Tumor Type

Germany
Malignant Lymphoma - Germinal center B-cell derived lymphomas
Project Profile
Funding Organizations
Research Organizations
Research Activities
Publication Policy

1:   ICGC Goals, Structure, Policies and Guidelines Section E.3 - Publication Policy HTML 
2:   Template Letters to Facilitate Communications HTML 
to ensure appropriate dialogue between data users and generators and for authors to contact ICGC members and editors
Clinic & Pathology

Germany: Christian-Albrechts-University Kiel
Georg-August-University Göttingen
Goethe University Frankfurt
Lymphoma Study Groups (NHL-BFM, GLSG, DSHNHL)
Ulm University
University Cancer Center Göttingen (CCC)
University Hospital Giessen
University Hospital Grosshadern, LMU Munich
University of Berlin
University of Duisburg-Essen
University of Lübeck
University of Würzburg
University Stuttgart

The availability of qualified materials is ensured by workpackages (WP) 1-3 which cover ethical aspects, patient recruitment from clinical trials as well as characterization of the materials and quality control. It applies the well established structures of the clinical trials groups and the core quality control pipeline of the MMML with main representatives of the DSHNHL, GLSG/EuMCL and NHL-BFM leading the clinical trial-related case acquistion (WP1). The quality control of the tumor samples is performed by the well established network of the German Lymphoma Reference Pathology Centers (WP2). The preparation of analytes (WP3) again follows established quality controlled processes established in the MMML. “Normal” germinal center B-cell subsets will be provided by a dedicated workpackage (WPN).

Sequencing & Analysis

Germany: Charité – University Medicine Berlin
Christian-Albrechts-University Kiel
Düsseldorf University
European Molecular Biology Laboratory (EMBL)
German Cancer Research Center (DKFZ)
University of Würzburg

High-throughput, step-wise progressive sequencing of genomic DNA from lymphomas and corresponding germline DNA (WP4) complemented by RNA (WP5, WP6) sequencing as well as methylome sequencing (WP7) will be performed. Due to the somatic mutation process being active also in normal germinal center B-cells analysis of “the germline” will be challenging and not possible in a classical sense (simply as peripheral blood or buccal smear cells might not represent to true “germline” counterpart of the malignant cells). Therefore, additional “normal” germinal center B-cell subsets will be analyzed for control purposes. The sequencing strategies will take into account the expected developments in throughput, techniques and cost development.

Complementary Studies

Germany: Charité – University Medicine Berlin
Christian-Albrechts-University Kiel
Düsseldorf University
German Cancer Research Center (DKFZ)
University of Würzburg

In three complementary studies of ICGC MMML-Seq focuses on:

1) The sequencing of the complete transcriptome of lymphomas samples with different phenotype
2) The analysis of the small RNAome in lymphoma
3) The sequencing of the complete methylome of lymphoma samples with different origin

All complementary studies as well as the genome sequencing project will analyze the same set of histologically and clinically well characterized samples to create maximum value from the analyses.

Data Storage, Analysis & Management

Germany: German Cancer Research Center (DKFZ)
University of Leipzig

Bioinformatics analysis of sequencing data on all levels (genome, mRNA and small-RNA transcriptomes, methylome) will be a key aspect of the work in ICGC-MMML-seq. After initial alignment of raw sequencing reads to a reference genome, mutations (point mutations, indels and copy number variations) need to be identified, transcripts assembled and analyzed for alternative splicing and allele-specific expression, and regions displaying differential DNA methylation detected. This work is carried out in WP8. Additionally, we will integrate sequencing data in WP9 to characterize genotype-phenotype associations, develop models of tumor progression and identify oncogenic pathways relevant for lymphoma pathogenesis. A major strength of the consortium is a unique alliance of strong bioinformatics groups who will share the workload. Data management of all sequence data and the genome sequence analysis will be undertaken by the Heidelberg group around R Eils (DKFZ), that has great experience already in other ICGC-consortia and has coordinated the central bioinformatics platform within the National Genome Research Network (NGFN) over more than six years. The Peter Stadler and Steve Hoffman group (Leipzig, IZBI, LIFE) is internationally known for its expertise in RNA-sequence analysis and have created novel algorithms particularly for the identification and characterisation of short and long ncRNA. The Löffler-group has contributed enormously to the international success of the German lymphoma research. The group is responsible for biometry and bioinformatics of the existing research consortia on “Molecular Mechanisms in Malignant Lymphoma (MMML)”. This enables future direct access to large data sets of carefully phenotyped patients treated in prospective trials. In addition all bioinformatics groups have expertise in the field of system biological modeling (structural pathway models, dynamic gene regulatory models). Löffler is leading a national systems biological network on lymphoma and leukemia clonal evolution (HaematoSys) to whom ICGC will synergize. The Leipzig Research center for civilization diseases LIFE is a novel large research activity to investigate gene environment interactions by profiling with Löffler is the coordinator of the center and Steve Hoffmann leads a research group on genome informatics. Finally, particular bioinformatics comes also through some of the sequencing workpackages e.g. by the group of Jan Korbel (WP4).

