adeno-associated virus (AAV) is a ubiquitous human helper-dependent parvovirus which may interact with human papillomaviruses (HPV) to modify a woman's risk of cervical neoplasia. This analysis was nested in a cohort study of low-income women receiving Pap smears as part of their family planning services. We selected cases (55 with high-grade cervical squamous intraepithelial lesions (HSIL) and 162 with low-grade LSIL) and controls (96 women with normal cervical cytology) and analyzed cervical DNA for AAV, using PCR amplification/dot blot hybridization, and HPV, using hybrid capture I. AAV positivity was associated with a significantly reduced risk of HSIL (age and HPV-adjusted odds ratio (aOR) = 0.32) yet not with LSIL (aOR = 0.78); 53.8% of HSIL, 66.9% of LSIL, and 70.7% of controls were AAV+. AAV appears to interact with HPV to reduce SIL risk; relative to the HPV-/AAV+ exposure, the respective aORs for HSIL and HPV+/AAV-, HPV+/AAV+, and HPV-/AAV+ were 17.0, 6.9, and 3.5. AAV+ was not associated with age, race, HPV status, or sexual or reproductive risk factors. These results strongly suggest that AAV may play a protective or inhibitory role in late stage cervical carcinogenesis. This conclusion needs to be verified in additional epidemiologic studies.
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PMID:Adeno-associated virus is associated with a lower risk of high-grade cervical neoplasia. 1126 51

Infection with specific human papillomavirus (HPV) types is the strongest risk factor in cervical carcinogenesis. In this study we analysed, by means of polymerase chain reaction (PCR), cervical specimens obtained from consenting women with abnormal Pap smears collected from 1996 to 1998. Consensus- and type-specific-primers directed PCR were used in order to detect the presence and to determine the most common HPV types: 6, 11, 16, 18, 31 and 33. Out of 1874 specimens, 1207 (64%) contained one or more HPV types. Approximately half HPVs were typed (621 out of 1207) and the others remained untyped (586 out of 1207), 51% and 49%, respectively. Beside low-risk HPV 6/11 (5%), the most frequently observed HPVs were high-risk HPV types, especially type 16 (12%), while HPV types 18 (2%), 31 (5%) and 33 (3%) were less frequent. The HPV positivity rate declined with age, although all HPV types were equally distributed in different age groups. The presence of HPV DNA significantly increased from 55% to 78% along with the severity of the cervical lesions, i.e. low- and high-grade squamous intraepithelial lesions (LSIL, HSIL). Undetermined HPV types, other than 6/11, 16, 18, 31 and 33 were equally distributed in LSIL and HSIL which indicates that they represent low- as well as high-risk HPV types. Our results indicated that HPV infections, especially those with HPV 16, represent a significant public health concern in Croatia.
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PMID:Evaluation of genital human papillomavirus infections by polymerase chain reaction among Croatian women. 1129 8

To evaluate the expression of nm23-H1 protein in normal, precancerous, and cancerous tissues of the uterine cervix and its role in cervical carcinogenesis, metastasis and recurrence, 82 cervical specimens, including 30 squamous cell carcinomas (SCC), 19 high- and 13 low-grade squamous intraepithelial lesions (HSILs and LSILs) and 20 normal samples, were stained using immunohistochemical method with streptavidin-biotin peroxidase immunostaining. The Chi-square and Fisher's exact tests, as well as Chi-square test for trend, were used for comparing nm23-H1 expression among normal, LSIL, HSIL, and cancerous tissues. The correlation of nm23 expression with metastasis or recurrence was analyzed using Fisher's exact test. There were significant differences in levels of nm23-H1 expression between LSIL and HSIL (P = 0.016) and between LSIL and SCC (P = 0.004), but not between HSIL and SCC or normal and LSIL samples. Furthermore, a positive relationship was demonstrated for high nm23-H1 protein expression and degree of malignant transformation (P < 0.05). Among the 30 SCC cases, high nm23-H1 expression did not show significant association with either carcinomatous metastasis or recurrence (P = 0.123, 0.372, respectively). High nm23-H1 expression appears related to critical progression of LSIL to HSIL but not to metastasis or recurrence of SCC.
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PMID:Nm23-H1 immunohistochemical expression in multisteps of cervical carcinogenesis. 1280 Dec 64

