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Diagnostik- und Forschungszentrum
Liquid BiopsyResearchDiagnostic and Research Center for Molecular BiomedicineResearch centers and institutesMedical University of Graz

Research team Heitzer

Research focus: Liquid Biopsy

PI's: Ellen Heitzer, Jochen Geigl

Focus: Tumors release components such as of cell-free DNA fragments (ctDNA, circulating tumor DNA) or viable cells (CTC, circulating tumor cells) into the circulation, which reflect their genetic or epigenetic landscape. Therefore, CTC and ctDNA can be used for molecular profiling and prognostication purposes for malignant diseases from blood and other body fluids. The Liquid Biopsy (LB) holds great promise for precision and personalized medicine and in particular, ctDNA has been demonstrated to be a valuable tool to detect cancer recurrence, to predict tumor burden and treatment response, as well as to identify resistance mechanisms and the emergence of novel actionable targets has been proven in numerous studies summarized monitor recurrence, resistance, metastasis and minimal residual disease. Our LB group at the D&F Institute of Human Genetics has extensive experience in the analysis of plasma DNA. We have established a plethora of plasma DNA based approaches to study genome-wide SCNAs and high-sensitivity approaches to detect specific mutations occurring at low allele frequencies. In this highly competitive field, our group is one of the most renowned in the field.

Network: Our group has many fruitful collaborations with the university as well as at national and international level:

  • Medical University of Graz: We have experienced clinical partners various types of solid tumors at the Division of Oncology, the Division of General Gynecology and the Department of Urology. Moreover, we collaborate with the Divisions of Hematology, Pediatric Haematology/Oncology and the Department of Orthopaedics and Trauma in the context of hematological diseases and sarcoma. In addition we have a longstanding collaboration with the Institute of Pathology at the MUG or the Department of Pathology, at the LKH II. Furthermore, we have an intensive collaboration with the Institute for Medical Informatics, Statistics and Documentation.
  • Our liquid biopsy-related research is performed within established international networks, i.e. through the CANCER-ID consortium (www.cancer-id.eu), a public-private partnership supported by Europe’s Innovative Medicines Initiative (IMI), which was coordinated by the University Medical Center Hamburg-Eppendorf (Prof. K. Pantel), University of Twente (Prof. L. Terstappen), Bayer HealthCare (Dr. T. Schlange) and Menarini (Dr. B. Baggiani) and which is now being continued by European Liquid Biopsy Society (ELBS).
  • Moreover, we have well established connections to leading liquid biopsy groups at the University of Cambridge, Cancer Research UK, the Memorial Sloan Kettering Cancer Center, the University of Wisconsin, University Medical Center Groeningen etc.

Our expertise has been recognized internationally by invitations to international congresses, reviews and book chapters in international journals.

Projects

Development of ctDNA analysis approaches

  • We aim to make analysis from plasma DNA amenable to clinical routine applications. Therefore we have already developed several ctDNA approaches which enable to noninvasively reconstruct the tumor genome. Using our plasma-seq approach, which is constantly improved, we are able to call for genomewide copy number alterations including focal alterations, which are driving forces for tumor progression. Our previous studies with plasma DNA from patients with cancer demonstrated highly variable allele frequencies of ctDNA. The comprehensive analysis of tumor genomes is greatly facilitated when plasma DNA has increased amounts of ctDNA. Therefore, we have developed a fast and cost-effective method to quantify the tumor level in a given sample. Currently we are working to increase the resolution of your approaches.
  • Duration: ongoing
  • Funded by: BioTechMed-Graz flagship project EPIAge, Cancer-ID (Europe’s Innovative Medicines Initiative grant agreement #115749), FWF Projekte P20338, P23284 und W 1226-B18, DKplus Metabolic and Cardiovascular Disease, Oesterreichische Nationalbank (Projekt 15093)
  • Project partners: Division of Oncology, Med Uni Graz, Department of Gynecology, Med Uni Graz, Department of Urology, Med Uni Graz, Division of Haematology, Med Uni Graz, Division of Paediatric Haematology/Oncology, Med Uni Graz, Division of Paediatric Orthopaedics, Med Uni Graz, R&D Institute of Pathology, Med Uni Graz, Department of Pathology, LKH II, Department of Internal Medicine, LKH Fürstenfeld, LKH Hochsteiermark, CEMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences: Christoph Bock, Berlin Institute of Health, JRG Computational Genome Biology: Martin Kircher

Biological Plasma DNA Profiling

  • We explore novel plasma DNA analysis strategies, which are based on the observation that cfDNA fragments are associated with the release of DNA from apoptotic cells after enzymatic processing since the distribution of their lengths has a mode near 166 bp. This size corresponds approximately to the DNA wrapped around a nucleosome (~147 bp) plus a linker fragment (~20 bp).  Since DNA region that are not bound to proteins are preferentially degraded during apoptosis, these region are less abundant in the circulation compared to the nucleosome protected regions. Due to this unique property of cfDNA nucleosome occupancy pattern can be inferred from next generation sequencing data and give hints about the activation status of genes or transcription factors enabling a functional analysis form plasma DNA sequencing.
  • Duration: ongoing
  • Funded by: BioTechMed-Graz flagship project EPIAge
  • Project partners: CEMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences: Christoph Bock, Berlin Institute of Health, JRG Computational Genome Biology: Martin Kircher

