Showing papers by "Jan Budczies published in 2013"

Online Survival Analysis Software to Assess the Prognostic Value of Biomarkers Using Transcriptomic Data in Non-Small-Cell Lung Cancer

Abstract: In the last decade, optimized treatment for non-small cell lung cancer had lead to improved prognosis, but the overall survival is still very short. To further understand the molecular basis of the disease we have to identify biomarkers related to survival. Here we present the development of an online tool suitable for the real-time meta-analysis of published lung cancer microarray datasets to identify biomarkers related to survival. We searched the caBIG, GEO and TCGA repositories to identify samples with published gene expression data and survival information. Univariate and multivariate Cox regression analysis, Kaplan-Meier survival plot with hazard ratio and logrank P value are calculated and plotted in R. The complete analysis tool can be accessed online at: www.kmplot.com/lung. All together 1,715 samples of ten independent datasets were integrated into the system. As a demonstration, we used the tool to validate 21 previously published survival associated biomarkers. Of these, survival was best predicted by CDK1 (p<1E-16), CD24 (p<1E-16) and CADM1 (p = 7E-12) in adenocarcinomas and by CCNE1 (p = 2.3E-09) and VEGF (p = 3.3E-10) in all NSCLC patients. Additional genes significantly correlated to survival include RAD51, CDKN2A, OPN, EZH2, ANXA3, ADAM28 and ERCC1. In summary, we established an integrated database and an online tool capable of uni- and multivariate analysis for in silico validation of new biomarker candidates in non-small cell lung cancer.

Differential expression of histone deacetylases HDAC1, 2 and 3 in human breast cancer - overexpression of HDAC2 and HDAC3 is associated with clinicopathological indicators of disease progression

Abstract: In breast cancer, the role of epigenetic alterations including modifications of the acetylation status of histones in carcinogenesis has been an important research focus during the last years. An increased deacetylation of histones leads to increased cell proliferation, cell migration, angiogenesis and invasion. Class 1 histone deacetylases (HDAC) seem to be most important during carcinogenesis. The immunhistochemical expression of HDAC1, 2 and 3 was analyzed on tissue microarrays (TMAs) from 238 patients with primary breast cancer. We analyzed the nuclear staining intensity (negative, weak, moderate, strong) as well as the percentage of positive tumor cells and calculated the immunoreactivity score (0–12). Expression was correlated with clinicopathological parameters and patient survival. In this cohort, we found a differential positive expression of HDAC1, HDAC2 and HDAC3. HDAC2 and HDAC3 expression was significantly higher in less differentiated tumors: HDAC2 (n=207), p<0.001 and HDAC3 (n=220), p<0.001 and correlated with negative hormone receptor status: HDAC2 (n=206), p=0.02 and HDAC3 (n=219), p=0.04. Additionally, a high HDAC2 expression was significantly associated with an overexpression of HER2 (n=203, p=0.005) and the presence of nodal metastasis (n=200, p=0.04). HDAC1 was highly expressed in hormone receptor positive tumors (n=203; p<0.001). As a conclusion, our results show that the class-1 HDAC isoenzymes 1, 2 and 3 are differentially expressed in breast cancer. HDAC2 and HDAC3 are strongly expressed in subgroups of tumor with features of a more aggressive tumor type.

A meta-analysis of gene expression-based biomarkers predicting outcome after tamoxifen treatment in breast cancer.

Abstract: To date, three molecular markers (ER, PR, and CYP2D6) have been used in clinical setting to predict the benefit of the anti-estrogen tamoxifen therapy. Our aim was to validate new biomarker candidates predicting response to tamoxifen treatment in breast cancer by evaluating these in a meta-analysis of available transcriptomic datasets with known treatment and follow-up. Biomarker candidates were identified in Pubmed and in the 2007–2012 ASCO and 2011–2012 SABCS abstracts. Breast cancer microarray datasets of endocrine therapy-treated patients were downloaded from GEO and EGA and RNAseq datasets from TCGA. Of the biomarker candidates, only those identified or already validated in a clinical cohort were included. Relapse-free survival (RFS) up to 5 years was used as endpoint in a ROC analysis in the GEO and RNAseq datasets. In the EGA dataset, Kaplan–Meier analysis was performed for overall survival. Statistical significance was set at p < 0.005. The transcriptomic datasets included 665 GEO-based and 1,208 EGA-based patient samples. All together 68 biomarker candidates were identified. Of these, the best performing genes were PGR (AUC = 0.64, p = 2.3E−07), MAPT (AUC = 0.62, p = 7.8E−05), and SLC7A5 (AUC = 0.62, p = 9.2E−05). Further genes significantly correlated to RFS include FOS, TP53, BTG2, HOXB7, DRG1, CXCL10, and TPM4. In the RNAseq dataset, only ERBB2, EDF1, and MAPK1 reached statistical significance. We evaluated tamoxifen-resistance genes in three independent platforms and identified PGR, MAPT, and SLC7A5 as the most promising prognostic biomarkers in tamoxifen treated patients.

