Biomedical subjects

M von Knebel Doeberitz

Publications and source records attributed to M von Knebel Doeberitz.

At least 19 recordsLinked to original sources

PubMed2006

Overexpression of a member of the pentraxin family (PTX3) in human soft tissue liposarcoma.

A unique feature of human soft tissue liposarcoma is a stable (12;16)(q13;p11) translocation observed mainly in myxoid and roundcell liposarcomas. This translocation results in FUS/CHOP fusion transcripts with a corresponding oncogenic protein. We hypothesised that genes downstream of FUS/CHOP might serve as attractive candidates for novel tumour associated antigens. Among a panel of analysed genes, only pentraxin related gene (PTX3) demonstrated high expression in liposarcomas as compared to normal tissues. The analysis of RNA and protein expression demonstrated concordant results. However, the level of RNA and protein overexpression did not correlate in all cases. Finally, PTX3 expression was not related to presence of a FUS/CHOP fusion transcript within the liposarcoma tissues. PTX3 has been associated with adipocyte differentiation and now, additionally, is characterised by a markedly increased expression in human soft tissue liposarcoma. This finding mandates further research efforts to clarify the exact role of PTX3 in liposarcoma oncogenesis.

Adult↗

PubMed2005

Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases.

Colorectal carcinomas (CRCs) with high microsatellite instability (MSI-H) share clinicopathological features distinctly different from their microsatellite stable (MSS) counterparts. Unlike MSS cancers, MSI-H CRCs occur predominantly in the right-sided colon and are often characterised by a strong lymphocyte infiltration. A poor differentiation pattern is found in most MSI-H CRCs, even though patients with MSI-H carcinomas seem to have a significantly longer survival after surgical resection. To clarify which factors contribute to the obvious paradoxon of a more favourable prognosis of MSI tumours, several clinical and histopathological features as well as the microsatellite status were evaluated in 120 colorectal cancer cases fulfilling clinical criteria (Bethesda) indicative for familial colorectal cancer. Microsatellite instability status and lymphocyte infiltration were related to tumour stage and patients' follow-up. Statistical analysis confirmed well-known relations, such as enhanced lymphocyte infiltration accompanied by Crohn's like reaction (CLR) in MSI-H cancers (CLR+ in 27 out of 47 MSI-H vs 14 out of 71 MSS CRCs, P<0.001). However, after stratification for depth of local invasion and penetration of the primary tumour, T3 tumours displaying MSI had a significantly lower rate of distant metastases (M1 in four out of 35 MSI-H vs 20 out of 41 MSS CRCs, P<0.001). A similar tendency was observed for CLR-positive CRCs (M1 in six out of 29 CLR+ vs 17 out of 45 CLR- CRCs, P=0.13). In a logistic regression model, the MSI-H phenotype and the presence of CLR were independent predictors of a low UICC stage (P=0.006 and 0.04, respectively). These data, together with the recent definition of highly immunogenic neo-antigens expressed in MSI-H tumour cells, suggest that MSI-H CRCs elicit a protective host response that may prevent metastasis formation.

Adult↗

PubMed2005

[Molecular pathogenesis of cervical cancer and its first steps].

Specific types of the human papillomaviruses (high risk human papillomaviruses) play an essential role in the pathogenesis of cervical cancer. Although infections by these viruses are very common in the general population, only few result in clinically relevant lesions. Continuous and deregulated expression of two viral oncoproteins E6 and E7 in basal or parabasal cells are required to induce and maintain neoplastic growth. In the course of an acute HPV-infection these genes are exclusively expressed in cell cycle arrested, terminally differentiated cells in the intermediate or superficial layers of the epithelium. Accidental activation of these genes in proliferating cells in the basal or parabasal cell layers results in interference with the cell cycle regulation, disturbances of the mitotic spindle apparatus and centrosome functions. This results in numerical and structural chromosome aberrations, chromosomal instability, increasing aneuploidy and initiates cervical carcinogenesis. The deregulated expression of the viral oncogene E7 is indicated by strong over-expression of the cellular p16(INK4a) gene product. This finding may have significant influence on novel strategies in cervical cancer diagnosis and screening. This review summarizes the basic molecular mechanisms of how papillomaviruses contribute to cellular transformation and how this can influence future diagnostic applications.

