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Interaction among folate, riboflavin, genotype, and cancer, with reference to colorectal and cervical cancer.

Epidemiological studies have linked low folate intake with an increased risk of epithelial cancers, including colorectal cancer and cervical cancer. Riboflavin has received much less attention, but there is increasing interest in the well-established role that flavins play in folate metabolism and the possible synergy of a protective effect between these 2 vitamins. Folate plays a key role in DNA synthesis, repair, and methylation, and this forms the basis of mechanistic explanations for a putative role for folate in cancer prevention. The role of folate in these processes may be modulated by genotype for the common C677T thermolabile variant of methylene tetrahydrofolate reductase (MTHFR), homozygosity for which is associated with lower enzyme activity, lower plasma and red blood cell folate, and elevated plasma homocysteine. Riboflavin, as FAD, is a cofactor for MTHFR and there is evidently some interaction among riboflavin status, folate status, and genotype in determining plasma homocysteine, a functional marker of folate status. The MTHFR C677T polymorphism appears to interact with folate and riboflavin in modulating cancer risk in a manner that varies according to cancer site. Most evidence points to a protective effect of this polymorphism for risk of colorectal cancer, but the effect on cervical cancer risk is not clear. The effect of this polymorphism on cancer risk seems to be further modulated by other factors, including alcohol and, in the case of cervical cancer, infection with the human papilloma virus. An additional factor determining the effect of diet and genotype interactions on cancer risk may be the stage of cancer development.

Colorectal Neoplasms↗

Prevalence of cervical cancer and feasibility of screening in rural China: a pilot study for the Shanxi Province Cervical Cancer Screening Study.

For cervical cancer screening to be feasible in developing countries, it must be accurate, inexpensive, and easy to administer. We conducted a pilot study in rural Shanxi Province, People's Republic of China, to determine disease prevalence and study feasibility in preparation for a large-scale comparative trial of 6 screening tests. One-hundred and thirty-six nonpregnant women with no history of hysterectomy, pelvic radiation, or Papanicolaou tests were screened in a rural clinic. Ten percent of the women enrolled reported abnormal vaginal bleeding and 45% reported abnormal vaginal discharge. The tests were the Papanicolaou test (both conventional and ThinPrep), a self-administered swab test by Hybrid Capture II for high-risk human papillomavirus (HPV), a test for high-risk HPV from residual PreservCyt medium, fluorescence spectroscopy, and visual inspection of the cervix by a clinician. All women also underwent colposcopy and biopsies as the reference standard. Biopsies showed 12 of 136 women had >/= high-grade squamous intraepithelial lesions (HGSIL). Screening was completed in 5 half-day sessions, the procedures went smoothly, and local cooperation was enthusiastic. Disease prevalence in Xiangyuan and Yangcheng Counties, Shanxi Province, can be estimated at 8.8% (95% CI, 4.5% to 15.0%). Screening 1000-2000 patients would be sufficient to detect a 10% difference in accuracy between diagnostic tests. The proposed large-scale trial is feasible.

Journal Article↗

Trends in the organization of cervical cancer screening.

Cervical cytological screening has been available in the UK for several decades, but has not achieved a significant reduction in the incidence of and mortality from cervical cancer. In this paper we describe past problems of cervical screening, discuss the impact of recent innovations to computerize call and recall, and suggest further improvements for the future.

Appointments and Schedules↗

Advanced cervical cancer therapy: concurrent radiation therapy and cisplatin chemotherapy for advanced cervical cancer--a toxicity report.

It is estimated that in 1988 there will be 12,900 cancers of the uterine cervix, representing 2.6% of cancers in women. Radiation therapy has been the primary mode of therapy/palliation; for the past 15-20 years survival results achieved with radiotherapy have plateaued. Attempts have been made to find agents to use with radiation aimed at decreasing recurrence and increasing survival. Phase II studies suggest cisplatin may be an excellent agent to combine with radiotherapy. This study was performed to evaluate the toxicity of this combination. Between December 10, 1980, and August 29, 1986, nine patients with advanced cervical cancer and poor prognosis and one patient with recurrent disease were enrolled. The Gynecologic Oncology Group (GOG) criteria for adverse effects were used in this study. Hematologic, gastrointestinal, genitourinary, and skin parameters were examined. Most adverse criteria had a score of 2 or less. Grade 2 nausea/vomiting was the most frequent problem. Anemia was the next most frequent and was the most serious problem encountered. Overall, the toxicity was acceptable; therefore it seems appropriate to proceed to larger studies to evaluate efficacy.

Adenocarcinoma↗

[Expression and clinical significance of Pin1 and Cyclin D1 in cervical cancer cell lines and cervical epithelial tissues].

