S Semper

Universitätsklinikum Erlangen

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Co-Authors

Markus Metzler

Universitätsklinikum Erlangen

Manuela Krumbholz

Universitätsklinikum Erlangen

U Jacobs

Friedrich-Alexander-Universität Erlangen-Nürnberg

Thorsten Langer

University of Freiburg

Ingmar Glauche

University Hospital Carl Gustav Carus

Heiko von Goessel

Universitätsklinikum Erlangen

Martin Schrappe

University Hospital Schleswig-Holstein

Meinolf Suttorp

TU Dresden

Johanna Eiblwieser

Universitätsklinikum Erlangen

Christian Volz

University of Freiburg

Cooperative Institutions

St Anna Children's Hospital

Universitätsklinikum Erlangen

St. Anna Children's Cancer Research Institute

Medical University of Vienna

Institut Curie

Friedrich-Alexander-Universität Erlangen-Nürnberg

Community College of Rhode Island

Cancer Research Institute of the Slovak Academy of Sciences

University Hospital Schleswig-Holstein

University of Lübeck

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Multimodal analysis of cell-free DNA whole-genome sequencing for pediatric cancers with low mutational burden

Nature Communications (2021)

Peter Peneder Adrian M. Stütz Didier Surdez Manuela Krumbholz S Semper

Sequencing of cell-free DNA in the blood of cancer patients (liquid biopsy) provides attractive opportunities for early diagnosis, assessment of treatment response, and minimally invasive disease monitoring. To unlock liquid biopsy analysis for pediatric tumors with few genetic aberrations, we introduce an integrated genetic/epigenetic analysis method and demonstrate its utility on 241 deep whole-genome sequencing profiles of 95 patients with Ewing sarcoma and 31 patients with other pediatric sarcomas. Our method achieves sensitive detection and classification of circulating tumor DNA in peripheral blood independent of any genetic alterations. Moreover, we benchmark different metrics for cell-free DNA fragmentation analysis, and we introduce the LIQUORICE algorithm for detecting circulating tumor DNA based on cancer-specific chromatin signatures. Finally, we combine several fragmentation-based metrics into an integrated machine learning classifier for liquid biopsy analysis that exploits widespread epigenetic deregulation and is tailored to cancers with low mutation rates. Clinical associations highlight the potential value of cfDNA fragmentation patterns as prognostic biomarkers in Ewing sarcoma. In summary, our study provides a comprehensive analysis of circulating tumor DNA beyond recurrent genetic aberrations, and it renders the benefits of liquid biopsy more readily accessible for childhood cancers.

Liquid biopsy

Cell-free fetal DNA

10.1038/s41467-021-23445-w

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Citations (140)

Cluster analysis of genomic ETV6–RUNX1 (TEL–AML1) fusion sites in childhood acute lymphoblastic leukemia

Leukemia Research (2008)

Heiko von Goessel U Jacobs S Semper Manuela Krumbholz Thorsten Langer

Breakpoint

ETV6

Minimal Residual Disease

clone (Java method)

Multiplex

10.1016/j.leukres.2008.11.001

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Citations (19)

Continuous therapy response references for BCR::ABL1 monitoring in pediatric chronic myeloid leukemia

Scientific Reports (2023)

Christian Volz Thomas Zerjatke Andrea Gottschalk S Semper Meinolf Suttorp

Abstract Response to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML) is monitored by quantification of BCR::ABL1 transcript levels. Milestones for assessing optimal treatment response have been defined in adult CML patients and are applied to children and adolescents although it is questionable whether transferability to pediatric patients is appropriate regarding genetic and clinical differences. Therefore, we analyzed the molecular response kinetics to TKI therapy in 129 pediatric CML patients and investigated whether response assessment based on continuous references can support an early individual therapy adjustment. We applied a moving quantiles approach to establish a high-resolution response target curve and contrasted the median responses in all patients with the median of the ideal target curve obtained from a subgroup of optimal responders. The high-resolution response target curve of the optimal responder group presents a valuable tool for continuous therapy monitoring of individual pediatric CML patients in addition to the fixed milestones. By further comparing BCR::ABL1 transcript levels with BCR::ABL1 fusion gene copy numbers, it is also possible to model the differential dynamics of BCR::ABL1 expression and cell number under therapy. The developed methodology can be transferred to other biomarkers for continuous therapy monitoring.

breakpoint cluster region

ABL

10.1038/s41598-023-45364-0

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Citations (1)

Identification of first and second genomic lesions in ETV6-RUNX1 positive childhood acute lymphoblastic leukaemia (ALL)

Klinische Pädiatrie (2009)

Manuela Krumbholz U Jacobs S Semper Heiko von Goessel Thorsten Langer

Background: The ETV6-RUNX1 translocation, resulting from t(12;21)(p13;q22), is the most common chromosomal translocation in childhood ALL. The genomic ETV6-RUNX1 fusion site is unique to individual patients and represents an ideal molecular marker for absolute quantification. This chromosomal translocation (“first-hit“) alone is insufficient to induce leukemia, additional secondary genetic events (“second-hit“) are necessary.

