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

Infection with specific genotypes of human papillomavirus (HPV) has been strongly implicated in cervical carcinogenesis. However, HPV infection alone is insufficient for malignant transformation of the cervical epithelium. An alteration of microsatellite repeats is the result of slippage owing to strand misalignment during DNA replication and is referred to as microsatellite instability (MSI). These defects in DNA repair pathways have been related to human carcinogenesis; however, the role of MSI in the tumorigenesis of cervical cancer remains unclear. The clinical and pathological features of cervical cancers which are MSI-positive have also not been fully characterized. This study investigated the prevalence of MSI in cervical cancer and its relationship to clinico-pathological characteristics and HPV infection. Polymerase chain reaction-based microsatellite assay combined with tissue microdissection was used to examine for MSI in 50 cervical squamous cell carcinomas in Hong Kong women. In addition, the immunohistochemical staining was performed to determine the expression of major DNA mismatch repair genes, hMSH2 and hMLH1. Six cases (12%) displayed a low frequency of MSI (MSL-L) showing MSI at one locus only in 5 loci examined. Seven cases (14%) showed a high frequency of MSI (MSI-H) having MSI at 2 or more loci. Grouping MSI-L and MSI-H cases together as MSI-positive, statistical analysis of HPV infection, tumor grade, clinical stage and clinical status failed to disclose differences between MSI-positive and MSI-negative cases (p > 0.05). However, MSI-H correlated with advanced stage of disease (p < 0.05). Individuals with MSI-H tumors appeared to have reduced overall survival compared to individuals with MSI-L and MSI-negative tumors, but the difference was not statistically significant (p = 0.059). An absence of either MSH2 or MLH1 expression was observed in 2 MSI-L and 4 MSI-H cases, respectively. The results suggest that MSI is present in a subgroup of cervical squamous cell carcinomas, and defects resulting in MSI may be related to tumor progression and possibly poor prognosis in cervical cancer.
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PMID:Microsatellite instability, expression of hMSH2 and hMLH1 and HPV infection in cervical cancer and their clinico-pathological association. 1158 36

Male breast cancer is a relatively rare disease that represents about 1% of all male malignancies. Its genetic basis has received little attention. Allelic imbalance, reflected by change in microsatellite repeat number (MSI) or loss of heterozygosity (LOH), is thought to play an important role in carcinogenesis. In this study we have examined DNA extracted from paraffin tissue from 15 patients treated for male breast cancer, for evidence of such abnormalities, at 20 different loci across the genome. Polymerase chain reaction amplified products of normal and tumor DNA pairs were compared by electrophoresis on Spreadex gels. MSI was detected in 5 patients; at a single site in 2 cases and at 3, 7 and 9 sites in another 3 cases. LOH was seen in 8 cases (53%); at more than one site in 4 of these. Two patients had allelic variation at 56 and 62% of assessable sites. The most unstable loci were D2S441 (33%) and D13S325 (27%). These observations indicate that replication errors and allelic loss characterise male breast cancer tissue in much the same way as they do in women. More studies will be needed to establish whether these are random lesions or whether there are specifically affected sites that occur in both male and female breast cancer.
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PMID:Loss of heterozygosity and microsatellite instability in male breast cancer. 1183 19

The FHIT gene is a putative tumour suppressor gene. In this study, we analysed a set of 50 gastric tumours for alterations of FHIT, and found 38 of 45 tumours (84%) exhibiting loss of heterozygosity (LOH) within the FHIT gene. We used both nested Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) and single step RT-PCR to analyse the FHIT transcripts and found 34 of 39 (87%) tumours and seven of the 11 (64%) corresponding non-cancerous tissues showed low or aberrant expression of FHIT mRNA and the appearance of the aberrant FHIT transcripts depended on the conditions of the RT-PCR. In these aberrant transcripts, frequent deletions and/or insertions were detected by direct sequencing. All breakpoints for deletions and insertions were at splicing sites. All insertions came from the adjacent introns, whose appearance was completely in accordance with the 'GU-AG' rule for pre-mRNA splicing. It may be suggested that an alternative splicing mechanism functions in the formation of these aberrant transcripts. The fragile nature of FRA3B within the FHIT gene could be responsible for the formation of the aberrant mRNA. Negative or reduced Fhit expression was detected in 39 of 50 tumours (78%). Moreover, an association was found between abnormal Fhit expression and positive node status (P=0.012). Thirteen of 48 tumours (27%) displayed microsatellite instability (MSI), among which 10 tumours also showed MSI within the FHIT gene. Furthermore, we detected an association between MSI and negative node status (P=0.02). We conclude that the abnormalities of FHIT, presumably associated with the unstable nature of FRA3B within the FHIT gene, are involved in the carcinogenesis of gastric cancer, and lack of mismatch repair (MMR) could possibly promote its alteration in a subset of gastric tumours.
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PMID:High frequency of LOH, MSI and abnormal expression of FHIT in gastric cancer. 1191 57

