TOP1 gene copy number in stage III colorectal cancer (CRC) samples: Association to prognosis.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 475-475
Author(s):  
Sune Boris Nygaard ◽  
Maria Unni Rømer ◽  
Ib Jarle Christensen ◽  
Signe Lykke Nielsen ◽  
David Hersi Smith ◽  
...  
Keyword(s):  
Predictive Value ◽  
Copy Number ◽  
Gene Copy Number ◽  
Tumor Location ◽  
Response To Therapy ◽  
Stage Iii ◽  
Gene Copy ◽  
Continuous Variables ◽  
Future Studies ◽  
Significant Difference

475 Background: TOP1 inhibitor treatment is frequently being used in combination therapy of metastatic CRC. This study aims to reveal whether TOP1 gene copy number associates with patient prognosis, since such a relationship may have significant implications for future studies aiming at validating the predictive value of TOP1 gene copy number. Methods: The study included TOP1 and CEN-20 FISH analyses (DAKO A/S Denmark) on FFPE tissue sections from 154 stage III CRC patients who did not receive adjuvant chemotherapy. TOP1 gene copy number, CEN-20 copy number and the TOP1/CEN-20 ratios were analyzed and correlated to overall survival (OS), to time to recurrence (TTR) of patients with CRC and to local recurrence (LR) in patients with rectal cancer (RC). Results: TOP1 copy number counts and the TOP1/CEN-20 ratios, age, gender and primary tumor location were separately added into a multivariate analysis as continuous variables. For OS and LR, TOP1 copy number was significant and the ratio was borderline significant with higher copy number associated with longer OS or longer time to LR. When the patients were dichotomized using the TOP1 median copy number, we found that patients with high TOP1 copy number in their tumor cells had a significant longer OS (HR: 0.68; 95% CI: 0.47-0.98; p = 0.04) compared to patients with low TOP1 copy number. Using the median TOP1/CEN-20 ratio to dichotomize, no significant differences were observed between patients with levels above or below the median ratio number for OS (HR: 0.76; 95% CI: 0.53-1.10; p = 0.14). TOP1 copy number divided the RC patients into two groups with a trend towards a significant difference in time to LR (HR: 0.56; 95% CI: 0.27-1.16; p = 0.11) with higher copy number. If the median ratio was used, a significant association with longer time to LR (HR: 0.43; 95% CI: 0.20-0.92; p = 0.03) was found. No significant associations between TOP1 copy number or ratio and TTR were observed. Conclusions: Increased TOP1 copy number is associated with longer OS in CRC patients and fewer LR in RC patients. Thus, future studies analyzing the association between TOP1 copy number and response to therapy in CRC patients should be planned in such a way that a prognostic and a predictive value of TOP1 can be separated.

scholarly journals PPP1R12A Copy Number Is Associated with Clinical Outcomes of Stage III CRC Receiving Oxaliplatin-Based Chemotherapy

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Chenbo Zhang ◽  
Ajian Li ◽  
Huaguang Li ◽  
Kangsheng Peng ◽  
Qing Wei ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Outcomes ◽  
Copy Number ◽  
Gene Copy Number ◽  
Tumor Location ◽  
Stage Iii ◽  
Gene Copy ◽  
Tissue Samples ◽  
Relative Copy Number ◽  
Colorectal Cancer Patients

Aim. To investigate the correlation between PPP1R12A gene copy number and clinical outcomes of oxaliplatin-based regimen in stage III colorectal cancer (CRC).Methods. A total of 139 paraffin-embedded tissue samples of stage III CRC patients who received oxaliplatin-based treatment after radical surgery were recruited. Genomic DNA was extracted and purified from paraffin-embedded sections. Quantitative PCR methods were used to detect the relative copy number (RCN) of PPP1R12A.Results. Statistical analysis demonstrated that low PPP1R12A RCN was associated with poor RFS (HR=2.186, 95% CI: 1.293–3.696;P=0.003) and OS (HR=2.782, 95% CI: 1.531–5.052;P<0.001). Additionally, when patients were stratified according to subgroups of stage III and tumor location, poor RFS and OS were also observed in the low PPP1R12A RCN group with significance (RFS: IIIBHR=2.870,P<0.001; colonHR=1.910,P=0.037; OS: IIIBHR=3.527,P<0.001; IIICHR=2.662,P=0.049; rectumHR=4.229,P=0.002).Conclusion. Our findings suggest the copy number of PPP1R12A can independently predict recurrence and overall survival of stage III colorectal cancer patients receiving oxaliplatin-based chemotherapy.