ETV6

RUNX1

10.1055/s-0029-1222654

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Multiplex Droplet Digital PCR-based Targeted Enrichment NGS for identification of tumor markers in Ewing Sarcoma (EwS)

Klinische Pädiatrie (2019)

Johanna Eiblwieser Manuela Krumbholz S Semper Jakob Zierk Markus Metzler

Background: Genomic EWSR1-FLI1 fusion sequences have been used as non-invasive tumor marker to assess therapy response in EwS patients by quantification of cell-free circulating tumor DNA in plasma samples. Since fresh-frozen tumor biopsies are often not available, fusion sequences have to be identified in highly fragmented DNA from formalin-fixed, paraffin-embedded (FFPE) specimen. Methods: Patient-specific EWS fusion genes were pre-amplified in a multiplex droplet digital PCR (mddPCR) using DNA from FFPE tumor samples. This library was then sequenced with the Ion S5 System. Results: The combination of mddPCR and targeted enrichment NGS improves the success rate for identification of genomic fusion sequences and facilitates their use as a biomarker for ctDNA monitoring. Analyses of ctDNA levels and clinical parameters from EWING2008 patients revealed correlation of ctDNA copy numbers and patients' risk factors. Discussion: MddPCR based targeted enrichment NGS strategy enables the identification of tumor specific fusion sequences from highly fragmented DNA samples and therefore allows their application as molecular tumor marker in a wider range of sample sources.

Multiplex

Circulating tumor DNA

genomic DNA

10.1055/s-0039-1687130

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Therapy assessment of pediatric chronic myeloid leukemia (CML) using combined analyses of RNA/DNA response dynamics

Klinische Pädiatrie (2020)

Christian Volz Andrea Gottschalk Manuela Krumbholz Christian Albert S Semper

Background Optimal treatment of pediatric CML requires a patient specific risk stratification and the comparability of individual therapy responses. A deeper understanding of the CML cells eradication dynamic is needed to make earlier therapy decisions. Methods: Besides transcript-based monitoring, DNA-based quantification was performed using the droplet digital PCR (ddPCR). A total of 1348 specimens from 65 pediatric CML patients were included. Therapy response models were designed separately for RNA-/DNA-monitoring. Data was evaluated using moving quantiles analyses. Results: Combined analyses show a stronger reduction of BCR-ABL1 transcripts compared to BCR-ABL1 copy numbers in the first three months of therapy. These data suggest that the initial reduction of CML cells is lower than the transcript-monitoring indicates. By applying moving quantiles analyses, patient specific therapy responses can be assigned to risk groups. Conclusion: RNA/DNA response models and moving quantiles analyses represent advanced diagnostic techniques to detect poor responders earlier. Prospectively, combined RNA-/DNA quantification may be used to assess the practicability of therapy stop trials.

Quantile

10.1055/s-0040-1709801

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Bimodal distribution of genomic MLL breakpoints in infant acute lymphoblastic leukemia

Klinische Pädiatrie (2009)

Rudolf Jung U Jacobs S Semper Thorsten Langer Anja Moericke

Background: A hallmark of infant leukemia is the high prevalence of chromosomal rearrangements involving the MLL gene. The most frequent partner genes are AF4, AF9, and ENL. Aim of this study was to assess breakpoint distribution within the MLL gene to evaluate association of recombination related sequence DNA motifs.

Breakpoint

10.1055/s-0029-1222648

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CtDNA release mechanisms in a therapeutic Ewing Sarcoma mouse model

Klinische Pädiatrie (2022)

Johanna Eiblwieser Manuela Krumbholz S Semper B Frey L Nagel

EWSR1-FLI1 fusion sequence levels in circulating tumor DNA (ctDNA) have been shown to be a valuable biomarker in Ewing Sarcoma (EwS) patients, which can be used for prediction of treatment response and risk stratification. However, it remains unclear, under which circumstances ctDNA is released into the blood stream during tumor development and therapeutic intervention.

Ewing's sarcoma

10.1055/s-0042-1748696

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