German Consortium for Translational Cancer Research DKTK

Heidelberg, Germany

German Consortium for Translational Cancer Research DKTK

Heidelberg, Germany
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Wiestler B.,German Cancer Research Center | Wiestler B.,Clinical Cooperation Units Neurooncology | Capper D.,University of Heidelberg | Hartmann C.,Leibniz University of Hanover | And 15 more authors.
Neuro-Oncology | Year: 2014

Background. Molecular biomarkers including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation, 1p/19q codeletion, and O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation may improve prognostication and guide treatment decisions for patients withWorld Health Organization (WHO) anaplastic gliomas. At present, each marker is individually tested by distinct assays. Illumina Infinium HumanMethylation450 BeadChip arrays (HM450) enable the determination of large-scale methylation profiles and genome-wide DNA copy number changes. Algorithms have been developed to detect the glioma CpG island methylator phenotype (GCIMP) associated with IDH1/2 mutation, 1p/19q codeletion, and MGMT promoter methylation using a single assay. Methods. Here, we retrospectively investigated the diagnostic and prognostic performance of these algorithms in comparison to individual marker testing and patient outcome in the biomarker cohort (n = 115 patients) of the NOA-04 trial. Results. Concordance for IDH and 1p/19q status was very high: In 92% of samples, the HM450 and reference data agreed. In discordant samples, survival analysis by Kaplan-Meier and Cox regression analyses suggested a more accurate assessment of biological phenotype by the HM450 analysis. The HM450-derived MGMT-STP27 model to calculate MGMT promoter methylation probability revealed this aberration in a significantly higher fraction of samples than conventional methylation-specific PCR, with 87 of 91 G-CIMP tumors predicted as MGMT promoter-methylated. Pyrosequencing of discordant samples confirmed the HM450 assessment in 14 of 17 cases. Conclusions. G-CIMP and 1p/19q codeletion are reliably detectable by HM450 analysis and are associated with prognosis in the NOA-04 trial. For MGMT, HM450 suggests promoter methylation in the vast majority of G-CIMP tumors, which is supported by pyrosequencing. © The Author(s) 2014.

von Bonin M.,German Cancer Research Center | Bray L.J.,University of Queensland | Freudenberg U.,Leibniz Institute of Polymer Research | Pishali Bejestani E.,German Cancer Research Center | And 3 more authors.
Stem Cells | Year: 2016

Skeletal metastasis of breast cancer is associated with a poor prognosis and significant morbidity. Investigations in other solid tumors have revealed an impairment in hematopoietic function upon bone marrow invasion. However, the interaction between disseminated breast cancer cells and the bone marrow microenvironment which harbors them has not been addressed comprehensively. Employing advanced co-culture assays, proteomic studies, organotypic models as well as in vivo xenotransplant models, we define the consequences of this interaction on the stromal compartment of bone marrow, affected molecular pathways and subsequent effects on the hematopoietic stem and progenitor cells (HSPCs). The results showed a basic fibroblast growth factor (bFGF)-mediated, synergistic increase in proliferation of breast cancer cells and mesenchymal stromal cells (MSCs) in co-culture. The stromal induction was associated with elevated phosphoinositide-3 kinase (PI3K) signaling in the stroma, which coupled with elevated bFGF levels resulted in increased migration of breast cancer cells towards the MSCs. The perturbed cytokine profile in the stroma led to reduction in the osteogenic differentiation of MSCs via downregulation of platelet-derived growth factor-BB (PDGF-BB). Long term co-cultures of breast cancer cells, HSPCs, MSCs and in vivo studies in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice showed a reduced support for HSPCs in the altered niche. The resultant non- conducive phenotype of the niche for HSPC support emphasizes the importance of the affected molecular pathways in the stroma as clinical targets. These findings can be a platform for further development of therapeutic strategies aiming at the blockade of bone marrow support to disseminated breast cancer cells. © 2016 AlphaMed Press.

Eleveld T.F.,University of Amsterdam | Oldridge D.A.,Children's Hospital of Philadelphia | Oldridge D.A.,University of Pennsylvania | Bernard V.,University Pierre and Marie Curie | And 55 more authors.
Nature Genetics | Year: 2015

The majority of patients with neuroblastoma have tumors that initially respond to chemotherapy, but a large proportion will experience therapy-resistant relapses. The molecular basis of this aggressive phenotype is unknown. Whole-genome sequencing of 23 paired diagnostic and relapse neuroblastomas showed clonal evolution from the diagnostic tumor, with a median of 29 somatic mutations unique to the relapse sample. Eighteen of the 23 relapse tumors (78%) showed mutations predicted to activate the RAS-MAPK pathway. Seven of these events were detected only in the relapse tumor, whereas the others showed clonal enrichment. In neuroblastoma cell lines, we also detected a high frequency of activating mutations in the RAS-MAPK pathway (11/18; 61%), and these lesions predicted sensitivity to MEK inhibition in vitro and in vivo. Our findings provide a rationale for genetic characterization of relapse neuroblastomas and show that RAS-MAPK pathway mutations may function as a biomarker for new therapeutic approaches to refractory disease. © 2015 Nature America, Inc. All rights reserved.