scholarly journals Estimation of total bacteria by real-time PCR in patients with periodontal disease

2016 ◽  
Vol 144 (1-2) ◽  
pp. 10-14 ◽  
Author(s):  
Gavrilo Brajovic ◽  
Branka Popovic ◽  
Miljan Puletic ◽  
Marija Kostic ◽  
Jelena Milasin
Keyword(s):  
Periodontal Disease ◽  
Real Time ◽  
Copy Number ◽  
Quantitative Estimation ◽  
Periodontal Diseases ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Additional Tool ◽  
Significant Difference ◽  
Total Bacteria

Introduction. Periodontal diseases are associated with the presence of elevated levels of bacteria within the gingival crevice. Objective. The aim of this study was to evaluate a total amount of bacteria in subgingival plaque samples in patients with a periodontal disease. Methods. A quantitative evaluation of total bacteria amount using quantitative real-time polymerase chain reaction (qRT-PCR) was performed on 20 samples of patients with ulceronecrotic periodontitis and on 10 samples of healthy subjects. The estimation of total bacterial amount was based on gene copy number for 16S rRNA that was determined by comparing to Ct values / gene copy number of the standard curve. Results. A statistically significant difference between average gene copy number of total bacteria in periodontal patients (2.55.107) and healthy control (2.37.106) was found (p=0.01). Also, a trend of higher numbers of the gene copy in deeper periodontal lesions (>7 mm) was confirmed by a positive value of coefficient of correlation (r=0.073). Conclusion. The quantitative estimation of total bacteria based on gene copy number could be an important additional tool in diagnosing periodontitis.

scholarly journals Topoisomerase 1(TOP1 ) gene copy number in stage III colorectal cancer patients and its relation to prognosis

2012 ◽  
Vol 7 (1) ◽  
pp. 101-111 ◽  
Author(s):  
Maria Unni Rømer ◽  
Sune Boris Nygård ◽  
Ib Jarle Christensen ◽  
Signe Lykke Nielsen ◽  
Kirsten Vang Nielsen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Copy Number ◽  
Gene Copy Number ◽  
Stage Iii ◽  
Gene Copy ◽  
Topoisomerase 1 ◽  
Colorectal Cancer Patients

Insulin-like growth factor 1 (IGF-1R) protein expression (PE) and gene copy number (GCN) for discrimination of response and outcome to figitumumab in NSCLC.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7597-7597 ◽  
Author(s):  
Murry W. Wynes ◽  
Simon Ekman ◽  
Bernadette Reyna Asuncion ◽  
Rafal Dziadziuszko ◽  
Bonnie S. Glisson ◽  
...  
Keyword(s):  
Copy Number ◽  
Gene Copy Number ◽  
Phase Iii ◽  
Gene Copy ◽  
Clinical Activity ◽  
Two Phase ◽  
Significant Difference ◽  
Score Method ◽  
Average Copy ◽  
Tumor Types