Cell Cycle↗

PubMed2005

The p53 codon 72 variation is associated with the age of onset of hereditary non-polyposis colorectal cancer (HNPCC).

The polymorphic variants at codon 72 of the p53 gene were shown to be functionally distinct in vitro, whereby the arginine (arg) variant induces apoptosis more efficiently than the proline (pro) variant. From the evidence that the DNA mismatch repair system and p53 interact to maintain genomic integrity, we hypothesized that the codon 72 variation may influence the age of onset of disease in HNPCC patients. We tested 538 patients for p53 codon 72 variants, including 167 unrelated patients with pathogenic germline mutations in MSH2 or MLH1 and colorectal carcinoma as first tumour, 126 patients with sporadic microsatellite stable colorectal cancers, and 245 healthy controls. The median age of onset was 41, 36, and 32 years for MSH2 or MLH1 mutation carriers with arg/arg, arg/pro, and pro/pro genotypes, respectively. The log rank test revealed significant differences in the age of onset between arg/arg and pro/pro individuals (p = 0.0002) and in arg/pro versus arg/arg and pro/pro individuals (p = 0.0026 and p = 0.0217, respectively). A Cox regression model indicated an additive mode of inheritance. No significant differences in age of onset were observed among different genotype carriers with microsatellite stable tumours. Our results suggest that p53 codon 72 genotypes are associated with the age of onset of colorectal carcinoma in a mismatch repair deficient background in a dose dependent manner. These findings may be relevant for preventive strategies in HNPCC.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Hematogenous tumor cell dissemination during colonoscopy for colorectal cancer.

BACKGROUND: It has long been suspected that mechanical influences may enhance the release of viable colorectal cancer cells into the circulation. The objective of this study was to determine the extent of hematogenous tumor cell spread in colorectal cancer patients during colonoscopy. METHODS: Peripheral venous blood samples were taken before and after colonoscopy from 44 patients with colorectal cancer. Blood samples were examined using a reverse-transcriptase polymerase chain reaction assay to amplify cytokeratin 20 transcripts. RESULTS: Eleven patients with colorectal cancer displayed circulating tumor cells before and after colonoscopy (25%), whereas tumor cells were detected in six of 44 patients (14%) only after the procedure (p = 0.03, McNemar's test: tumor cell detection before after colonoscopy). All control samples consistently tested negative. CONCLUSIONS: Mechanical forces may result in enhanced release of viable colorectal cancer cells into the circulation; however, the clinical significance of these results needs to be clarified.

Adenocarcinoma↗

PubMed2004

[Viral carcinogenesis of head and neck tumors].

Approximately 15% of malignant diseases are caused by infectious agents. Human papilloma viruses (HPV) can be frequently found in oral carcinomas, especially tonsillar cancer. A group of HPV-infected tumors shows clear signs for a virally induced transformation process: high-risk HPVs can be detected in all tumor cells, the viral oncogenes E6 and E7 are constantly expressed and lead to upregulation of cellular p16(INK4a), a cyclin-dependent kinase inhibitor. The patients frequently lack typical risk factors associated with head and neck cancers such as drinking and smoking. Epstein-Barr viruses (EBV) are associated with lymphoproliferative disorders and cause nasopharyngeal carcinoma (NPC). NPC has a high incidence in some East Asian countries. In this review, the molecular pathogenesis of HPV- and EBV-associated malignancies are described and the clinical relevance of the presented findings is discussed.

Epstein-Barr Virus Infections↗

PubMed2004

Detection of disseminated tumour cells as a potential surrogate-marker for monitoring palliative chemotherapy in colorectal cancer patients.