BACKGROUND & OBJECTIVE: Peptidyl-prolyl cis/trans isomerase Pin1 is prevalently overexpressed in human cancers. Up-regulation of Pin1 elevates the expression of Cyclin D1, and plays an important role in tumorigenesis and tumor progression. This study was to investigate the expression and clinical significance of Pin1 and Cyclin D1 in cervical cancer cell lines and cervical epithelial tissues. METHODS: The expression of Pin1 and Cyclin D1 in cervical cancer cell lines HeLa, SiHa, C33a and Caski were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Their expression in 88 samples of cervical tissues, including 10 samples of normal cervix, 21 samples of cervical intraepithelial neoplasia (CIN), and 57 samples of invasive cervical cancer, were detected by immunohistochemistry. RESULTS: The mRNA and protein levels of Pin1 were significantly higher in HeLa, SiHa, C33a, and Caski cells than in normal cervical epithelial tissues (P<0.05). The expression of Pin1 increased progressively along with the disease process from normal cervix to CIN, and to invasive cervical cancer (0%, 47.62%, 64.91%, P<0.05). Pin1 expression had no relation to disease stage (FIGO), pathologic grade, and pelvic lymph node metastasis status (P>0.05). The positive rate of Pin1 was significantly higher in cervical adenocarcinoma than in cervical squamous cell carcinoma (100% vs. 60.0%, P<0.05). In cervical cancer tissues, the overexpression of Pin1 was positively correlated to that of Cyclin D1 (P<0.05). CONCLUSIONS: Pin1 is overexpressed in HeLa, SiHa, C33a and Caski cell lines as well as in cervical cancer tissues. The overexpression of Pin1 is closely related to Cyclin D1 expression in cervical cancer. The aberrant expression of Pin1 and Cyclin D1 might contribute to tumorigenesis of cervical cancer.

Adenocarcinoma↗

HER-2/neu oncogene amplification in cervical cancer studied by fluorescent in situ hybridization.

Oncogene amplification, such as HER-2/neu (C-erbB-2), is a manifestation of genetic instability often associated with the genesis and progression of cancer, including cervical cancer. Oncogene overexpression is traditionally studied using immunohistochemistry. We previously reported studies of oncogene amplification in breast cancer using fluorescent in situ hybridization (FISH), where the data support the hypothesis that HER-2/neu is a prognostic marker of poor outcome. To explore further the possible significance of HER-2/neu oncogene amplification in cervical cancer, we conducted a pilot study of 24 cervical cancer cases. The HER-2/neu FISH probe (Vysis, Inc., Downers Grove, IL) was used to measure gene amplification, with a chromosome 17 centromeric probe as an internal control. Out of 24 cases studied, 23 were informative. Of the 23 informative cases, 2 (8.7%) were found to be amplified. The rest (21 out of 23 or 91.3%) were nonamplified. Both amplified cases were invasive adenocarcinoma. Although the sample size of this pilot study may be somewhat small, the data obtained so far clearly demonstrated that detection of oncogene amplification in cervical cancer is not only feasible but is very sensitive, and suggest that further exploration using a larger sample size may be warranted.

Adenocarcinoma↗

Susceptibility locus for epidermodysplasia verruciformis not linked to cervical cancer in situ.

Cervical cancer is strongly associated with infection by oncogenic forms of human papillomavirus (HPV), mainly HPV 16 and HPV 18. The aim of this study was to test if a locus previously mapped to a region on chromosome 17 qter in patients with epidermodysplasia verucciformis (EV) and psoriasis and considered to be responsible for an increased susceptibility to HPV 5, also is linked to increased HPV susceptibility in cervical cancer in situ. We also wanted to test whether HPV 16 positivity cluster in families with cervical cancer. DNA was extracted from formalin fixed biopsies of 224 affected from 77 families diagnosed with cervical cancer in situ. Two microsatellite markers (D17S939 and D17S802) containing the locus were genotyped and linkage analysis was performed. No linkage was found to any of the two markers, neither when considering all cancer cases as affected nor when only considering HPV 16 infected cancer cases as affected in the analysis. We conclude that the susceptibility locus for HPV 5 infections associated with EV and psoriasis does not seem to affect susceptibility to HPV 16, frequently detected in cervical cancer. Also, positivity for HPV 16 did not show a significant clustering in families.

Epidermodysplasia Verruciformis↗

Association of risk factors for cervical cancer and human papilloma viruses in invasive cervical cancer.

Our study was carried out on 70 patients with invasive squamous carcinoma of the uterine cervix (CC) or invasive adenocarcinoma of the uterine cervix at all stages, admitted to the University Department of Gynecology and/or to the Institute of Oncology in Ljubljana. The patients were not selected by age. A questionnaire on known risk factors in CC was filled in for each of the 70 patients, and two tumor smears were taken for the determination of human papilloma viruses (HPV) 16 and 18 by means of in situ hybridization and polymerase chain reaction (PCR). Each patient also had the serum level of vitamin A determined. The results of our study revealed a correlation between HPV 16 or 18 infection (60:40) and CC. When analysing some already known risk factors, no statistically significant difference could be established for any of the factors studied, except for the age at first birth.