The rapid progress in molecular biology has allowed the identification of the genes involved in different functions of normal cells and has also improved our understanding of the mechanisms of human carcinogenesis. The human papillomavirus (HPV) is a small double-stranded DNA tumor virus and its genes can manipulate cell cycle control to promote viral persistence and replication. The E6 and E7 proteins of high-risk HPV bind to cell cycle regulatory proteins and interfere with both G1/S and G2/M cell cycle checkpoints much more effectively than the low-risk HPV. The difference between the ability of low and high-risk HPV types to induce immortalization and transformation may well lie in their abilities to interact with the various cell cycle components, resulting in the loss of multiple cell cycle checkpoints, which are important in host genome fidelity, thus potentially resulting in accumulation of genetic abnormalities. Cervical cancer is one of the leading malignancies in women worldwide, with substantial morbidity and mortality. According to current concepts, HPV is recognized as the single most important causal agent in the pathogenesis of this cancer. HPV infection clearly precedes the development of malignancy, while being regularly associated with cervical cancer precursor lesions (all grades of squamous intraepithelial lesions). HPV-infected low-grade squamous intraepithelial lesion (SIL) has three possible outcomes: a) it may regress; b) it can persist; or c) it can make a clinical progression to in situ or invasive carcinoma. It has been well established by prospective cohort studies that the spontaneous regression rate increases in parallel with follow-up duration. In contrast, the clinical progression of lesions usually takes place quite rapidly, i.e. during the first two years from diagnosis. The mechanisms responsible for this divergent clinical behavior of HPV-associated squamous intraepithelial lesions are largely unknown, but currently under intense study in different laboratories worldwide.
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PMID:Regulation of cell cycles is of key importance in human papillomavirus (HPV)-associated cervical carcinogenesis. 1292 Apr 76

Whereas two key steps in cervical carcinogenesis are integration of high-risk human papillomavirus (HR-HPV) and acquisition of an unstable host genome, the temporal association between these events is poorly understood. Chromosomal instability is induced when HR-HPV E7 oncoprotein is overexpressed from heterologous promoters in vitro. However, it is not known whether such events occur at the "physiologically" elevated levels of E7 produced by deregulation of the homologous HR-HPV promoter after integration. Indeed, an alternative possibility is that integration in vivo is favored in an already unstable host genome. We have addressed these issues using the unique human papillomavirus (HPV) 16-containing cervical keratinocyte cell line W12, which was derived from a low-grade squamous intraepithelial lesion and thus acquired HPV16 by "natural" infection. Whereas W12 at low passage contains HPV16 episomes only, long-term culture results in the emergence of cells containing integrated HPV16 only. We show that integration of HPV16 in W12 is associated with 3' deletion of the E2 transcriptional repressor, resulting in deregulation of the homologous promoter of the integrant and an increase in E7 protein levels. We further demonstrate that high-level chromosomal instability develops in W12 only after integration and that the forms of instability observed correlate with the physical state of HPV16 DNA and the level of E7 protein. Whereas intermediate E7 levels are associated with numerical chromosomal abnormalities, maximal levels are associated with both numerical and structural aberrations. HR-HPV integration is likely to be a critical event in cervical carcinogenesis, preceding the development of chromosomal abnormalities that drive malignant progression.
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PMID:Acquisition of high-level chromosomal instability is associated with integration of human papillomavirus type 16 in cervical keratinocytes. 1497 79

High-risk human papillomaviruses (HPVs) are major etiological agents of cervical cancer. Despite excellent epidemiological evidence for a direct role of HPV-16 in cervical carcinogenesis, molecular pathways underlying carcinogenesis in vivo remain obscure. The E7 gene is required for immortalization and maintenance of the transformed phenotype in vitro; however, little is known about its role for tumorigenesis in vivo. The E7 gene codes for an unstable protein the abundance of which in cervical biopsies is unknown. We show here that E7 protein levels strongly increase during cervical carcinogenesis, underlining its fundamental role in cervical cancer. The E7 protein was found predominantly in the nucleus and to a minor extent in the cytoplasm in the cervical cancer cell line Ca Ski in vitro and in invasive cervical carcinoma in situ, suggesting that nuclear resident E7 plays a major role in cervical carcinogenesis in humans. The retinoblastoma protein (pRb) is a major E7-target in vitro. We show here that pRb expression is initially upregulated in LSIL and disappears in later stages concomitant with increased E7 levels, suggesting that E7-driven degradation of pRb is involved in cervical tumorigenesis in humans.
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PMID:High level HPV-16 E7 oncoprotein expression correlates with reduced pRb-levels in cervical biopsies. 1515 61

High-risk human papillomavirus are essential for the development of cervical cancer; however, TP53 is the most frequently altered tumor suppressor gene among tumors and is described as a cofactor for cervical carcinogenesis. TP53 has two common polymorphic forms encoding either proline or arginine, at position 72, and the presence of homozygous arginine has been reported as a risk factor for cervical cancer in many populations. We evaluated the effect of this TP53 polymorphism in a northern Portuguese population. We analyzed blood samples of 385 women; 20 with low-grade squamous intraepithelial lesion (SIL), 56 with high-grade SIL, 164 with invasive cervical cancer, and 145 healthy controls, using allele specific-polymerase chain reaction methodology. We observed an increased frequency of the Arg/Arg genotype in the cancer group, but no statistical significance was found between cases and controls (P>0.05). Our results indicate that there is no association between the presence of the Arg allele in codon 72 of TP53 polymorphism and risk of cervical cancer in our population.
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PMID:TP53 codon 72 polymorphism and risk for cervical cancer in Portugal. 1589 86


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