In a pilot study the effect of palliative chemotherapy on the detection rates of circulating tumour cells in peripheral venous blood of stage IV colorectal cancer patients was investigated. The results indicate a recruitment of tumour cells during chemotherapy and suggest a poorer survival for tumour cell positive patients. Circulating tumour cells have been shown to be a potential prognostic factor in patients who undergo curative resection for colorectal cancer. The effect of chemotherapy on the detection rates of disseminated tumour cells in blood has not yet been adequately investigated. Objective of this pilot-study was to analyze circulating tumour cells in peripheral venous blood of colorectal cancer patients undergoing chemotherapy in order to evaluate its potential value as a surrogate-marker for predicting clinical outcome after chemotherapy. Our hypothesis was that chemotherapy results in a reduction of the detection rates of circulating tumour cells in colorectal cancer patients. Forty-two Stage IV patients were examined at three different time points before and during palliative chemotherapy for the presence of disseminated tumour cells, using a previously described RT-PCR-assay for cytokeratin 20. 80.1% of the patients showed disseminated tumour cells at least once. Before chemotherapy, patients with multi-organ metastases were positive in 62.5%, patients with locally limited disease in only 14.3%. After the first chemotherapy, the detection rates in the latter group increased to 62.5%, for all patients in the same time from 46.3% to 57.5%. Clinical therapy responders showed an increase in the detection rates from 28.5% before to 71.4% after chemotherapy. In contrast, chemotherapy had no effect on tumour cell detection rates of patients with progressive disease (57% before vs. 60% after therapy). Patients with detected circulating tumour cells showed a shorter overall survival than patients without circulating tumour cells (83 vs. 53 weeks). Clinical therapy responders on average lived only 3 weeks longer than non-responders. In contrast to the original hypothesis, our data suggest a recruiting of circulating tumour cells during chemotherapy in advanced colorectal cancer. Further investigations are needed to clarify the potential role of circulating tumour cells for monitoring chemotherapy in these patients.

Antineoplastic Agents↗

PubMed2002

New markers for cervical dysplasia to visualise the genomic chaos created by aberrant oncogenic papillomavirus infections.

Extensive research over the past 20 years provided strong evidence that persistent infections with high risk type human papillomaviruses (HR-HPVs) cause cervical cancer. However, depending on their age, more than 20% of normal women are infected with these viruses and only very few develop clinically relevant dysplastic lesions or even cancer. During an acute HPV infection, expression of viral genes, in particular the viral E6 and E7 oncogenes is restricted to differentiated epithelial cells, which lost the capability to replicate their genomes and are therefore at no further risk for acquiring functionally relevant mutations upon genotoxic damage. High grade cervical dysplasia, however, is initiated by deregulated expression of viral oncogenes in replicating epithelial stem cells. Here, the E6-E7 gene products submerge control of the cell cycle and mitotic spindle pole formation through complex interactions with various cellular protein complexes and induce severe chromosomal instability. The detailed molecular analysis of these interactions allowed to define new biomarkers for dysplastic cervical cells. E7 for example induces increasing expression of the cyclin dependent kinase inhibitor p16(ink4a) in dysplastic cells. This can be used to identify dysplastic cells in histological slides, cytological smears or samples taken for biochemical analyses with an yet unmet fidelity. Detection of specific viral mRNAs derived from integrated HPV genomes in advanced precancers can be used to identify lesions with a particularly high risk for progression into invasive carcinomas (APOT assay). These new markers will result in a modified classification of cervical precancers and improved screening assays. Here, we review the basic concept and potential clinical applications of these new developments.

Biomarkers, Tumor↗

PubMed2001

Frameshift peptide-derived T-cell epitopes: a source of novel tumor-specific antigens.

