Research Program "Molecular Diagnostics, Early Detection, and Biomarker Development (MDEB)"

The DKTK Program Molecular Diagnostics, Early Detection, and Biomarker Development is dedicated to the discovery of novel diagnostic, prognostic and predictive molecular markers, the development of approaches for cancer prevention, and the translation of these findings into robust biomarkers to improve the clinical management of cancer patients.

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A wealth of molecular data has been generated within DKTK for selected tumor entities. These will be the basis for the development of robust biomarkers for urgent clinical challenges, including novel stratification schemes for pediatric and adult patients with brain tumors and for patients with metastasis in gastrointestinal cancer, the prediction of adjuvant treatment response in breast and ovarian cancer, and biomarkers of relapse and resistance in the management of acute leukemia patients. Several efforts in biomarker development will be in close interactions with the other DKTK Programs. The further expansion the established molecular tumor boards will be imperative for a successful translation of this work.

This Program will develop and validate new techniques for molecular diagnostics by focusing on the analyses of i) liquid biopsies, especially circulating tumor DNA (ctDNA) in body fluids, ii) the non-protein coding information of tumor cell genomes and iii) the proteome of tumor cells.

In cancer prevention, the focus will be on further progress in screening for colorectal cancer (CRC) and its implementation to reduce the burden of this common disease.
 

Selected major translational highlights

Preclinical research:
1. DKTK researchers T. Oellerich and H. Serve (F/MZ) contributed to the collaborative, international study that validated SAMHD1 as a biomarker for prognosis and therapy response in AML, using mouse models of retroviral AML transplantation, as well as retrospective analyses of AML samples from adult patients (Schneider et al., Nat Med 2017).

2. Led by DKTK scientists S. Fröhling and A. Stenzinger (HD), collaborative work involving six DKTK sites (B, DD, FR, HD, M, TÜ) and several non-DKTK German collaborators, compared several systems for the classification of variants detected by large-scale sequencing, and developed and proposed a generalizable classification concept for precision oncology (Leichsenring et al., Int J Cancer 2019).

3. DKTK researchers F. Hertwig, A. Eggert and J.H. Schulte (B), deciphered a new risk group classifier for neuroblastoma patients that will revolutionize individualized treatment in patients with ultra-high-risk neuroblastoma (Ackermann et al., Science 2018).

4. A new genetic mechanism of extrachromosomal circular DNA, which drives oncogenic genome remodeling in neuroblastoma and other cancers was described (Koche et al., Nat Genet 2020).

5. Coordinated by A. Stenzinger (HD) the panel-based Tumor Mutational Burden (TMB) measurement (as a quantitative assessment of the number of somatic mutations within a tumor genome), which is highly relevant for immunotherapy, was harmonized and standardized, and critical sources of variation were assessed (Stenzinger et al., J Thorac Oncol 2020). The published study provided real-world evidence that all evaluated panels can be used to estimate Tumor mutational burden (TMB) in a routine diagnostic setting, and identified important parameters for reliable tissue TMB assessment that require careful control.

6. Led by DKTK researchers D. Capper (B), and S. Pfister, A. von Deimling (HD), a collaborative study group involving scientists from all DKTK sites (B, DD, E/D, F/MZ, FR, HD, M, TÜ), as well as other national and international sites, developed a novel DNA methylation-based classifier for CNS tumors and provided global access to it via an internet portal (Capper et al., Nature 2018).

7. In collaboration with researchers at Vanderbilt University School of Medicine, the group led by H. Brenner (HD) developed and validated a polygenic risk score in a genetic analysis of participants in CRC screening study in Germany, which enables stratification of colorectal neoplasms for CRC screening (Weigl et al., Gastroenterology 2018; Cardoso et al., Lancet Oncol 2021).

Clinical studies:
8. Scientists led by C. Eckert (B), within the ALL-REZ BFM Trial Group (NCT00114348), found that the prognosis of children with late bone marrow B cell ALL relapses could be improved by refined response classification and integration of genetics (Eckert et al., J Clin Oncol 2019).

9. DKTK scientists identified NTRK fusions as a top ‘very high’ priority target in pediatric patients through the INFORM pipeline and successful treatment (CR/PR in most patients) within the LOXO-101 trial (NCT03834961).

Coordinators

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Prof. Dr. Hermann Brenner

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Prof. Dr. Peter Lichter

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Prof. Dr. Gudio Reifenberger