Adenocarcinoma↗

High human papillomavirus oncogene mRNA expression and not viral DNA load is associated with poor prognosis in cervical cancer patients.

PURPOSE: Cervical cancer is now known to be caused by infection with an oncogenic type of the human papillomavirus (HPV). However, little is known about the continued role of HPV once cancer has been established. Here, we describe the quantitative relation between HPV DNA copy number and mRNA expression of the viral oncogenes (E6 and E7) and the prognostic value of both measures in cervical cancer patients. EXPERIMENTAL DESIGN: We studied the number of viral DNA copies and the level of HPV E6/E7 mRNA expression in 75 HPV 16-positive or HPV 18-positive International Federation of Gynecology and Obstetrics stage Ib and IIa cervical cancer patients. Measurements were done with quantitative PCR. DNA copy number analysis was done on pure tumor cell samples enriched with flow sorting. mRNA expression data were compensated for the percentage of tumor cells included. RESULTS: The number of viral DNA copies was not predictive of survival in cervical cancer patients. In contrast, high HPV E6/E7 mRNA expression was strongly related to an unfavorable prognosis (P = 0.006). In a multivariate Cox model for overall survival, including all known prognostic variables and stratified for HPV type, the level of E6/E7 mRNA expression was an independent prognostic indicator, second only to lymph node status. No correlation was observed between DNA copy number and the level of HPV E6/E7 mRNA expression, which reflects that not all DNA copies are equally transcriptionally active. CONCLUSIONS: Cervical cancer patients with high HPV E6/E7 oncogene mRNA expression have a worse survival independently from established prognostic factors.

Adult↗

Whole genome tiling path array CGH analysis of segmental copy number alterations in cervical cancer cell lines.

Cervical cancer is the second most common malignancy in women worldwide, with high risk subtypes of human papillomavirus (HPV) constituting the major etiological agent. However, only a small percentage of women infected by the virus develop disease, suggesting that additional host genetic alterations are necessary for disease progression. In this study we examined the genomes of a panel of commonly used model cervical cancer cell lines using a recently developed whole genome tiling path array for CGH analysis. Detailed analysis of genomic profiles enabled the detection of many novel aberrations, which may have been missed by conventional cytogenetic methods. In total, 27 minimal regions of recurrent copy number alteration were identified that are potentially involved in tumorigenesis. Interestingly, fine mapping of the 3q gain, which is associated with the progression of precursor lesions to invasive cervical cancer, identified a minimal region of alteration harboring genes distinct from previous candidates. Novel regions of gene amplification, including the coamplification of both the Birc and MMP gene clusters on 11q22, were also evident. Lastly, characterization of genomic structure at sites of HPV integration identified the copy number gain of host cellular sequences between the viral-host genomic boundaries in both SiHa and SW756, suggesting a direct role for HPV integration in the development of genetic abnormalities that initiate cervical cancer. This work represents the highest resolution look at a cervical cancer genome to date and offers definitive characterization of the alteration status of these cancer cell lines.

Cell Line, Tumor↗

Oral contraceptives: relations to mammary cancer, benign breast lesions, and cervical cancer.

The results of experimental studies on the relationship of estrogens and oral contraceptives to mammary lesions demonstrate that the type of response obtained depends largely on the species and strain of animal that is employed. A variety of clinical studies has failed to demonstrate that estrogen can cause mammary cancer, this lack of effort correlates with the results obtained in various studies in animals. Similar relationships exist for oral contraceptives, and the clinical data show good agreement in demonstrating that the contraceptive steroids do not have a tumorigenic effect on the human mammary gland. Estrogen can increase the occurrence of cervical cancer in certain strains of mice, but apparently this effect is not observed in other species of animals, including man. The preponderance of data shows that oral contraceptives do not adversely affect the occurence of abnormal Papanicolaou smears, cervical dysplasia, cervical cancer in situ, or invasive cervical cancer.

Breast Diseases↗

Cervical cancer screening.

Cervical cytology has proved to be one of the most successful examples of cancer screening and has resulted in significant decreases in incidence and mortality from invasive cervical cancer in regions in which comprehensive programs have been instituted. A standardized system of reporting abnormal cervical cytology, the Bethesda System has been developed and revised to reflect our current understanding of HPV-related precancers. The Pap smear has been the backbone of cervical cancer screening programs in North America over the past five decades; however, recent advances, including liquid-based cytology, HPV typing, and direct visualization techniques, are proposed to address the inherent weaknesses of cytologic screening in women who are screened. The problem of unscreened and underscreened women exists and accounts for most cases of invasive cancer. Widespread screening hopefully one day will lead to a significant decrease in the mortality of cervical cancer, the second most common female malignancy worldwide. Another means of preventing this disease involves HPV vaccines, which are in development but are not ready for use outside of a clinical trial.