Barrow T.M.,Albert Ludwigs University of Freiburg | Barrow T.M.,German Consortium for Translational Cancer Research DKTK | Barrow T.M.,German Cancer Research Center | Michels K.B.,Albert Ludwigs University of Freiburg | Michels K.B.,Brigham and Women's Hospital
Biochemical and Biophysical Research Communications | Year: 2014

Epigenetic epidemiology includes the study of variation in epigenetic traits and the risk of disease in populations. Its application to the field of cancer has provided insight into how lifestyle and environmental factors influence the epigenome and how epigenetic events may be involved in carcinogenesis. Furthermore, it has the potential to bring benefit to patients through the identification of diagnostic markers that enable the early detection of disease and prognostic markers that can inform upon appropriate treatment strategies. However, there are a number of challenges associated with the conduct of such studies, and with the identification of biomarkers that can be applied to the clinical setting. In this review, we delineate the challenges faced in the design of epigenetic epidemiology studies in cancer, including the suitability of blood as a surrogate tissue and the capture of genome-wide DNA methylation. We describe how epigenetic epidemiology has brought insight into risk factors associated with lung, breast, colorectal and bladder cancer and review relevant research. We discuss recent findings on the identification of epigenetic diagnostic and prognostic biomarkers for these cancers. © 2014 Elsevier Inc. All rights reserved.

Bock B.C.,German Cancer Research Center | Bock B.C.,University of Heidelberg | Stein U.,Max Delbrück Center for Molecular Medicine | Stein U.,Charité - Medical University of Berlin | And 7 more authors.
Cancer Research | Year: 2014

The Helmholtz Alliance Preclinical Comprehensive Cancer Center (PCCC; hosted the "1st International Kloster Seeon Meeting on Mouse Models of Human Cancer" in the Seeon monastery (Germany) from March 8 to 11, 2014. The meeting focused on the development and application of novel mouse models in tumor research and high-throughput technologies to overcome one of the most critical bottlenecks in translational bench-to-bedside tumor biology research. Moreover, the participants discussed basic molecular mechanisms underlying tumor initiation, progression, metastasis, and therapy resistance, which are the prerequisite for the development of novel treatment strategies and clinical applications in cancer therapy. © 2014 American Association for Cancer Research.

Voloshanenko O.,German Cancer Research Center | Voloshanenko O.,University of Heidelberg | Erdmann G.,German Cancer Research Center | Erdmann G.,University of Heidelberg | And 25 more authors.
Nature Communications | Year: 2013

Aberrant regulation of the Wnt/β-catenin pathway has an important role during the onset and progression of colorectal cancer, with over 90% of cases of sporadic colon cancer featuring mutations in APC or β-catenin. However, it has remained a point of controversy whether these mutations are sufficient to activate the pathway or require additional upstream signals. Here we show that colorectal tumours express elevated levels of Wnt3 and Evi/Wls/GPR177. We found that in colon cancer cells, even in the presence of mutations in APC or β-catenin, downstream signalling remains responsive to Wnt ligands and receptor proximal signalling. Furthermore, we demonstrate that truncated APC proteins bind β-catenin and key components of the destruction complex. These results indicate that cells with mutations in APC or β-catenin depend on Wnt ligands and their secretion for a sufficient level of β-catenin signalling, which potentially opens new avenues for therapeutic interventions by targeting Wnt secretion via Evi/Wls. © 2013 Macmillan Publishers Limited. All rights reserved.