The EndoPredict Gene-Expression Assay in Clinical Practice - Performance and Impact on Clinical Decisions

Abstract: The validated EndoPredict assay is a novel tool to predict the risk of metastases of patients with estrogen receptor positive, HER2 negative breast cancer treated with endocrine therapy alone. It has been designed to integrate genomic and clinical information and includes clinico-pathological factors such as tumor size and nodal status. The test is feasible in a decentral setting in molecular pathology laboratories. In this project, we investigated the performance of this test in clinical practice, and performed a retrospective evaluation of its impact on treatment decisions in breast cancer. During one year, EndoPredict assays from 167 patients could be successfully performed. For retrospective evaluation of treatment decisions, a questionnaire was sent to the clinical partner. Regarding the molecular EP class, samples from 56 patients (33.5%) had a low-risk, whereas 111 patients (66.5%) showed a high-risk gene profile. After integration of the clinicopathological factors the combined clinical and molecular score (EPclin) resulted in a low-risk group of 77 patients (46.4%), while 89 (53.6%) had a high risk EPclin score. The EPclin-based estimated median 10-year-risk for metastases with endocrine therapy alone was 11% for the whole cohort. The median handling time averaged three days (range: 0 to 11 days), 59.3% of the tests could be performed in three or less than three days. Comparison of pre- and post-test therapy decisions showed a change of therapy in 37.7% of patients. 16 patients (12.3%) had a change to an additional chemotherapy while 25.4% of patients (n = 33) changed to an endocrine therapy alone. In 73 patients (56.2%) no change of therapy resulted. In 6.1% of patients (n = 8), the patients did not agree to the recommendation of the tumor board. Our results show that the EndoPredict assay could be routinely performed in decentral molecular pathology laboratories and the results markedly change treatment decisions.

Emotional Development in Adults with Autism and Intellectual Disabilities: A Retrospective, Clinical Analysis

Abstract: Individuals with intellectual disability (ID) are at risk for additional autism spectrum disorders (ASD). A large amount of research reveals deficits in emotion-related processes that are relevant to social cognition in ASD. However, studies on the structure and level of emotional development (ED) assessing emotional maturity according to the normative trajectory in typically developing children are scares. The level of ED can be evaluated by the ‘Scheme of Appraisal of Emotional Development’ (SAED), a semi-structured interview with a close caregiver. The SAED assesses the level of emotional developmental based on a five stage system in 10 domains, for example, ‘interaction with peers’ or ‘object permanence’, which are conducive to the overall emotional developmental level. This study examined the ED as measured by the SAED in 289 adults (mean age: 36 years) with ID with and without additional ASD. A lower level in ED was observed in ASD/ID combined that corresponded to the ED of typically developing children aged 1.5–3 years versus an ED with a corresponding age of 3–7 years in ID individuals without ASD. Moreover, distinct strengths in ‘object permanence’, and weaknesses in ‘interaction’, ‘verbal communication’, ‘experience of self’, ‘affect differentiation’, ‘anxiety’, and ‘handling of material objects’ led to a characteristic pattern of ED in ASD. SAED domains with highest discriminative power between ID individuals with and without ASD (5/10) were used to predict ASD group membership. The classification using a selection of SAED domains revealed a sensitivity of 77.5% and a specificity of 76.4%. ASD risk increased 2.7-fold with every SAED level. The recognition of delayed and uneven pattern of ED contributes to our understanding of the emotion-related impairments in adults with ID and ASD these individuals. Assessment of intra-individual ED could add value to the standard diagnostic procedures in ID, a population at risk for underdiagnosed ASD.