Colposcopy↗

Serological response to HPV 16 in cervical dysplasia and neoplasia: correlation of antibodies to E6 with cervical cancer.

Sera from patients with cervical cancer, cervical intraepithelial neoplasia (CIN) and non-genital cancers, and from healthy individuals, were investigated for antibodies to human papilloma virus (HPV) early proteins E4, E6 and E7 and the major capsid protein LI by Western blot analysis of recombinant HPV proteins. There was a significantly higher prevalence of sera with antibodies to E6 in cervical cancer patients than in healthy individuals or in CIN or non-genital-cancer patients. Antibodies to E7 were detected in 25% of cervical-cancer patients, which is significantly higher than in HPV-associated cervical lesions or in control populations, but not significantly different from the incidence in patients with non-genital cancers. Antibodies to LI were found more frequently in CIN, while antibodies to E4 had a similar prevalence in cervical-cancer, cervical-dysplasia and non-genital-cancer groups, with 24% in the controls. The inability to detect antibodies to E6 and E7 in the majority of cervical-cancer patients limits the application of this methodology to the monitoring of HPV infection and the development of cervical cancer. However, the latter approach may be useful in combination with other assay systems which allow detection of different, including conformational, epitopes of HPV E6 and/or E7 recombinant proteins.

Adult↗

Papillomavirus-like particle vaccines for cervical cancer.

Most cervical cancers are now known to be caused by human papillomavirus (HPV) infections. This provides an opportunity to prevent a major cause of cancer deaths in women through vaccination. Subunit vaccines based upon non-infectious papillomavirus-like particles (VLPs) are attractive candidates to prevent infection by oncogenic HPVs, and clinical trials are now underway. In addition, the strongly immunogenic characteristics of VLPs raise the possibility that they could also serve as vehicles for inducing therapeutic responses against HPV-induced neoplasia and other diseases.

Animals↗

CEBPG demonstrates oncogene functions and modulates the expression of genes involved in cervical cancer related pathways.

BACKGROUND: Cervical cancer is a major cause of female cancer incidence and mortality globally. Targeted therapy shows promise with higher efficacy and fewer side effects, yet effective biomarkers are needed. CEBPG, a bZIP transcription factor, has attracted attention as a potential biomarker and therapeutic target. It promotes tumor growth in various cancers, but its role in cervical cancer is unclear. The aim of this study is to investigate the expression, biological function, and transcriptional regulatory mechanisms of CEBPG in cervical cancer. METHODS: This study analyzed CEBPG expression in cervical cancer using The Cancer Genome Atlas (TCGA) data, overexpressed it in HeLa cells, and conducted proliferation, apoptosis, migration, and invasion experiments. RNA sequencing (RNA-seq) revealed CEBPG's transcriptional regulatory network. RESULTS: Our findings revealed that CEBPG expression was significantly higher in cervical cancer than in normal tissues. Overexpression of CEBPG in HeLa cells significantly enhanced proliferation, migration, and invasion while repressing apoptosis. RNA-seq analysis identified numerous differentially expressed genes (DEGs) enriched in pathways critical for tumorigenesis and progression, such as angiogenesis, cell proliferation, and migration. Bioinformatics analysis identified 27 potential transcriptional targets of CEBPG, several of which were associated with poor prognosis and higher expression in cervical cancer tissues. CONCLUSIONS: CEBPG may contribute to malignant phenotypes in cervical cancer, potentially through the transcriptional regulation of specific target genes. The high expression of CEBPG in cervical cancer and its demonstrated role in promoting malignancy through transcriptional regulation provide novel insights into the molecular mechanisms of cervical carcinogenesis and progression. This offers directions for further exploration of CEBPG as a potential therapeutic target and biomarker.

CEBPG↗

Palliative care in cervical cancer.

1. Cervical cancer is the most frequent cancer in females and also the most frequent among female genital cancers. 2. Ever though the modality of diagnostic procedures for early detection has improved, in fact most of the patients present in the late stages, so the disease is already incurable, and palliative care is really needed. 3. Palliative care is needed not only for the terminally ill patients, but can be started at the time the cancer is diagnosed. 4. Palliative care is a multidisciplinary approach requiring teamwork. 5. Palliative care in Indonesia, especially in Dr. Soetomo Hospital, is a new modality in the fight against cancer, so we suffer many disadvantages, e.g., disability, limitation, lack of experience. However, such problems will stimulate the team to learn more.

Analgesics↗