Genetic analytical techniques were carried out to identify mutations in adenomatous polyposis coli (APC) gene and K-ras oncogene in colorectal tumourigenesis. These two genes are said to be early mutation genes among other mutation genes that constitute the model for colorectal tumourigenesis. To do this analysis, DNA was isolated from colorectal formalin fixed paraffin-embedded tumour tissue sections. The sections were deparaffinised, digested in proteinase-K, followed by DNA isolation. The DNA was amplified by Polymerase Chain Reaction (PCR), screened by using Denaturing Gradient Gel Electrophoresis (DGGE) or Single Strand Conformation Polymorphism (SSCP) and then sequenced. These results lend support to the fact that colorectal cancer and indeed cancer in general develops through a multi-step process; also that accumulation of genetic mutations underlie the development of neoplasia. We are in the process of extending this study to cancer of oesophagus to see if a similar or parallel model of carcinogenesis holds and in what sequence it is.
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PMID:Lessons learned from colorectal model of tumourigenesis. 1195 50

Molecular-based diagnosis ofthyroid carcinomas can be more easily establishedby utilizing specific mRNAs that are expressed in a restricted manner in cancer tissues. Accordingly, several cancer-specific mRNAs in thyroid carcinomas have been identified by means of sequence specific-differential display (SS-DD), serial analysis of gene expression (SAGE) and other new techniques. By using these cancer-specific mRNAs, some new methods of preoperative diagnosis of thyroid carcinomas have been developed. In one such method, Aspiration Biopsy-Reverse Transcription-Polymerase Chain Reaction (ABRP), RNA is extracted from leftover cells within the needle used for fine needle aspiration biopsies (FNABs), thereby allowing cytological and molecular-based diagnoses to be performed simultaneously. ABRP provides both RNA information and a cytological diagnosis without further invasion to the patient. By ABRP detection of cancer-specific mRNAs, papillary, anaplastic and medullary carcinomas and a part of malignant lymphomas can be accurately diagnosed preoperatively. It remains to be clarified why cancer-specific mRNAs, especially those that are overexpressed in fetal tissues, can clearly distinguish benign tissues from carcinomas, while genomic alternations, such as mutations in the RAS or P53 gene cannot. Further, the widely accepted hypothesis of multi-step carcinogenesis cannot explain some of the clinical and experimental findings of thyroid carcinomas. Considering these facts, we propose a novel hypothesis of thyroid carcinogenesis, the "germ-cell carcinogenesis" hypothesis, in which cancer cells derive from the remnants of fetal thyroid germ cells (thyroblasts) instead of normal thyroid follicular cells.
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PMID:Cancer-specific mRNAs in thyroid carcinomas: detection, use, and their implication in thyroid carcinogenesis. 1208 Dec 46

Organisms control the specificity and frequency with which they mutate via their complement of proteins. The mismatch repair (MMR) proteins correct errors after they are made. The DNA polymerases of the cell determine the response to damaged DNA which has not been repaired by excision. Polymerase action can be considered as consisting of three main steps: addition of a base, proofreading of the added nucleotide and elongation. Each of these steps is kinetically complex and can be modulated. The modulation accounts for different behaviors of organisms in response to stress. The recent findings of DNA polymerases with properties appropriate for dealing with damaged DNA may help to account for the phenomenon of spontaneous mutation and for the hypermutability associated with immunoglobulin maturation and carcinogenesis.
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PMID:The "A" rule revisited: polymerases as determinants of mutational specificity. 1250 59

During the last few decades a substantial amount of evidence has accumulated proving that the abrogation of the normal p53 pathway is a critical step in the initiation and progression of tumors. Decoding the genetic mechanisms involved in carcinogenesis requires screening for consistent genetic tumor alterations, including those concerning the p53 gene. Thus, practical, efficient, and inexpensive techniques for accurate determination of p53 mutational status are needed. Polymerase chain reaction/single-strand conformation polymorphism (PCR-SSCP) analysis is considered to be a useful tool to investigate the role of the p53 gene in the development and progression of human cancers. The sensitivity of the method can be increased considerably by varying the experimental conditions. Here we demonstrate a scheme of PCR-SSCP optimization for detection of p53 gene mutations of patients with various cancers. Optimal conditions for PCRSSCP of p53 exons 4-9 are reported. Such PCR-SSCP optimization could allow an increase in the sensitivity and reproducibility of the technique and facilitates screening of large series of patients to assess the clinical significance of p53 mutations in human cancers. Using the optimized PCR-SSCP analysis we screened Bulgarian patients with invasive breast cancer for p53 gene mutations and registered a 33.33% frequency of mutations. To date, there are no data concerning the p53 status of Bulgarian breast cancer patients. Screening for p53 gene mutations enables an accurate and routine determination of the p53 status of patients with cancer and may be applied in clinical oncology to cancer diagnosis, prediction of prognosis and response to treatment.
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PMID:Optimized polymerase chain reaction-based single-strand conformation polymorphism analysis of p53 gene applied to Bulgarian patients with invasive breast cancer. 1464 33

