Colorectal cancer is the third most common cancer and a major cause of cancer-related deaths. Early detection of colonic lesions can reduce the incidence and mortality of colorectal cancer. ...Colonoscopy is the screening test for colorectal cancer with the highest efficacy, but its acceptance in the general public is rather low. To identify suitable tumor-derived markers that could detect colorectal cancer in blood samples, we analyzed the methylation status of a panel of genes in sera of affected patients.
Using methylation-specific quantitative PCR, we analyzed the methylation of ten marker genes in sera of healthy individuals and patients with colorectal cancer.
Only HLTF, HPP1/TPEF, and NEUROG1 DNA methylation was detectable in at least 50% of patients with colorectal cancers. Whereas HLTF and HPP1/TPEF preferentially detected advanced and metastasized colorectal cancers, NEUROG1 methylation was detectable in UICC stages I-IV at a similar rate. Compared with other methylation markers, such as ALX4, SEPT9, and vimentin, NEUROG1 shows a higher sensitivity for colorectal cancer at UICC stages I and II. At a specificity of 91%, NEUROG1 reached a sensitivity of 61% (confidence interval, 50.4-70.6%) for the detection of colorectal cancers. Furthermore, detection of NEUROG1 methylation was independent of age and gender.
Methylation of the NEUROG1 gene is frequently found in sera of patients with colorectal cancers independent of tumor stage. The quantitative detection of NEUROG1 DNA methylation in serum is a suitable approach for the non-invasive screening for asymptomatic colorectal cancer.
Soluble MICA in malignant diseases Holdenrieder, Stefan; Stieber, Petra; Peterfi, Andrea ...
International journal of cancer,
1 February 2006, Letnik:
118, Številka:
3
Journal Article
Comparative proteomics identified the vitamin E-binding plasma protein afamin as a potential novel tumor marker for ovarian
cancer. In addition, we observed in a previous small study decreased plasma ...concentrations of apolipoprotein A-IV (apoA-IV)
in preoperative patients with kidney cancer. The aim of this study was therefore to analyze afamin and apoA-IV in a large
case-control study to evaluate the diagnostic utility of the two potential novel tumor markers in ovarian cancer patients.
We measured plasma concentrations of afamin and apoA-IV by means of a specific sandwich-type ELISA using affinity-purified
polyclonal and monoclonal antibodies in 181 ovarian cancer patients of various clinical stages, 399 patients with benign gynecologic
diseases, including endometriosis, and 177 controls and compared results with those for the conventional ovarian cancer tumor
marker cancer antigen 125 (CA125). Afamin concentrations decreased from a median of 70.7 mg/L (range, 34.6-116.1 mg/L) in
healthy controls to 65.2 mg/L (range, 20.2-206.6 mg/L) in patients with benign gynecologic diseases to 56.0 mg/L (range, 4.7-96.0
mg/L) in ovarian cancer patients ( P < 0.001 for all pairwise comparisons). Similar results were obtained with apoA-IV concentrations decreasing from 13.0 mg/dL
(range, 5.5-34.0 mg/dL) in controls to 11.7 mg/dL (range, 2.0-32.3 mg/dL) in benign conditions to 9.4 mg/dL (range, 0.3-29.5
mg/dL) in ovarian cancer (all P < 0.001). Receiver operating characteristic analysis for differentiating ovarian cancer patients from healthy controls revealed
for a specificity of 90% sensitivity values of 92.4%, 42.4%, and 40.8% for CA125, afamin, and apoA-IV, respectively. Afamin,
but not apoA-IV, added independent diagnostic information to CA125 and age for differentiating ovarian cancer from benign
and healthy samples; the odds ratio of ovarian cancer was reduced by 44% for each doubling of afamin ( P = 0.032). The relatively low sensitivity, however, clearly indicates that afamin and apoA-IV alone are not sufficiently suitable
as diagnostic markers for ovarian cancer. Afamin contributes, however, independent diagnostic information to CA125, thus establishing
its potential as an adjunct marker to CA125. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1127–33)
Hypermethylation of DNA is an epigenetic alteration commonly found in colorectal cancer (CRC) and can also be detected in blood samples of cancer patients. Methylation of the genes helicase-like ...transcription factor (HLTF) and hyperplastic polyposis 1 (HPP1) have been proposed as prognostic, and neurogenin 1 (NEUROG1) as diagnostic biomarker. However the underlying mechanisms leading to the release of these genes are unclear. This study aimed at examining the possible correlation of the presence of methylated genes NEUROG1, HLTF and HPP1 in serum with tissue breakdown as a possible mechanism using serum lactate dehydrogenase (LDH) as a surrogate marker. Additionally the prognostic impact of these markers was examined.
Pretherapeutic serum samples from 259 patients from all cancer stages were analyzed. Presence of hypermethylation of the genes HLTF, HPP1, and NEUROG1 was examined using methylation-specific quantitative PCR (MethyLight). LDH was determined using an UV kinetic test.