Project Publications
Project Summary

The ICGC-MMML-Seq (Molecular Mechanisms in Malignant Lymphoma by Sequencing) Consortium is the continuation of a long and outstanding tradition of interdisciplinary, multicenter and formalized collaboration in the field of lymphoma research in Germany. It is based on strongly interacting networks of reference pathologists, lymphoma scientists and clinical trial groups. These groups have joined-up in the ICGC-MMML-Seq with internationally renowned groups in the field of high-throughput sequencing and sequence analysis. The partners have broad experience in large international sequencing consortia. A unique alliance of strong bioinformatics groups with distinct and complementary expertise and a clear share of the workload will cover data management, sequence analysis, genotype-phenotype association and pathway modeling in the most efficient way.

The ICGC-MMML-Seq Consortium aims at analyzing germinal-center derived B-cell malignant (non-Hodgkin) lymphomas (GCB-lymphomas). The core subtypes of GCB-lymphoma to be analysed will be follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma/leukemia (BL) with clinical or histologic variants or grey-zone forms to be added. The selection of this tumor type is based on its frequency (GCB-lymphomas are by far the most frequent malignant lymphomas in children and adults), its clinical relevance (30-50% of patients die from the disease), its socio-economic burden (GCB-lymphomas are systemic and frequently chronic diseases requiring recurrent cost-intensive therapies), the availability of qualified material (from the systematic collection in reference pathologies, clinical trials and the MMML research network) and overlapping biologic/genetic features. The analysis pipeline of the ICGC-MMML-Seq contains three pre-analysis workpackages responsible for standardized sample acquisition through the clinical trials groups (WP1), reference pathology (WP2) and preparation of analytes (WP3), which widely uses the established structure of the German MMML lymphoma network. A special WPN will in addition provide samples from normal B-cells in order to challenge the “germline problem inherent to B cells” which suffers somatic mutations under physiologic conditions. Sequencing will cover genome (WP4), transcriptome (WP5), small RNAome (WP6) and DNA-methylome (WP7). Due to the expected changes in sequencing technology and costs the steering committee will centrally monitor and allocate all sequencing slots of the consortium to ensure cost effective usage of funds for highest quality sequencing. In an initial pilot phase sequences of a restricted but utmost informative sets of tumors and controls will be obtained whereas the second phase production will scale up to all GCB-lymphomas and germline controls to be analyzed. Stepwise analysis of sequence data will be performed in two workpackages (WP8 and WP9) which shall ensure integrative and most comprehensive evaluation of all sequencing data. Central coordination (WP C1) is supported by the steering committee and supervised by Scientific and Ethical Advisory Boards which well renowned experts agreed to join.

A special “ICGC Scientist” shall ensure international exchange with other ICGC groups (particularly the project dealing with chronic lymphocytic leukemia in Barcelona). Perspectively, the ICGC-MMML-Seq is even prepared to rapidly translate findings from the ICGC sequencing pipeline into clinics through the unique collections from clinical trials readily available for molecular analysis.

Principal Investigators

• Prof. Dr. med. Reiner Siebert (Coordinator ICGC-MMML-Seq)
• Dr. Ole Ammerpohl
• PD Dr. Hans Binder
• Dr. Vera Binder
• Prof. Dr. Arndt Borkhardt
• Dr. Benedikt Brors
• Dr. Birgit Burkhardt
• Prof. Dr. Martin Dreyling
• Prof. Dr. Roland Eils
• Prof. Dr. Martin-Leo Hansmann
• Dr. Steve Hoffmann
• PD Dr. Michael Hummel
• PD Dr. Wolfram Klapper
• Dr. Jan Korbel
• apl Prof. Dr. Dieter Kube
• Prof. Dr. Ralf Küppers
• Prof. Dr. Peter Lichter
• Prof. Dr. Markus Loeffler
• Prof. Dr. Peter Möller
• Prof. Dr. Philip Rosenstiel
• Prof. Dr. Andreas Rosenwald
• Prof. Dr. Stefan Schreiber
• Prof. Dr. Peter Stadler
• Prof. Dr. Lorenz Trümper

Lead Jurisdiction