Microsatellite instability (MSI) caused by defective DNA mismatch repair (MMR) is a hallmark of hereditary nonpolyposis colorectal cancers (HNPCC) but also occurs in about 15% of sporadic tumors. If instability affects microsatellites in coding regions, translational frameshifts lead to truncated proteins often marked by unique frameshift peptide sequences at their C-terminus. Since MSI tumors show enhanced lymphocytic infiltration and our previous analysis identified numerous coding mono- and dinucleotide repeat-bearing candidate genes as targets of genetic instability, we examined the role of frameshift peptides in triggering cellular immune responses. Using peptide pulsed autologous CD40-activated B cells, we have generated cytotoxic T lymphocytes (CTL) that specifically recognize HLA-A2.1-restricted peptides derived from frameshift sequences. Among 16 frameshift peptides predicted from mutations in 8 different genes, 3 peptides conferred specific lysis of target cells exogenously loaded with cognate peptide. One peptide derived from a (-1) frameshift mutation in the TGFbetaIIR gene gave rise to a CTL bulk culture capable of lysing the MSI colorectal cancer cell line HCT116 carrying this frameshift mutation. Given the huge number of human coding microsatellites and assuming only a fraction being mutated and encoding immunologically relevant peptides in MSI tumors, frameshift protein sequences represent a novel subclass of tumor-specific antigens. It is tempting to speculate that a frameshift peptide-directed vaccination approach not only could offer new treatment modalities for existing MSI tumors but also might benefit asymptomatic at-risk individuals in HNPCC families by a prophylactic vaccination strategy.

Amino Acid Sequence↗

PubMed2001

Systematic identification of genes with coding microsatellites mutated in DNA mismatch repair-deficient cancer cells.

Microsatellite instability (MSI) caused by deficient DNA mismatch-repair functions is a hallmark of cancers associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome but is also found in about 15% of all sporadic tumors. Most affected microsatellites reside in untranslated intergenic or intronic sequences. However, recently few genes with coding microsatellites were also shown to be mutational targets in MSI-positive cancers and might represent important mutation targets in their pathogenesis. The systematic identification of such genes and the analysis of their mutation frequency in MSI-positive cancers might thus reveal major clues to their functional role in MSI-associated carcinogenesis. We therefore initiated a systematic database search in 33,595 distinctly annotated human genes and identified 17,654 potentially coding mononucleotide repeats (cMNRs) and 2,028 coding dinucleotide repeats (cDNRs), which consist of n > or = 6 and n > or = 4 repeat units, respectively. Expression pattern and mutation frequency of 19 of these genes with the longest repeats were compared between DNA mismatch repair-deficient (MSI(+)) and proficient (MSS) cancer cells. Instability frequencies in these coding microsatellite genes ranged from 10% to 100% in MSI-H tumor cells, whereas MSS cancer cells did not show mutations. RT-PCR analysis further showed that most of the affected genes (10/15) were highly expressed in tumor cells. The approach outlined here identified a new set of genes frequently affected by mutations in MSI-positive tumor cells. It will lead to novel and highly specific diagnostic and therapeutic targets for microsatellite unstable cancers.

Adenocarcinoma↗

PubMed2001

Overexpression of p16(INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri.

Cytological screening for cervical cancer or its precursors using Papanicolaou's smear test (Pap test) has been highly efficient to reduce the morbidity and mortality of cervical cancer. However, evaluation of the Pap test relies on subjective diagnostic parameters and is affected by a high rate of false-positive and false-negative results. More objective diagnostic parameters to identify truly dysplastic or neoplastic cells in cervical smears as well as in cervical biopsy samples would therefore avoid insecurity for many patients and the high screening costs associated with repeated testing. Cervical dysplasia is induced by persistent infections through high-risk types of human papillomaviruses (HPVs). Outgrowth of dysplastic lesions is triggered by increasing expression of two viral oncogenes, E6 and E7, which both interact with various cell cycle-regulating proteins. Among these is the retinoblastoma gene product pRB, which is inactivated by E7. pRB inhibits transcription of the cyclin-dependent kinase inhibitor gene p16(INK4a). Increasing expression of the viral oncogenes in dysplastic cervical cells might thus be reflected by increased expression of p16(INK4a). In line with this hypothesis, we observed marked overexpression of p16(INK4a) in all cervical intraepithelial neoplasm (CIN) I lesions (n = 47) except those associated with low-risk HPV types (n = 7), all CIN II lesions (n = 32), all CIN III lesions (n = 60) and 58 of 60 invasive cervical cancers. In contrast, no detectable expression of p16(INK4a) was observed in normal cervical epithelium (n = 42), inflammatory lesions (n = 48) and low-grade cervical lesions (CIN I) associated with low-risk HPV types (n = 7). Dysplastic cells could also be identified in cervical smears using a specific p16(INK4a) monoclonal antibody. These data demonstrate that p16(INK4a) is a specific biomarker to identify dysplastic cervical epithelia in sections of cervical biopsy samples or cervical smears.

