Cancer Biomarkers - Volume 4, issue 2

Authors: Grünhage, Frank | Jungck, Matthias | Lamberti, Christof | Schulte-Witte, Hildegard | Plassmann, Dominik | Becker, Ursula | Rahner, Nils | Aretz, Stefan | Friedrichs, Nicolaus | Buettner, Reinhard | Sauerbruch, Tilman | Lammert, Frank

Article Type: Research Article

Abstract: Mutations of the base excision repair gene MUTYH have been reported as underlying genetic defects in autosomal-recessive familial adenomatous polyposis (FAP). Our aim was to determine the frequency of the most common mutations (p.Tyr165Cys and p.Gly382Asp) in patients with strong evidence for familial colorectal cancer (fCRC). Methods: We recruited 93 patients with fCRC but no indication for monogenic CRC syndromes (FAP, hereditary non-polyposis colorectal cancer). Tumors showed regular expression of MLH1 and MSH2, and microsatellite instability was excluded. Sporadic CRC patients (n=93) and ‘hyper-normal’ controls without any adenomas in screening colonoscopies (n=93) were studied for comparison. Results: …In the fCRC group, two patients carried biallelic mutations (p.Tyr165Cys/p.Tyr165Cys, p.Tyr165Cys/p.Gly382Asp), while four patients displayed a heterozygous genotype (3 × p.Tyr165Cys/wt, 1 × p.Gly382Asp/wt). In contrast, only two p.Gly382Asp/wt patients were detected in the sporadic CRC group and one p.Gly382Asp carrier was observed in ‘hyper-normal’ controls, and the p.Tyr165Cys risk allele was absent in both control groups. Association tests demonstrated an increased odds ratio (OR) for CRC in carriers of the p.Tyr165Cys risk allele among fCRC patients, as compared to sporadic CRC patients and controls (OR 2.38; p=0.03). Conclusions: In our cohort the prevalence of pathogenic MUTYH mutations was increased among fCRC patients compared to sporadic CRC and controls. The association of the p.Tyr165Cys mutation with fCRC indicates that this variant represents a susceptibility factor in a defined subgroup of CRC patients with a positive family history. Show more

Keywords: Complex trait, colon neoplasm, DNA repair, familial cancer, genetic susceptibility

DOI: 10.3233/CBM-2008-4201

Citation: Cancer Biomarkers, vol. 4, no. 2, pp. 55-61, 2008

Authors: Shekari, Mohammad | Sobti, Ranbir Chander | Tamandani, Dor Mohammad Kordi | Malekzadeh, Keyanoosh | Kaur, Pushpinder | Suri, Vanita

Article Type: Research Article

Abstract: Cervical cancer is one of the most common neoplastic diseases affecting women, with a combined world wide incidence of almost half a million new cases. Reduced DNA repair capacity (DRC) can render a high risk of developing many types of cancer; including cervical cancer. Polymorphisms in DNA repair genes may contribute the genetic instability and carcinogenesis. Smoking experience and use of oral contraceptives have been confirmed to be risk factors for cervical cancer. The purpose of the present study was, therefore to investigate APE-1 genotypes (Asp/Asp, Asp/Glu, Glu/Glu) with different histological subtypes in cases compared with controls. It has been …observed that Asp/Glu with Glu/Glu genotypes that combined we observed statistically significant with protective effect for developing of cervix cancer (OR-0.51, 95% CI 0.31–0.83, p-0.006). The combined Asp/Glu with Glu/Glu genotypes who were using oral contraceptives were shown to be statistically significant with reduced risk of cervical cancer (OR-0.22 95% CI- 0.11–0.47, p-0.0002). It has been suggested that significantly correlation between HPV 16 and users of oral contraceptives in certain APE-1 genotypes with reduced risk in developing cervix cancer. In conclusion we observed statistical significant association with reduced risk of cervix cancer in APE-1 with different genotypes, though, on the other hand, in association between HPV type 18 and those having SCC, highly increased risk of cervical cancer was observed. Show more

Keywords: Cervix cancer, HPV, smoking, oral contraceptive, APE-1, polymorphism

DOI: 10.3233/CBM-2008-4202

Citation: Cancer Biomarkers, vol. 4, no. 2, pp. 63-71, 2008

Authors: Mano, António | Falcão, Amílcar | Godinho, Isabel | Santos, Jorge | Leitão, Fátima | de Oliveira, Carlos | Caramona, Margarida

