Plasma diagnostics of cell-free nucleic acids in malignant disease: towards actionable health information in Laboratory Medicine


Michael Neumaier, MD PhD

EFLM President

Institute for Clinical Chemistry, Medical Faculty Mannheim of Heidelberg University, Mannheim, Germany


The detection of malignant disease has been among the most daunting challenges for Laboratory Medicine for a number of reasons. To acknowledge the importance of the recent analytical developments, one needs to appreciate the methodological capabilities available in routine diagnostic health care so far.

Traditionally confined to the phenotypic analysis in blood and bodily fluids, laboratory diagnostics had to rely on surrogate markers as defined by monoclonal antibodies since the 1980s. The vast majority of these markers are normal tissue differentiation antigens – mostly proteins – and are by no means “tumour-specific”, but rather “tumour-associated” and thus are not recommended for early and primary diagnosis. Importantly, no markers exist in Laboratory Medicine to assess tumour variability, dignity and tissue of origin, internal microheterogeneities and dynamic biological properties, the tumour´s different metastatic capacity or ability to lie dormant for years.

Irrespective of the limitations of phenotypic analysis, all tumours feature molecular defects for the initiation of malignant growth and progression of systemic disease. With the advent of Genomics and functional Genomics, these defects are routinely being investigated by the Molecular Pathologist as specific genomic footprints in the tumour tissue.

Recent advances in molecular methods now allow the identification of these tumour-specific genetic footprints in blood and bodily fluids, thus changing the tables for Laboratory Medicine. As genetic defects constitute potential targets for new biomolecular therapies e.g. antibodies or small molecules, the molecular tumour profiles of circulating tumour-derived cell-free nucleic acids in blood (liquid profiling) represent actionable health information with direct impact for clinical decision-making. There is a rapidly increasing body of literature demonstrating the implications of liquid profiling (aka liquid biopsy) for therapeutic decisions, early detection of therapy failure due to escaping mechanisms. Very recently, the combination of proteomic approaches in combination with the detection of circulating tumour-DNA has been suggested for early primary diagnosis and possibly for screening for some cancers (1). Interestingly, the “protein diagnostic arm” in this study really represented well-known classical serum tumour markers like CEA, PSA, CA-125 and others.

The presentation will focus on the systematic principles, recent analytical advances and their implications and the potential that a combined genotype/phenotype strategy may have for future improved cancer diagnostics in Laboratory Medicine.



  • Cohen JD et al. Science (2018); 359 (6378), 926-930


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