Biomarkers, Tumor↗

PubMed2001

Sensitive detection of rare cancer cells in sputum and peripheral blood samples of patients with lung cancer by preproGRP-specific RT-PCR.

RT-PCR-based amplification of transcripts expressed in cancer but not in normal non-neoplastic cells is increasingly used for the sensitive detection of rare disseminated or exfoliated cancer cells to improve cancer staging and early detection protocols. However, these assays are frequently hampered by false-positive test results due to low-level transcription of the marker genes in normal cells. To overcome these limitations, target transcripts have to be identified that are tightly suppressed in normal non-neoplastic tissues, whereas they should be actively transcribed in the respective cancer cells. Here, we tested RT-PCR assays for 7 neuroendocrine marker transcripts including NCAM, PGP 9.5, gastrin, gastrin receptor, synaptophysin, preprogastrin-releasing peptide (preproGRP) and GRP-receptor to detect rare exfoliated tumor cells in peripheral venous blood and sputum samples from patients with lung cancer. Among these preproGRP RT-PCR was the only assay with which illegitimate transcription in blood or sputum samples from healthy donors or patients with unrelated diseases did not interfere. However, it reproducibly detected up to 10 small-cell lung cancer cells diluted in either 10 ml blood or 5 ml sputum samples. Single blood and sputum samples were collected directly before diagnostic bronchoscopy from 175 patients suspected to have lung cancer. Twenty-six of these had small-cell lung cancer (SCLC). Thereof, 13 patients (50%) tested positive in the blood sample and 5 of 23 patients (22%) tested positive in the sputum sample. Moreover, among 92 patients with non-small-cell lung cancer (NSCLC) 25 patients (27%) had disseminated cancer cells in peripheral blood. Amplification of preproGRP transcripts from clinical samples is a sensitive and specific assay to detect disseminated or exfoliated lung cancer cells either in peripheral blood or sputum samples.

Biomarkers, Tumor↗

PubMed2001

Detection of integrated papillomavirus sequences by ligation-mediated PCR (DIPS-PCR) and molecular characterization in cervical cancer cells.

Human papillomavirus (HPV) genomes usually persist as episomal molecules in HPV associated preneoplastic lesions whereas they are frequently integrated into the host cell genome in HPV-related cancers cells. This suggests that malignant conversion of HPV-infected epithelia is linked to recombination of cellular and viral sequences. Due to technical limitations, precise sequence information on viral-cellular junctions were obtained only for few cell lines and primary lesions. In order to facilitate the molecular analysis of genomic HPV integration, we established a ligation-mediated PCR assay for the detection of integrated papillomavirus sequences (DIPS-PCR). DIPS-PCR was initially used to amplify genomic viral-cellular junctions from HPV-associated cervical cancer cell lines (C4-I, C4-II, SW756, and HeLa) and HPV-immortalized keratinocyte lines (HPKIA, HPKII). In addition to junctions already reported in public data bases, various new fusion fragments were identified. Subsequently, 22 different viral-cellular junctions were amplified from 17 cervical carcinomas and 1 vulval intraepithelial neoplasia (VIN III). Sequence analysis of each junction revealed that the viral E1 open reading frame (ORF) was fused to cellular sequences in 20 of 22 (91%) cases. Chromosomal integration loci mapped to chromosomes 1 (2n), 2 (3n), 7 (2n), 8 (3n), 10 (1n), 14 (5n), 16 (1n), 17 (2n), and mitochondrial DNA (1n), suggesting random distribution of chromosomal integration sites. Precise sequence information obtained by DIPS-PCR was further used to monitor the monoclonal origin of 4 cervical cancers, 1 case of recurrent premalignant lesions and 1 lymph node metastasis. Therefore, DIPS-PCR might allow efficient therapy control and prediction of relapse in patients with HPV-associated anogenital cancers.