Article Type: Research Article

Abstract: Purpose: The aim of the present work was to evaluate the usefulness of CA-125 normalized in time area under the curve (CA-125 AUC) to signalise epithelial ovarian cancer relapse. Patients and Methods: Data from a hundred and eleven patients were submitted to two different approaches based on CA-125 AUC increase values to predict patient relapse. In Criterion A total CA-125 AUC normalized in time value (AUC i ) was compared with the immediately previous one (AUC i − 1 ) using the formulae AUC i ≥ F …∗ AUC i − 1 (several F values were tested) to find the appropriate close related increment associated to patient relapse. In Criterion B total CA-125 AUC normalised in time was calculated and several cut-off values were correlated with patient relapse prediction capacity. Results: In Criterion A the best accuracy was achieved with a factor (F) of 1.25 (increment of 25% from the previous status), while in Criterion B the best accuracies were achieved with cut-offs of 25, 50, 75 and 100 IU/mL. The mean lead time to relapse achieved with Criterion A was 181 days, while with Criterion B they were, respectively, 131, 111, 63 and 11 days. Conclusion: Based on our results we believe that conjugation and sequential application of both criteria in patient relapse detection should be highly advisable. CA-125 AUC rapid burst in asymptomatic patients should be firstly evaluated using Criterion A with a high accuracy (0.85) and with a substantial mean lead time to relapse (181 days). If a negative answer was obtained then Criterion B should performed to confirm the absence of relapse. Show more

Keywords: Ovarian cancer, CA-125, CA-125 kinetics, follow-up, relapse, recurrence

DOI: 10.3233/CBM-2008-4203

Citation: Cancer Biomarkers, vol. 4, no. 2, pp. 73-81, 2008

Authors: Hbibi, A. Tadlaoui | Lagorce, C. | Wind, P. | Spano, J.P. | Des Guetz, G. | Milano, G. | Benamouzig, R. | Rixe, O. | Morere, J.-F. | Breau, J.-L. | Martin, A. | Fagard, R.

Article Type: Research Article

Abstract: Aims: The Epidermal Growth Factor-Receptor (EGF-R) is frequently overexpressed in colorectal carcinoma (CRC) and patients can benefit from anti-EGF-R therapy. Yet, the relationship, within tumours, between EGF-R and the activity of downstream effectors such as the non-receptor tyrosine kinase p60c-src and the signal transducer and activator of transcription 3 (STAT3) has not been extensively analyzed. Methods and results: We evaluated EGF-R, tyrosine 416-phosphorylated p60c-src (P-p60c-src), STAT3 and tyrosine 705-phosphorylated STAT3 (P-STAT3) on Tissue Micro Array (TMA) from 126 patients with CRC. Composite immunohistochemistry scores based on the intensity of labelling and the percentage of positive cells were determined …on TMA for EGF-R, P-p60c-src, STAT3 and P- STAT3. A high score was found in 56%, 61%, 62% and 27% of the cases for EGF-R, P-p60c-src, STAT3 and P-STAT3 respectively. There was a significant correlation between EGF-R and P-p60c-src (p=0.006) and between P-p60c-src and P-STAT3 (p=0.0009). STAT3 was significantly correlated with vascular emboli (p=0.03) and perineural invasion (p=0.02). Conclusions: The correlations between EGF-R, P-p60-src and P-STAT3 and some stage-related pathological features point to a critical role for a EGF-R-connected p60c-src-kinase-mediated pathway involving STAT3 and contributing to cell survival and proliferation within CRC tumours. Show more

Keywords: Colorectal carcinoma, EGF-R, p60c-src, STAT3, tyrosine-phosphorylation

DOI: 10.3233/CBM-2008-4204

Citation: Cancer Biomarkers, vol. 4, no. 2, pp. 83-91, 2008

Authors: Macías, M. | Dean, M. | Atkinson, A. | Jiménez-Morales, S. | García-Vazquez, F.J. | Saldaña-Alvarez, Y. | Ramírez-Bello, J. | Chávez, M. | Orozco, L.

