Comparison of RNA-seq and microarray-based models for clinical endpoint prediction
Background Gene expression profiling is being widely applied in cancer research to identify biomarkers for clinical endpoint prediction. Since RNA-seq provides a powerful tool for transcriptome-based applications beyond the limitations of microarrays, we sought to systematically evaluate the performance of RNA-seq-based and microarray-based classifiers in this MAQC-III/SEQC study for clinical endpoint prediction using neuroblastoma as a model. Results We generate gene expression profiles from 498 primary neuroblastomas using both RNA-seq and 44 k microarrays. Characterization of the neuroblastoma transcriptome by RNA-seq reveals that more than 48,000 genes and 200,000 transcripts are being …
Rationale and design of the CRAFT (Continuous ReAssessment with Flexible ExTension in Rare Malignancies) multicenter phase II trial.
Background Approvals of cancer therapeutics are primarily disease entity specific. Current molecular diagnostic approaches frequently identify actionable alterations in rare cancers or rare subtypes of common cancers for which the corresponding treatments are not approved and unavailable within clinical trials due to entity-related eligibility criteria. Access may be negotiated with health insurances. However, approval rates vary, and critical information required for a scientific evaluation of treatment-associated risks and benefits is not systematically collected. Thus clinical trials with optimized patient selection and comprehensive molecular characterization are essential for translati…
Genetic contribution to alcohol dependence: Investigation of a heterogeneous german sample of individuals with alcohol dependence, chronic alcoholic pancreatitis, and alcohol-related cirrhosis
The present study investigated the genetic contribution to alcohol dependence (AD) using genome-wide association data from three German samples. These comprised patients with: (i) AD; (ii) chronic alcoholic pancreatitis (ACP); and (iii) alcohol-related liver cirrhosis (ALC). Single marker, gene-based, and pathway analyses were conducted. A significant association was detected for the ADH1B locus in a gene-based approach (puncorrected = 1.2 × 10-6; pcorrected = 0.020). This was driven by the AD subsample. No association with ADH1B was found in the combined ACP + ALC sample. On first inspection, this seems surprising, since ADH1B is a robustly replicated risk gene for AD and may therefore be …
Abstract LB-287: Identification of patients at risk for tumor predisposition syndromes based on the evaluation of sporadic cancer exome sequencing data: experiences from the NCT/DKTK MASTER program
Abstract The MASTER (Molecularly Aided Stratification for Tumor Eradication Research) Program of the NCT (National Center for Tumor Diseases) Heidelberg and the DKTK (German Cancer Consortium) is situated at the interface of cancer genomics and clinical oncology to provide whole exome/genome and transcriptome sequencing to selected patients with unmet medical need, and to evaluate the utility of such an approach regarding molecular stratification and individualized, biology-guided treatment. The program has enabled implementation of a shared, DKTK-wide workflow for rapid-turnaround clinical sequencing, comprising all steps from sample processing to reporting of results by a dedicated molecu…
XRCC5 as a Risk Gene for Alcohol Dependence : Evidence from a Genome-Wide Gene-Set-Based Analysis and Follow-up Studies in Drosophila and Humans
Genetic factors play as large a role as environmental factors in the etiology of alcohol dependence. Although genome-wide association studies (GWAS) enable systematic searches for loci not hitherto implicated in the etiology of alcohol dependence, many true findings may be missed due to correction for multiple testing. The aim of the present study was to circumvent this limitation by searching for biological system-level differences, and then following up these findings in humans and animals. Gene-set based analysis of GWAS data from 1333 cases and 2168 controls identified 19 significantly associated gene-sets of which five could be replicated in an independent sample. Clustered in these ge…
Validating comprehensive next-generation sequencing results for precision oncology : The NCT/DKTK molecularly aided stratification for tumor eradication research experience
Purpose Rapidly evolving genomics technologies, in particular comprehensive next-generation sequencing (NGS), have led to exponential growth in the understanding of cancer biology, shifting oncology toward personalized treatment strategies. However, comprehensive NGS approaches, such as whole-exome sequencing, have limitations that are related to the technology itself as well as to the input source. Hence, clinical implementation of comprehensive NGS in a quality-controlled diagnostic workflow requires both the standardization of sequencing procedures and continuous validation of sequencing results by orthogonal methods in an ongoing program to enable the determination of key test parameter…
Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers
Abstract The clinical relevance of comprehensive molecular analysis in rare cancers is not established. We analyzed the molecular profiles and clinical outcomes of 1,310 patients (rare cancers, 75.5%) enrolled in a prospective observational study by the German Cancer Consortium that applies whole-genome/exome and RNA sequencing to inform the care of adults with incurable cancers. On the basis of 472 single and six composite biomarkers, a cross-institutional molecular tumor board provided evidence-based management recommendations, including diagnostic reevaluation, genetic counseling, and experimental treatment, in 88% of cases. Recommended therapies were administered in 362 of 1,138 patient…
Revised risk estimation and treatment stratification of low- and intermediate-risk neuroblastoma patients by integrating clinical and molecular prognostic markers.
Abstract Purpose: To optimize neuroblastoma treatment stratification, we aimed at developing a novel risk estimation system by integrating gene expression–based classification and established prognostic markers. Experimental Design: Gene expression profiles were generated from 709 neuroblastoma specimens using customized 4 × 44 K microarrays. Classification models were built using 75 tumors with contrasting courses of disease. Validation was performed in an independent test set (n = 634) by Kaplan–Meier estimates and Cox regression analyses. Results: The best-performing classifier predicted patient outcome with an accuracy of 0.95 (sensitivity, 0.93; specificity, 0.97) in the validation coh…
RSPO2 gene rearrangement: a powerful driver of β-catenin activation in liver tumours
ObjectiveWe aimed at the identification of genetic alterations that may functionally substitute for CTNNB1 mutation in ß-catenin-activated hepatocellular adenomas (HCAs) and hepatocellular carcinoma (HCC).DesignLarge cohorts of HCA (n=185) and HCC (n=468) were classified using immunohistochemistry. The mutational status of the CTNNB1 gene was determined in ß-catenin-activated HCA (b-HCA) and HCC with at least moderate nuclear CTNNB1 accumulation. Ultra-deep sequencing was used to characterise CTNNB1wild-type and ß-catenin-activated HCA and HCC. Expression profiling of HCA subtypes was performed.ResultsA roof plate-specific spondin 2 (RSPO2) gene rearrangement resulting from a 46.4 kb microd…
An integrated genome research network for studying the genetics of alcohol addiction
Alcohol drinking is highly prevalent in many cultures and contributes to the global burden of disease. In fact, it was shown that alcohol constitutes 3.2% of all worldwide deaths in the year 2006 and is linked to more than 60 diseases, including cancers, cardiovascular diseases, liver cirrhosis, neuropsychiatric disorders, injuries and foetal alcohol syndrome. Alcoholism, which has been proven to have a high genetic load, is one potentially fatal consequence of chronic heavy alcohol consumption, and may be regarded as one of the most prevalent neuropsychiatric diseases afflicting our society today. The aim of the integrated genome research network 'Genetics of Alcohol Addiction'-which is a …