Base Sequence↗

PubMed2001

The nonsteroidal anti-inflammatory drugs aspirin and indomethacin attenuate beta-catenin/TCF-4 signaling.

Increasing epidemiological and experimental evidence implicates non-steroidal anti-inflammatory drugs (NSAIDs) as anti-tumorigenic agents. The precise mechanisms whereby NSAIDs exert their anti-neoplastic effects remain poorly understood. Studies from hereditary and sporadic colorectal cancer (CRC) patients suggest that NSAIDs may interfere with initiating steps of carcinogenesis, i.e. disturbances within the beta-catenin signaling pathway. We therefore investigated beta-catenin/TCF signaling in response to aspirin or indomethacin, respectively, in four CRC cell lines (SW948, SW480, HCT116, LoVo). Both, aspirin and indomethacin inhibited transcription of a beta-catenin/TCF-responsive reporter gene in a dose dependent manner. In addition, the beta-catenin/TCF transcriptional target cyclin D1 was downregulated by both drugs. Endogenous beta-catenin levels remained unaffected by either drug. Moreover, indirect immunofluorescence studies revealed no significant changes of subcellular beta-catenin localization in either cell line after NSAID treatment. Likewise, binding of the beta-catenin/TCF complex to its specific DNA-binding sites was not altered, as demonstrated by electrophoretic mobility shift assay (EMSA) of nuclear extracts derived from NSAID treated cells. These results strongly suggest that aspirin and indomethacin attenuate the transcription of beta-catenin/TCF-responsive genes, by modulating TCF activity without disrupting beta-catenin/TCF complex formation.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2001

Comparative analysis of tumor cell dissemination in mesenteric, central, and peripheral venous blood in patients with colorectal cancer.

BACKGROUND: Metastatic disease in colorectal cancer results from hematogenic dissemination of tumor cells. This dissemination can be explained by 2 concepts: (1) regional spread of tumor cells via portal venous drainage into the liver as the first site of metastasis and (2) early spread of tumor cells into central and peripheral venous blood as evidence of systemic hematogenic tumor cell dissemination. HYPOTHESIS: Tumor cell detection in different blood compartments could help to understand the predominant pattern of hematogenic tumor cell dissemination in colorectal cancer. DESIGN: Prospective consecutive series. SETTING: University hospital. PATIENTS AND METHODS: Mesenteric, central, and peripheral venous blood samples from 40 patients with colorectal cancer were examined by cytokeratin 20 reverse transcriptase polymerase chain reaction. MAIN OUTCOME MEASURES: Sensitivity and specificity of cytokeratin 20 reverse transcriptase polymerase chain reaction, and frequency of tumor cell detection in different blood compartments. RESULTS: Tumor cells were found in mesenteric venous blood of 20 of 40 patients, central venous blood of 6 of 40 patients, and peripheral venous blood of 2 of 19 patients. The detection rate in mesenteric venous blood was significantly higher than that in central and peripheral venous blood (P<.001). CONCLUSIONS: The significantly higher detection rate in mesenteric venous blood emphasizes the importance of the filter function of the liver for circulating tumor cells in portal venous blood. Tumor cell detection in central and peripheral venous blood, however, shows that this filtering process is limited and indicates early systemic hematogenic tumor cell dissemination in colorectal cancer.

Biomarkers, Tumor↗

PubMed2001

Molecular tools in the detection of micrometastatic cancer cells--technical aspects and clinical relevance.