7597 Background: Early clinical data suggested figitumumab (F), an anti-IGF-1R antibody, had clinical activity in several tumor types. However, two phase III studies, A4021016 carboplatin/paclitaxel (CP) +/- F in 1st line treatment or A4021018 erlotinib (E) +/- F in 2nd line therapy for patients with advanced NSCLC, were closed prematurely due to futility. Neither study used biomarker driven selection criteria. The aim of this study was to retrospectively examine the phase III specimens in order to determine if IGF-1R PE or GCN could discriminate response and/or outcome to F. Methods: IGF-1R PE was determined by immunohistochemistry (IHC) and the tumor specimens were scored using the H-score method (0-300) with separate enumeration of membranous and cytoplasmic components and then combination of these scores. GCN was evaluated by bright field silver in situ hybridization (SISH) with recording the average copy number for 50 tumor cells. Results: IHC was evaluable in 25 CP+F, 20 CP, 27 E+F and 26 E specimens whereas SISH was evaluable in 24, 17, 21 and 22 specimens, respectively. Median PE for membrane, cytoplasm and both in A4021016 were 130, 110 and 120 and in A4021018 they were 135, 140 and 140. Median GCN was 1.88 and 1.98 for A4021016 and A4021018, respectively. There were no significant differences in PE or GCN between treatment arms within each study. Neither PE nor GCN were able to discriminate between response/non-response or disease control/progression in either study. Likewise, neither study showed a significant difference in OS or PFS when using the median cut-points for either PE or GCN. Conclusions: Neither IGF1R PE or GCN were able to discriminate response or outcome in the limited quantity of specimens available from two studies that examined the IGF-1R targeted therapy figitumumab.

The predictive value of hENT 1 molecule for gemcitabine treatment in bladder cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15540-e15540
Author(s):  
Didem Sener Dede ◽  
Aydan Kilicaslan ◽  
Muhammed Bulent Akinci ◽  
Umut Demirci ◽  
Gozde Tahtaci ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Patients ◽  
Predictive Value ◽  
Stage Iv ◽  
Response To Therapy ◽  
Stage Iii ◽  
Low Grade ◽  
Nucleoside Transporter ◽  
Control Tissue ◽  
Significant Difference

e15540 Background: Human equilibrative nucleoside transporter 1 (hENT1) is the nucleoside transporter protein which plays the main role for transportation of gemcitabine into the cells. We aim to assess the predictive value of the hENT 1 molecule in bladder cancer patients treated with gemcitabine based chemoterapy. Methods: Clinically and histologically documented stage III and stage IV invazive bladder cancer patients were included in the study. The patients were assessed retrospectively. All patients were received gemsitabine-platine based chemotherapy as the first line treatment. Spesific hENT1 antibody staining was performed on the chemo-naive bladder tumor specimens immunuhistochemically. Vascular endotel and lymphocytes served as an external positive control for hENT 1 immunuhistochemistry. Staining intensity was graded as 0,absent; 1+, less intens than control tissue, 2, equally positive as control tissue; 3, more intense than control tissue. Tumor spesimens with having 3+ intensity staining in >50% of the tumor cells were accepted as showing high expression of hENT 1. Results: Fifty one patients were included in the study. The median age was 67 (range 41-85). Ninety two percent(n=52) of patients were male. Twenty six (46.4%) and 25 (44.6%) patients were stage III and stage IV disease at the beginning of the therapy, respectively. Thirty four (60.7%) patients were in neoadjuvant treatment group and 17 (30.4%) patients were in metastatic group. Tumor grades could be assessed in 33 patients; 2 (11.4%) were low grade and 31 (88%) were high grade. The median folllow up period was 13 (range 1-58) months. In neoadjuvant group 5 (14%) patients have low hENT 1 level and 21 (60%) patients have high hENT 1 level. In metastatic group 1 (5%) patients have low hENT1 level and 13 (95%) patients have high hENT 1 level. We found no statistically significant difference between hENT 1 low and hENT 1 high groups in terms of response to therapy in metastatic and neoadjuvant groups (p=0.426 and p=0.684 respectively). Conclusions: More stuides are needed to demonstrate the real role of hENT 1 molecule in terms of response to gemsitabine treatment.

scholarly journals Automated Analysis of Protein Expression and Gene Amplification within the Same Cells of Paraffin-Embedded Tumour Tissue