Hypermethylation of HLTF and HPP1 was detected significantly more often in patients with elevated LDH levels (32% vs. 12% p = 0.0005, and 68% vs. 11% p < 0.0001, respectively). Also, higher LDH values correlated with a higher percentage of a fully methylated reference in a linear fashion (Spearman correlation coefficient 0.18 for HLTF p = 0.004; 0.49 p < .0001 for HPP1). No correlation between methylation of NEUROG1 and LDH was found in this study. Concerning the clinical characteristics, high levels of LDH as well as methylation of HLTF and HPP1 were significantly associated with larger and more advanced stages of CRC. Accordingly, these three markers were correlated with significantly shorter survival in the overall population. Moreover, all three identified patients with a worse prognosis in the subgroup of stage IV patients.
We were able to provide evidence that methylation of HLTF and especially HPP1 detected in serum is strongly correlated with cell death in CRC using LDH as surrogate marker. Additionally, we found that prognostic information is given by both HLTF and HPP1 as well as LDH. In sum, determining the methylation of HLTF and HPP1 in serum might be useful in order to identify patients with more aggressive tumors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
HCC is diagnosed in approximately half a million people per year, worldwide. Staging is a more complex issue than in most other cancer entities and, mainly due to unique geographic characteristics of ...the disease, no universally accepted staging system exists to date. Focusing on survival rates we analyzed demographic, etiological, clinical, laboratory and tumor characteristics of HCC-patients in our institution and applied the common staging systems. Furthermore we aimed at identifying the most suitable of the current staging systems for predicting survival.
Overall, 405 patients with HCC were identified from an electronic medical record database. The following seven staging systems were applied and ranked according to their ability to predict survival by using the Akaike information criterion (AIC) and the concordance-index (c-index): BCLC, CLIP, GETCH, JIS, Okuda, TNM and Child-Pugh. Separately, every single variable of each staging system was tested for prognostic meaning in uni- and multivariate analysis. Alcoholic cirrhosis (44.4%) was the leading etiological factor followed by viral hepatitis C (18.8%). Median survival was 18.1 months (95%-CI: 15.2-22.2). Ascites, bilirubin, alkaline phosphatase, AFP, number of tumor nodes and the BCLC tumor extension remained independent prognostic factors in multivariate analysis. Overall, all of the tested staging systems showed a reasonable discriminatory ability. CLIP (closely followed by JIS) was the top-ranked score in terms of prognostic capability with the best values of the AIC and c-index (AIC 2286, c-index 0.71), surpassing other established staging systems like BCLC (AIC 2343, c-index 0.66). The unidimensional scores TNM (AIC 2342, c-index 0.64) and Child-Pugh (AIC 2369, c-index 0.63) performed in an inferior fashion.
Compared with six other staging systems, the CLIP-score was identified as the most suitable staging system for predicting prognosis in a large German cohort of predominantly non-surgical HCC-patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Transarterial chemoembolization (TACE) therapy is an effective locoregional anticancer treatment for liver cancer patients. Serum biomarkers involved in immunogenic cell death may be valuable for ...early predicting therapy response and estimating prognosis. Sera of 50 prospectively and consecutively included hepatocellular carcinoma (HCC) patients, undergoing TACE therapy, were taken before and 24 h after TACE application. In these samples, soluble biomarkers involved in immunogenic cell death, and among them, high-mobility group box 1 (HMGB1), soluble receptor of advanced glycation end products (sRAGE), and DNase activity were measured. They were compared with radiological response to therapy. A total of 71 TACE therapies were evaluated, of which 32 were classified as “no progression,” and 39, as “progression.” While HMGB1 levels increased already 24 h after TACE, there was an early decrease of sRAGE and DNase activity. Pretherapeutic and 24-h values of sRAGE were significantly higher in the no progression group than those in the progression group. There was no difference with respect to treatment response for DNase and HMGB1. Soluble RAGE is a new parameter with predictive relevance in primary liver cancer patients undergoing TACE therapy.
Purpose: Aberrant CpG island hypermethylation is a feature of a subgroup of colorectal cancers, which can be detected in the serum
of affected patients. This study was designed to identify ...methylation targets with prognostic significance in the serum of
patients with colorectal cancer.
Experimental Design: In a gene evaluation set consisting of sera from 24 patients with local colorectal cancers, 14 with metastasized disease,
and 20 healthy controls, the genes HPP1/TPEF, HLTF , and hMLH1 were identified as potential serum DNA methylation markers. These genes were further analyzed in a test set of sera of 104
patients with colorectal cancer.
Results: Methylation of HLTF, HPP1/TPEF , and hMLH1 was found to be significantly correlated with tumor size, and methylation of HLTF and HPP1/TPEF was significantly associated with metastatic disease and tumor stage. Moreover, methylation of HPP1/TPEF was also associated with serum carcinoembryonic antigen. The prognostic relevance of methylation of these genes was tested
in pretherapeutic sera of 77 patients with known follow-up. Patients with methylation of HPP1/TPEF or HLTF were found to have unfavorable prognosis ( P = 0.001 and 0.008). In contrast, serum methylation of hMLH1 was not associated with a higher risk of death. Multivariate analysis showed methylated HPP1 and/or HLTF serum DNA to be independently associated with poor outcome and a relative risk of death of 3.4 (95% confidence interval,
1.4-8.1; P = 0.007).