Tumour subtype stratification based on liquid biopsy

  • The estimation of prognosis and treatment strategies increasingly depends on the stratification of tumours into different entities or subtypes. The most comprehensive molecular-based taxonomy of breast cancer is based on a combination of gene expression and somatic copy number alterations (SCNA) called integrative clusters (IntClust). We are investigating whether these subclusters can be formed directly from plasma DNA and whether this leads to improved stratification of women with breast cancer. By including primary tumour analyses, we will gain an unprecedented view of breast cancer genome evolution. We are also pursuing similar approaches in prostate cancer.
  • Duration: 2019-2022
  • Funded by: FWF KLI 710, KLI 764
  • Project partners: Divisions of Gynaecology, Oncology and Department of Urology at the Medical University of Graz, Diagnostic and Research Institute of Pathology at the Med Uni Graz, Institute of Medical Informatics, Statistics and Documentation, CEMM: Christoph Bock, Jerome Galon (Paris)

Standardisation of liquid biopsy approaches

  • CANCER-ID is a European consortium supported by Europe’s Innovative Medicines Initiative (IMI). The Public-Private-Partnership with currently 36 partners from 13 countries and aims at the establishment of standard protocols for and clinical validation of blood-based biomarkers. It brings together experts from academic and clinical research, innovative Small-to-Medium sized Enterprises (SMEs), diagnostics companies and the pharmaceutical industry thus providing a unique setting for establishing clinical utility of liquid biopsies. Our group has been leading the ctDNA working group. The conclusion from our group is that our comprehensive multicenter comparisons of ccfDNA preanalytical and analytical work flows are an important contribution to establishing evidence-based guidelines for clinically feasible (pre)analytical work flows.
  • Duration: Cancer-ID 2015-2019, ELBS: since 2020
  • Funded by: CANCER-ID, a project funded by the Innovative Medicines Joint Undertaking (IMI JU; #115749-1)
  • Project partners: Public-Private-Partnership with currently 36 partners from 13 countries

Christian Doppler-Laboratories: Liquid Biopsy for Early Cancer Detection

  • A CD lab enables scientific collaboration between globally leading biotech companies in the fields of pre-analytics and molecular diagnostics, and scientists at the MUG. We were granted a Christian Doppler (CD) laboratory with a seven-year budget of 2.08 mio. EUR and two industry partner, i.e. Freenome and PreAnalytiX. Currently a lack of knowledge about the nature and biology of circulating tumor DNA (ctDNA) prevents a rapid application of blood-based tests for early cancer detection. Therefore, the main goal of our CD Laboratory is to further elucidate ctDNA biology, improve existing analytical methods, and develop advanced bioinformatics tools that will enable detection of cancer at its earliest stage (Modul 1). In addition we focus on the pre-analytical requirements of liquid biopsy to ensure reliable data generation (Modul 2). Merging clinical and genomic data through the use of sophisticated bioinformatics approaches and databases will ultimately improve the early detection rate of cancer patients.
  • Duration: 2017-2024
  • Funded by: Christian Doppler Research Laboratory for Liquid Biopsies for Early Detection of Cancer funded by the Austrian Federal Ministry for Digital and Economic Affairs
  • Project partners: PreAnalytiX, Freenome, D&R Institute of Pathology, Med Uni Graz, Divisions of General Gynaecology and Oncology, Department of Urology, Med Uni Graz, CeMM, ABCSG, CBMed, St. Anna Kinderkrebsforschung, Chris Smith, Nitzan Rosenfeld (Cancer Research UK Cambridge Institute), Tony Godfrey (School of Medicine, Boston University), Muhammed Murtaza (University of Wisconsin School of Medicine and Public Health), Ed Schuuring, Harry Groen (University of Groningen), Caus Lindbjerg Andersen (Aarhus University), Anders Stahlberg (University of Gothenburg), Abteilung für Pathologie am LKH II, Abteilung für Chirurgie der Barmherzigen Brüder, Abteilung für Chirurgie am LKH II

Diagnostic and Research Institute of Human Genetics

Ellen Heitzer  
T: +43 316 385 73819
E: ellen.heitzer(at)medunigraz.at
Ellen Heitzer
Research profile

Diagnostic and Research Institute of Human Genetics

Jochen Bernd Geigl 
T: +43 316 385 73832
E: jochen.geigl(at)medunigraz.at
Jochen Geigl
Research profile
CD-Labor

Non-invasive cancer screening

Liquid Biopsy has a wide range of uses in cancer treatment and is used for ongoing monitoring of the course of therapy. It is also considered to be a promising approach for early cancer detection by examining a blood sample without tissue biopsies. A Christian Doppler Laboratory was set up together with corporate partner Freenome Holdings and funded by the Federal Ministry for Digitization and Business Location.

For a broad use of Liquid Biopsy outside of clinical studies and research projects, the sensitivity and accuracy or the predictive and prognostic value of the ctDNA must be evaluated in large prospective studies.

Further Information

Christian Doppler Labor

Video aus der Reihe "Wissenswert"

Team

Members