A novel mutagenic compound, 9-(4'-aminophenyl)-9H- pyrido[3,4-b]indole (aminophenylnorharman, APNH), is shown to be formed by the in vitro enzymatic reaction of 9H-pyrido[3,4-b]indole (norharman) and aniline. APNH generates DNA adducts (dG-C8-APNH), and is potently genotoxic to bacteria and mammalian cells. APNH has also been demonstrated to be formed in vivo from norharman and aniline, and suggested to be a new type of endogenous mutagenic compound. To determine its carcinogenic activity, long-term administration of APNH was investigated in 93 male and 90 female F344 rats. Rats were fed diets containing 0, 20 or 40 p.p.m. from 7 weeks of age. All animals were killed after 85 weeks treatment and necropsy was performed. Hepatocellular carcinomas (HCCs) were induced at incidences of 10 and 79% in male rats fed 20 and 40 p.p.m. APNH, and 34% in female rats fed 40 p.p.m. of APNH, respectively. In addition, colon adenocarcinomas were found at incidences of 3 and 9% in male rats, and 4 and 13% in female rats fed 20 and 40 p.p.m. of APNH, respectively. Other tumors, including thyroid carcinomas and mononuclear cell leukemia, were also seen in rats fed APNH. Polymerase chain reaction-single strand conformation polymorphism analysis revealed beta-catenin gene mutations in 24% of HCCs and K-ras, beta-catenin and Apc gene mutations were found in 22, 44 and 33% of colon cancers induced by APNH, respectively. Most mutations occurred at G:C base pairs. beta-Catenin protein accumulations in the nucleus and cytoplasm were also revealed in both liver and colon tumors. Thus, APNH induced liver and colon cancers with K-ras, beta-catenin and Apc gene mutations in F344 rats.
Carcinogenesis 2004 Oct
PMID:Carcinogenicity of aminophenylnorharman, a possible novel endogenous mutagen, formed from norharman and aniline, in F344 rats. 1514 89

Esophageal carcinoma is characterized by a widely ranged incidence variation among the different geographic regions. Anyang is a county in Henan Province of North China with the highest prevalence of esophageal carcinoma. Human papillomavirus (HPV) infection has been linked to the etiology of esophageal cancer in this area. In this study, we investigated correlations of the polymorphisms at low molecular weight polypeptide (LMP) and transporters with antigen processing (TAP) genes, with the risk of esophageal carcinoma. DNA extracted from either tumor specimens or esophageal epithelial cells was used to test HPV infection. Peripheral blood lymphocyte DNA was used for LMP/TAP genotyping. Polymerase chain reaction was performed to analyze HPV infection and LMP/TAP gene polymorphisms. The combined effect of LMP/TAP gene polymorphisms and HPV infection on esophageal carcinoma was analyzed by using unconditional logistic regression models. The TAP2 codons 379 isoleucine carriers and LMP7 codons 145 lysine carriers were found to be more susceptible to esophageal carcinoma (OR = 2.74, 95% CI = 1.15-6.49, P = 0.023 for TAP2; OR = 2.19, 95% CI = 1.09-4.37, P = 0.027 for LMP7). Patients carrying homozygous LMP7/TAP2 haplotype C, which contained the glutamine at LMP7 codons 145 and the isoleucine at TAP2 codons 379, were more prone to develop esophageal carcinoma (OR = 2.96, 95% CI = 1.13-7.81, P = 0.027). An additive effect on the risk of esophageal carcinoma development was found among individuals carrying LMP7/TAP2 haplotype C and infected by HPV (OR = 4.33, 95% CI = 2.53-7.42, P < 0.0001). LMP7/TAP2 haplotype C may act as the risk factor in esophageal carcinoma development and it may influence the tumorigenesis in HPV infected individuals.
Carcinogenesis 2005 Jul
PMID:LMP7/TAP2 gene polymorphisms and HPV infection in esophageal carcinoma patients from a high incidence area in China. 1577 87

The effects of 1,25-dihydroxyvitamin D3 are mediated by binding to a specific intracellular vitamin D receptor (VDR), which has been identified in a variety of tissues. Certain polymorphisms in the VDR gene have been associated with various neoplasms. For this purpose, we studied whether VDR TaqI or FokI genotype are associated with serum 25-hydroxyvitamin D3 in 52 controls and 26 patients with colorectal cancer. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP), and agarose gel electrophoresis tecniques were used to detect these polymorphisms. We measured 25-hydroxyvitamin D3 serum levels by ELISA. The frequencies of the FF, Ff and ff genotypes were 73.1%, 11.5%, 15.4% in colorectal cancer patients and 38.5%, 59.6%, 1.9% in healthy controls, respectively. We observed the T allele in 50% and 58.7%, and the t allele in 50% and 41.3% of colorectal cancer patients and the control group, respectively. In patients with colorectal cancer who have TT genotype, serum 25-hydroxyvitamin D3 level was lower than those with Tt/tt genotype (p:0.016). The frequency of subjects with TTFf or TtFf genotype in colorectal cancer patients was very low compared with all other genotypes (OR = 0.112; 95%CI 0.030-0.419). These data suggest that VDR TtFf or TTFf genotypes may protect against colorectal carcinogenesis. However, further studies are necessary to confirm these findings.
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PMID:Investigation of the VDR gene polymorphisms association with susceptibility to colorectal cancer. 1724 90


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