Conclusions: These data show that the methylation status of specific genes in the serum of patients with colorectal cancer has the potential
to become a pretherapeutic predictor of outcome.
Nucleosomes, complexes of DNA and histone proteins, are released during cell death into the blood circulation. Elevated serum and plasma levels have been found in various forms of cancer, but also in ...autoimmune diseases and acute situations such as stroke, trauma, and during sepsis. Here, the clinical relevance of circulating nucleosomes for diagnosis, staging, prognosis, and therapeutic monitoring of cancer is reviewed. Several studies have shown that levels of nucleosomes are significantly higher in serum and plasma of cancer patients in comparison to healthy controls. However, because of elevations of nucleosome levels in patients with benign diseases relevant for differential diagnosis, they are not suitable for cancer diagnosis. Concerning tumor staging, nucleosome levels correlate with tumor stage and presence of metastases in gastrointestinal cancer, but not in other tumor types. Prognostic value of circulating nucleosomes is found in lung cancer in univariate analyses, but not in multivariate analyses. Circulating nucleosomes are most informative for the monitoring of cytotoxic therapy. Strongly decreasing levels are mainly found in patients with remission of disease, whereas constantly high or increasing values are associated with progressive disease during chemo‐ and radiotherapy. In addition, therapy outcome is already indicated by the nucleosomal course during the first week of chemo‐ and radiotherapy in patients with lung, pancreatic, and colorectal cancer as well as in hematologic malignancies. Despite their non‐tumor‐specificity, kinetics of nucleosomes are valuable markers for the early estimation of therapeutic efficacy and may be helpful to adapting early cancer therapy in the future.
Purpose: Besides new therapeutic drugs, effective diagnostic tools indicating early the efficacy of therapy are required to improve
the individual management of patients with nonoperable cancer ...diseases.
Experimental Design: In prospectively collected sera of 128 patients with newly diagnosed small cell lung cancer receiving first-line chemotherapy,
the courses of nucleosomes, progastrin-releasing peptide (ProGRP), neuron-specific enolase (NSE), cytokeratin-19 fragments
(CYFRA 21-1), and carcinoembryonic antigen were investigated and correlated with therapy response objectified by computed
tomography before start of the third treatment course.
Results: In univariate analyses, high levels and insufficient decreases of nucleosomes, ProGRP, NSE, and CYFRA 21-1 during the first
and second cycles of therapy correlated with poor outcome. Insufficient response to therapy was most efficiently indicated
by the baseline values of nucleosomes, ProGRP, and CYFRA 21-1 before the second therapy cycle reaching areas under the curve
(AUC) of 81.8%, 71.3%, and 74.9% in receiver operating characteristic curves, respectively. Combinations of nucleosomes with
ProGRP (AUC 84.1%), CYFRA 21-1 (AUC 82.5%), and NSE (AUC 83.6%) further improved the diagnostic power in the high specificity
range and yielded sensitivities of 47.1%, 35.3%, and 35.3% at 95% specificity, respectively. In multivariate analyses, including
clinical and biochemical variables, only performance score and nucleosomes before cycle 2 were found to independently indicate
therapy response.
Conclusions: Biochemical markers specifically identified patients with insufficient therapy response at the early treatment phase and
showed to be valuable for diseases management of small cell lung cancer.
Selective Internal Radiation Therapy (SIRT) is a new and effective locoregional anticancer therapy for colorectal cancer patients with liver metastases. Markers for prediction of therapy response and ...prognosis are needed for the individual management of those patients undergoing SIRT.
Blood samples were prospectively and consecutively taken from 49 colorectal cancer patients with extensive hepatic metastases before, three, six, 24 and 48 h after SIRT to analyze the concentrations of nucleosomes and further laboratory parameters, and to compare them with the response to therapy regularly determined 3 months after therapy and with overall survival.
Circulating nucleosomes, cytokeratin-19 fragments (CYFRA 21-1), carcinoembryonic antigen (CEA), C-reactive protein (CRP) and various liver markers increased already 24 h after SIRT. Pretherapeutical levels of CYFRA 21-1, CEA, cancer antigen 19-9 (CA 19-9), asparate-aminotransferase (AST) and lactate dehydrogenase (LDH) as well as 24 h values of nucleosomes were significantly higher in patients suffering from disease progression (N = 35) than in non-progressive patients (N = 14). Concerning overall survival, CEA, CA 19-9, CYFRA 21-1, CRP, LDH, AST, choline esterase (CHE), gamma-glutamyl-transferase, alkaline phosphatase, and amylase (all 0 h, 24 h) and nucleosomes (24 h) were found to be prognostic relevant markers in univariate analyses. In multivariate Cox-Regression analysis, the best prognostic model was obtained for the combination of CRP and AST. When 24 h values were additionally included, nucleosomes (24 h) further improved the existing model.
Panels of biochemical markers are helpful to stratify pretherapeutically colorectal cancer patients for SIR-therapy and to early estimate the response to SIR-therapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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