2010 ◽  
Vol 33 (2) ◽  
pp. 105-112 ◽  
Author(s):  
Timo Gaiser ◽  
Lissa Berroa-Garcia ◽  
Ralf Kemmerling ◽  
Aparajita Dutta ◽  
Thomas Ried ◽  
...  
Keyword(s):  
Protein Expression ◽  
Copy Number ◽  
Simultaneous Detection ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Fish Analysis ◽  
Tissue Sections ◽  
Automated Algorithm ◽  
Significant Difference ◽  
Copy Number Changes

Background: The simultaneous detection of protein expression and gene copy number changes in patient samples, like paraffin-embedded tissue sections, is challenging since the procedures of immunohistochemistry (IHC) and Fluorescence in situ Hybridization (FISH) negatively influence each other which often results in suboptimal staining. Therefore, we developed a novel automated algorithm based on relocation which allows subsequent detection of protein content and gene copy number changes within the same cell.Methods: Paraffin-embedded tissue sections of colorectal cancers were stained for CD133 expression. IHC images were acquired and image coordinates recorded. Slides were subsequently hybridized with fluorescently labeled DNA probes. FISH images were taken at the previously recorded positions allowing for direct comparison of protein expression and gene copy number signals within the same cells/tissue areas. Relocation, acquisition of the IHC and FISH images, and enumeration of FISH signals in the immunophenotyped tumour areas were done in an automated fashion.Results: Automated FISH analysis was performed on 13 different colon cancer samples that had been stained for CD133; each sample was scored for MYC, ZNF217 and Chromosome 6 in CD133 positive and negative glands. From the 13 cases four (31%) showed amplification for the MYC oncogene and seven of 13 (54%) cases were amplified for ZNF217. There was no significant difference between CD133 positive tumour and CD133 negative tumour cells.Conclusion: The technique and algorithm presented here enables an easy and reproducible combination of IHC and FISH based on a novel automated algorithm using relocation and automated spot counting.

Biomarker Analyses and Final Overall Survival Results From a Phase III, Randomized, Open-Label, First-Line Study of Gefitinib Versus Carboplatin/Paclitaxel in Clinically Selected Patients With Advanced Non–Small-Cell Lung Cancer in Asia (IPASS)

2011 ◽  
Vol 29 (21) ◽  
pp. 2866-2874 ◽  
Author(s):  
Masahiro Fukuoka ◽  
Yi-Long Wu ◽  
Sumitra Thongprasert ◽  
Patrapim Sunpaweravong ◽  
Swan-Swan Leong ◽  
...  
Keyword(s):  
Overall Survival ◽  
Copy Number ◽  
Egfr Mutation ◽  
Gene Copy Number ◽  
Phase Iii ◽  
Egfr Mutations ◽  
Gene Copy ◽  
First Line ◽  
Egfr Gene ◽  
Significant Difference

Purpose The results of the Iressa Pan-Asia Study (IPASS), which compared gefitinib and carboplatin/paclitaxel in previously untreated never-smokers and light ex-smokers with advanced pulmonary adenocarcinoma were published previously. This report presents overall survival (OS) and efficacy according to epidermal growth factor receptor (EGFR) biomarker status. Patients and Methods In all, 1,217 patients were randomly assigned. Biomarkers analyzed were EGFR mutation (amplification mutation refractory system; 437 patients evaluable), EGFR gene copy number (fluorescent in situ hybridization; 406 patients evaluable), and EGFR protein expression (immunohistochemistry; 365 patients evaluable). OS analysis was performed at 78% maturity. A Cox proportional hazards model was used to assess biomarker status by randomly assigned treatment interactions for progression-free survival (PFS) and OS. Results OS (954 deaths) was similar for gefitinib and carboplatin/paclitaxel with no significant difference between treatments overall (hazard ratio [HR], 0.90; 95% CI, 0.79 to 1.02; P = .109) or in EGFR mutation–positive (HR, 1.00; 95% CI, 0.76 to 1.33; P = .990) or EGFR mutation–negative (HR, 1.18; 95% CI, 0.86 to 1.63; P = .309; treatment by EGFR mutation interaction P = .480) subgroups. A high proportion (64.3%) of EGFR mutation–positive patients randomly assigned to carboplatin/paclitaxel received subsequent EGFR tyrosine kinase inhibitors. PFS was significantly longer with gefitinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation (HR, 0.48; 95% CI, 0.34 to 0.67) but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation (HR, 3.85; 95% CI, 2.09 to 7.09). Conclusion EGFR mutations are the strongest predictive biomarker for PFS and tumor response to first-line gefitinib versus carboplatin/paclitaxel. The predictive value of EGFR gene copy number was driven by coexisting EGFR mutation (post hoc analysis). Treatment-related differences observed for PFS in the EGFR mutation–positive subgroup were not apparent for OS. OS results were likely confounded by the high proportion of patients crossing over to the alternative treatment.