Article Type: Research Article

Abstract: RB1 mutation detection has greatly improved the clinical management of retinoblastoma and provides critical information to predict the risk of inheriting the disease. We screened for RB1 gene sequence alterations in both peripheral blood and tumor specimens from a total of 48 Mexican retinoblastoma patients using an SSCP-based screening approach followed by sequencing. Overall, 21 (43.8%) cases were bilateral and 27 (56.2%) were unilateral. Interestingly, 51.8% of unilateral patients developed the tumor before age 1 year and 10 of wich (71.4%) were diagnosed before the age of 6 months. Thirteen different oncogenic mutations were detected in 14/48 (29.2%) patients, 9 …of which were germline (64.3%). Six of these mutations are novel (IVS3-1G>T, 125X, 389X, 610X, 750X and −149G>T). The most frequent types of mutation were frameshift and nonsense (30.8% each). Moreover, 5 intronic variants were identified, two of which are novel (g.41908 C/A and g.161976del6T). Loss of heterozygosity of the RB1 gene as assessed by intron1/BamHI and intron17/XbaI intragenic markers was 50.0% (18 of 36 informative cases), being higher in tumors with known mutations (76.9% vs 34.8%). This low mutation detection rate and the earlier age at diagnosis in unilateral retinoblastoma cases suggest that other RB1 inactivating mechanisms could be present in the retinoblastoma development. In this study, mutation analysis was not helpful to distinguish sporadic and hereditary retinoblastoma, so, other approaches are needed to improve the molecular diagnosis of retinoblastoma and supports further investigations of Mexican retinoblastoma patients. Show more

Keywords: Retinoblastoma, RB1 gene, mutations, loss of heterozygosity, Mexican patients

DOI: 10.3233/CBM-2008-4205

Citation: Cancer Biomarkers, vol. 4, no. 2, pp. 93-99, 2008

Authors: Dejligbjerg, Marielle | Grauslund, Morten | Christensen, Ib Jarle | Tjørnelund, Jette | Buhl Jensen, Peter | Sehested, Maxwell

Article Type: Research Article

Abstract: Histone deacetylase inhibitors (HDACi) are promising epigenetic cancer chemotherapeutics rapidly approaching clinical use. HDACi increases acetylation levels of histone and non-histone proteins and causes an alteration in gene-expression levels, ultimately resulting in proliferation arrest or apoptosis of especially cancer cells. However, the precise mechanism of action of this class of therapeutics and the genes implicated in sensitivity remain obscure. Hence, there is a need for identifying predictive biomarkers. In this study, we examined the gene-expression levels of selected possible HDACi biomarkers, as suggested in the literature. This was correlated with the inherent sensitivity towards the HDACi belinostat in a panel …of 18 wild-type cancer cell lines with up to a 30-fold difference in chemosensitivity, which matched IC50 data from the NCI60 screen. Of 16 genes examined, 4 showed a correlation in their expression levels to belinostat sensitivity: Ornithine decarboxylase (ODC1), v-ski sarcoma viral oncogene homolog (SKI), signal transducer and activator of transcription 1 (STAT1), and thymidylate synthetase (TYMS). Including ODC and SKI simultaneously further strengthened the model. Further, there was no correlation between sensitivity and intracellular belinostat uptake or with histone and tubulin acetylation. Therefore, the genes identified in this study may be potential biomarkers for predicting clinical HDACi sensitivity. Show more

Keywords: HDACi, belinostat, predictive biomarker, sensitivity, cancer cell panel

DOI: 10.3233/CBM-2008-4206

Citation: Cancer Biomarkers, vol. 4, no. 2, pp. 101-109, 2008

Authors: Liu, Yanqun | Zhao, Yi | Wu, ChiYu | Ho, Kok Sun | Koh, Poh Koon | Chong, Stephanie Fook | Eu, Kong Weng

Article Type: Research Article

Abstract: Although E-cadherin expression is frequently reduced in colorectal cancers (CRCs), this does not appear to be due to gene mutation or allele loss. We investigated the hypothesis that promoter methylation could be responsible for supression of E-cadherin expression in 142 pairs of sporadic CRCs and respective normal mucosae. E-cadherin expression was examined by Western blot. E-cadherin methylation at two promoter regions was quantitatively measured by methylation specific real time PCR (MethyLight). We found that E-cadherin protein levels were significantly lower in CRCs, even in Dukes' A tumors, compared to normal mucosae. Decreased E-cadherin protein expression in CRCs was an independent …poor prognostic factor in multivariate disease-free survival analysis. However, the extent of DNA methylation was extremely modest at both regions of the E-cadherin promoter. There was no correlation between DNA methylation and E-cadherin protein levels in either tumors or matched normal tissues. These findings suggested that supression of E-cadherin expression in CRCs is a significant event and is possibly involved in both carcinoma development and progression. However, our data did not support a crucial role of promoter methylation of the E-cadherin gene in the remarkable downregulation of E-cadherin expression in CRCs. Methylated E-cadherin gene as a CRC biomarker therefore needs further validation. Show more

Keywords: E-cadherin downregulation, epigenetic silencing, methyLight, colorectal cancer

DOI: 10.3233/CBM-2008-4207

Citation: Cancer Biomarkers, vol. 4, no. 2, pp. 111-120, 2008