New network topology approaches reveal differential correlation patterns in breast cancer

Abstract: Background Analysis of genome-wide data is often carried out using standard methods such as differential expression analysis, clustering analysis and heatmaps. Beyond that, differential correlation analysis was suggested to identify changes in the correlation patterns between disease states. The detection of differential correlation is a demanding task, as the number of entries in the gene-by-gene correlation matrix is large. Currently, there is no gold standard for the detection of differential correlation and statistical validation.

Histopathological regression grading matches excellently with local and regional spread after neoadjuvant therapy of rectal cancer

Abstract: Histopathological regression grading has been shown to predict outcome in chemoradiated rectal cancer. Lymph node spread is still considered the most important single prognostic parameter. Therefore, we investigated the association of regression grading with tumor spread in a single center retrospective cohort. 102 consecutive patients who had undergone neoadjuvant therapy for rectal adenocarcinoma were included. Surgery was performed, including total mesorectal excision. Pathological examination included UICC staging and Dworak's five-tier tumor regression grading. Histological complete response was achieved in 16.7% of cases. Dworak's regression grading and a simplified two tier scheme both correlated excellently with ypT, ypN and UICC stage. However, cases with poor histological response were strongly represented in ypN0. Tumor regression grading is a reliable method for assessment of response to neoadjuvant therapy, but the optimal cut-off for separating good and poor response remains to be established based on clinical outcome.

Abstract P2-09-03: Antitumor activity of the glutaminase inhibitor, CB-839, in triple-negative breast cancer

Abstract: Glutamine (Gln) serves as an important source of energy and building blocks for many tumor cells. The first step in Gln utilization is its conversion to glutamate (Glu) by the mitochondrial enzyme glutaminase. CB-839 is a potent, selective, and orally bioavailable inhibitor of both splice variants of glutaminase (KGA and GAC). CB-839 inhibits recombinant GAC with an IC50 of 25) that included a mixture of TNBC and ER/Her2-positive subtypes. The TNBC subtype displayed the greatest sensitivity to CB-839 treatment (IC50s ranging from 5-100 nM) and this sensitivity was correlated with: i) dependence on extracellular Gln for growth (r = 0.83, p Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-09-03.

Hormone receptor-dependent regulation of ABAT and beta-alanine metabolism in breast cancer.

Abstract: 11112 Background: Recently, we identified beta-alanine as biomarker for breast cancer using GC-MS based metabolomics. Beta-alanine is increased in breast cancer compared to normal tissues and in th...

Lokalrezidiv des kolorektalen Karzinoms: Ergebnisse der chirurgischen Therapie

Abstract: Trotz standardisierter operativer Techniken und multimodaler Therapiekonzepte treten kolorektale Karzinomrezidive in bis zu 20% der Falle auf. In der kurativen Therapie dieser Patienten bildet die radikale Resektion den zentralen Bestandteil. Das Ziel dieser Arbeit war es, die Ergebnisse in der Behandlung des lokoregionaren Rezidivs des kolorektalen Karzinoms zu evaluieren. Im Zeitraum Januar von 1995 bis Dezember 2007 wurden 82 Patienten wegen eines kolorektalen Karzinomrezidivs operiert, deren Primartumor R0-reseziert worden war. Neben Patienten-, Tumor- und Therapiecharakteristika wurden das Auftreten von postoperativen Komplikationen sowie die Re-Rezidiv-Freiheit erfasst und das rezidivfreie und das Gesamtuberleben nach der Methode von Kaplan und Meier berechnet. Bei 60 der 82 Patienten (73%) wurde eine Resektion durchgefuhrt, bei 52% (31/60) gelang eine erneute R0-Resektion. Die postoperative Morbiditat lag bei 39% (31/82), die Rate an Relaparotomien bei 13% (11/82) und die Letalitat bei 7% (6/82). 48% aller Operierten erhielten ein permanentes Stoma. Ein Re-Rezidiv entwickelten 52% (16/31). Die 5-Jahres-Uberlebensrate betragt bei den R0-resezierten Patienten 35% (11/31). Ausgedehnte Re-Operationen ermoglichen haufig eine erneute R0-Resektion. Trotz relevanter Morbiditat erscheint die Letalitat vertretbar. Entscheidend fur die Prognose ist das Re-Rezidiv.