Budczies J.,Charite University Hospital | Budczies J.,German Cancer Research Center | Budczies J.,German Consortium for Translational Cancer Research DKTK | von Winterfeld M.,Charite University Hospital | And 15 more authors.
Oncotarget | Year: 2015

The majority of patients with solid malignancies die from metastatic burden. However, our current understanding of the mechanisms and resulting patterns of dissemination is limited. Here, we analyzed patterns of metastatic progression across 16 major cancer types in a cohort of 1008 patients with metastatic cancer autopsied between 2000 and 2013 to assess cancer specific progression patterns of disease and related risk predictions. The frequency and location of metastases were evaluated in and across 1) 16 major cancers, 2) smoking- and non-smoking-related cancers and 3) adeno- and squamous cell carcinoma. Associations between primary and secondary sites were analyzed by the fractional and the relative risk methods. We detected significantly different cancer specific patterns of metastatic progression with specific relative risk profiles for secondary site involvement. Histology and smoking etiology influenced these patterns. Backward analysis showed that metastatic patterns help to predict unknown primary sites. Solid malignancies maintain a unique and recurrent organ tropism to specific secondary sites which does not appear to be strongly influenced by advances in cancer medicine as shown by comparison with previous data sets. The delineated landscape of metastatic progression patterns is a comprehensive data resource to both clinical and basic scientists which aids fostering new hypotheses for cancer research and cancer therapies.

PubMed | Charité - Medical University of Berlin, German Consortium for Translational Cancer Research DKTK and University of Duisburg - Essen
Type: Journal Article | Journal: Pediatric blood & cancer | Year: 2016

Survivors of heritable retinoblastoma carry a high risk to develop second cancers. Eye-preserving radiotherapy raises this risk, while the impact of chemotherapy remains less defined.This population-based study characterizes the impact of all treatment modalities on second cancers incidence and type after retinoblastoma treatment in Germany. Data on second cancer incidence in 648 patients with heritable retinoblastoma treated between 1940 and 2008 at the German national reference center for retinoblastoma were analyzed to identify associations with treatment.The cumulative incidence ratio (per 1,000 person years) of second cancers was 8.6 (95% confidence interval 7.0-10.4). Second cancer incidence was influenced by type of retinoblastoma treatment but not by the year of diagnosis or by sex. Radiotherapy and systemic chemotherapy increased the incidence of second cancers (by 3.0- and 1.8-fold, respectively). While radiotherapy was specifically associated with second cancers arising within the periorbital region in the previously irradiated field, chemotherapy was the strongest risk factor for second cancers in other localizations. Soft tissue sarcomas and osteosarcomas were the most prevalent second cancers (standardized incidence ratio 179.35 compared to the German population).Second cancers remain a major concern in heritable retinoblastoma survivors. Consistent with previous reports, radiotherapy increased second cancer incidence and influenced type and localization. However, chemotherapy was the strongest risk factor for second malignancies outside the periorbital region. Our results provide screening priorities during life-long oncological follow-up based on the curative therapy the patient has received and emphasize the need for less-detrimental therapies for children with heritable retinoblastoma.

PubMed | German Consortium for Translational Cancer Research DKTK and University of Duisburg - Essen
Type: Journal Article | Journal: Cancer | Year: 2016

After a pilot study on skin cancer screening was performed between 2003 and 2004 in Schleswig-Holstein, Germany, the country implemented what to the authors knowledge is the first nationwide skin cancer screening program in the world in 2008. The objective of the current study was to provide details regarding mortality trends in Schleswig-Holstein and Germany in relation to the screening.Annual age-standardized mortality rates for skin melanoma (using the 10th Revision of the International Statistical Classification of Diseases and Related Health Problems [ICD-10] code C43) and malignant neoplasms of ill-defined, secondary, and unspecified sites (ICD-10 code C76-C80) were analyzed. The European Standard population was used for age standardization. A bias analysis was performed to estimate the number of skin melanoma deaths that may have been incorrectly counted as ICD-10 code C76-C80 when the skin melanoma mortality declined in Schleswig-Holstein.The observed mortality decline in Schleswig-Holstein 5 years after the pilot study was accompanied by a considerable increase in the number of deaths due to malignant neoplasms of ill-defined, secondary, and unspecified sites (ICD-10 code C76-C80) that is not explainable by an increase in the incidence of these neoplasms. Incorrect assignment of 8 to 35 and 12 to 23 skin melanoma deaths per year among men and women, respectively, as ICD-10 code C76-C80 during 2007 through 2010 could explain the transient skin melanoma mortality decline observed in Schleswig-Holstein. Five years after implementation of the program, the nationwide skin melanoma mortality increased (age-standardized rate change of +0.4 per 100,000 person-years [95% confidence interval, 0.2-0.6] in men and +0.1 per 100,000 person-years [95% confidence interval, -0.1 to 0.2] in women).Although the current analyses raise doubts that the skin cancer screening program in Germany can reduce the skin cancer mortality rate, the authors do not believe the program should be immediately stopped. Further in-depth evaluations are required. Cancer 2016;122:432-437. 2015 American Cancer Society.

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