Analysis of IGF1R gene copy number by silver in situ hybridization (SISH) in non-small cell lung cancer (NSCLC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7525-7525
Author(s):  
M. W. Wynes ◽  
S. Singh ◽  
R. Dziadziuszko ◽  
K. Dziadziuszko ◽  
K. Jaskiewicz ◽  
...  
Keyword(s):  
Copy Number ◽  
Statistical Difference ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Medical Systems ◽  
Gene Copies ◽  
Potential Biomarker ◽  
Significant Difference ◽  
The Mean ◽  
Pathological Stages

7525 Background: IGF1R is a potential biomarker for predicting outcome of NSCLC patients (pts) treated with therapeutics targeting the IGF1R signaling pathway. SISH can be expeditiously analyzed on a bright field microscope given that the morphology of the tissue is observed concurrent to the scoring of discrete gene signals. Methods: An experimental SISH probe designed by Ventana Medical Systems (Tucson, AZ) was used to evaluate IGF1R gene copy number on a tissue microarray containing triplicate samples from 189 pts surgically treated for NSCLC (median follow-up 4 years and 5-year survival probability of 40%). Valid results, at least one core with sufficient tumor content for assessment, were obtained for 166 patients. There were 128 males; 93 squamous cell carcinomas (SCC), 47 adenocarcinomas, 5 large cell carcinomas and 21 other histologies. The pathological stages were I: 68, II: 37 and III/IV: 60. The mean number of IGF1R gene copies/nuclei/core was determined by a board certified pathologist counting 50 nuclei in each core. The mean number of IGF1R gene copies/nuclei/patient was determined by using, within the triplicates, the core with the highest gene copy number/nuclei. Results: The mean number of IGF1R gene copies/nuclei per patient was 2.26 (range: 1.12 - 7.56; standard deviation 0.81). The median copy number was 2.11. The pts were divided into two groups, those with 2.1 genes/nuclei or less and those with greater than 2.1 genes/nuclei. There was no statistical difference related to gender (p=0.422) or between pathological stages, (p=0.221). However, there was a highly significant difference between the two categories when considering histological pattern. Among patients with SCC, 66.3% had high copy number compared to 33.7 % in non-SCC histologies (p=0.008). Analysis of overall survival comparing pts with low vs. high IGF1R gene copy number revealed no statistical difference in the median survival: 1.5 yrs (95% CI 0–3.7 yrs) vs. 3.3 yrs (2.0–4.5 yrs) or the 3-year survival: 46% (35–57%) vs. 52% (41–63%). Conclusions: IGF1R gene copy number detected by SISH is higher in SCC than in other histologies of NSCLC, but does not associate with gender, pathological stage or survival. IGF1R SISH should be further explored as a predictive biomarker for IGF1R therapeutics. [Table: see text]

Assessment of HER-2/neu, с-MYC and CCNE1 gene copy number variations and protein expression in endometrial carcinomas

2019 ◽  
Vol 41 (2) ◽  
Author(s):  
L.G. Buchynska ◽  
◽  
O.V. Brieieva* ◽  
N.P. Iurchenko ◽  
◽  
...  
Keyword(s):  
Protein Expression ◽  
Copy Number ◽  
Gene Copy Number ◽  
Copy Number Variations ◽  
Gene Copy ◽  
Her 2 ◽  
Endometrial Carcinomas
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