The frequent failure to reduce the mortality due to epithelial cancers by common medical intervention results primarily from early dissemination of cancer cells, which is missed by conventional diagnostic procedures used for tumor staging. Individual carcinoma cells present in regional lymph nodes, blood or distant organs (e.g., bone marrow) can be detected by sensitive immunologic or molecular methods. Here, we review recently developed molecular assays for the detection of individual micrometastatic cancer cells and their clinical application in patients with epithelial tumors.

Biomarkers, Tumor↗

PubMed2001

Evaluation of Bethesda guidelines in relation to microsatellite instability.

PURPOSE: The Bethesda guidelines were developed for selection of patients whose tumors should be tested for high microsatellite instability. This study examined the validity of the different Bethesda criteria in relation to microsatellite instability status to simplify their use in clinical practice. METHODS: A total of 164 patients with colorectal or hereditary nonpolyposis colorectal cancer-associated cancers were registered on the basis of the Amsterdam criteria without age limitations (11 cases), multiple tumors (2 cases), the accumulation of colorectal cancer in the family (no first-degree relatives affected or the index patient's age up to 50 years; 45 cases), an early age at onset up to 50 years (13 cases), morphologic and histopathologic manifestations (right-sided colorectal cancer, mucinous undifferentiated histology; 1 case), and the Bethesda criteria (92 cases). The microsatellite instability status of tumors was determined using the International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer marker reference panel. RESULTS: When applying all Bethesda criteria, high microsatellite instability tumors were identified in our hereditary nonpolyposis colorectal cancer registry with a sensitivity of 87 percent. Twenty-nine percent (27/92) of the Bethesda-positive patients displayed high microsatellite instability compared with 6 percent of patients (4/72) not meeting these criteria (P < 0.001). Only Bethesda Criteria 1, 3, and 4 showed a significantly different distribution of the microsatellite instability status when compared with those of the remaining patients registered (P < or = 0.001). These three criteria detected high microsatellite instability tumors in 48 percent (10/21), 50 percent (18/36), and 31 percent (21/67) of patients, respectively. When applying these criteria only, a cumulative detection rate of 77 percent of all (24/31) high microsatellite instability cases was found, thereby identifying 89 percent of high microsatellite instability tumors among the Bethesda-positive patients. Patients matching Criteria 1, 3, and 4 frequently showed hMSH2 or hMLH1 germline mutations and tumor-specific loss of protein expression. CONCLUSION: In our hereditary nonpolyposis colorectal cancer registry the complete Bethesda criteria showed the highest sensitivity to identify patients with high microsatellite instability tumors. However, for general medical practice outside academic centers, three criteria are reasonably accurate for adequate high microsatellite instability tumor selection.

Adult↗

PubMed2001

[Aspects of molecular pathogenesis of cervical cancer in establishing new tumor markers for early detection and diagnosis].

The mortality rates of cervical cancer could be drastically reduced by the implementation of population wide cytological screening test for women (Pap-Test). However, these screening tests are hampered by high rates of false positive and false negative results, pointing to the urgent demand for improved screening technologies. High risk human papillomaviruses were identified as the causal agents of cervical cancer. The detection of the viral infection allows to identify patients at risk, however, about 5-30% of the normal female population harbours these viruses and only very few of these develop clinically relevant lesions. The activity of two viral oncogenes E6 and E7 initiates in a long term process neoplastic transformation in few of the HPV harbouring cells. As consequence of the expression of E7 a cellular marker protein (p16) is increasingly expressed in dysplastic cells. Monoclonal antibodies directed against p16 allow therefore to specifically identify dysplastic cells and derived invasive cancers in histological slides but also cytological smears (CINtec Assay). In advanced preneoplastic lesions HPV genomes are often integrated into cellular chromosomes. This leads to enhanced expression of the viral oncogenes. The detection of specific viral mRNA transcripts derived from integrated HPV genomes allows to identify preneoplastic lesions with a particularly high risk for progression to invasive cancers (APOT-assay). These findings will allow to establish highly sensitive, but specific and cost efficient new cancer early detection assays.

Biomarkers, Tumor↗