Cell‐free DNA — Minimally invasive marker of hematological malignancies

Abstract

Although tumor cells are the most reliable source of tumor DNA, biopsy of the tumor is an invasive procedure that should be avoided in some cases. The main limitation of any biopsy is sampling of one tumor site, which may not represent all malignant clones due to the heterogeneity of the tumor. These clones respond to treatment differently and thus directly influence survival of the patient. Circulating cell-free DNA (cfDNA) is released from multiple tumor sites, reflects overall heterogeneity of the tumor, and correlates with its progression. Detection of tumor-specific genetic and epigenetic aberrations in cfDNA could have a direct impact on molecular diagnosis, prognosis, follow-up of disease, monitoring of minimal residual disease, and response to treatment. While most cfDNA data are still experimental, they are very promising. This review focuses on cfDNA in hematological malignancies. K E Y W O R D Sacute lymphoblastic leukemia, acute myeloid leukemia, multiple myeloma, myelodysplastic syndromes | INTRODUCTION AND HISTORYIn recent years, significant advances in diagnosis and treatment of cancer have been made. Nevertheless, invasive and painful procedures, such as tissue or bone marrow (BM) biopsy, are gold standard for disease diagnosis and monitoring. At the same time, they should be avoided in some cases-if BM is fibrotic or tumor tissue is not easily accessible.1 As a single tumor site is sampled during BM biopsy, it may not contain all malignant clones. 2,3 As these clones react to treatment differently, they directly influence survival of patients; thus, easily accessible markers that would mirror the entire heterogeneity of the tumor are sought after. Such putative markers are present in peripheral blood (PB), for example, circulating tumor cells (CTC) or circulating nucleic acids. 3,4 Biopsies of PB-the so-called liquid biopsies-are at the center of attention of researchers as well as clinicians and represent a newer and more comprehensive approach to obtain tumor information. Analysis of circulating molecules (microRNA, cell-free DNA, and others) as well as CTC might describe the tumor in more detail.Cell-free DNA (cfDNA) is one of these possibilities.CfDNA is formed by DNA fragments. These fragments are gathered from all tumor sites into circulation; thus, they mirror the complexity and heterogeneity of the entire tumor. 3 CfDNA may serve as an excellent diagnostic marker as it reflects the disease in more detail than existing biomarkers. Moreover, because of easy access, cfDNA sampling is suitable for repeated analyses. 4 As it correlates with disease progression, it could serve as a prognostic marker as well. 5,6The first reference of cfDNA dates back to 1948. In that year, CfDNA may shortly become such a marker. | CHARACTERISTICS OF CFDNAMolecules of cfDNA are extracellular fragments of short doublestranded DNA found in PB and other body fluids, for example, in urine, saliva, breast milk, and synovial fluid. 16,17 Generally, cfDNA is found in very low concentrations in PB of HD (10-100...

Dynamics of tumor‐specific cfDNA in response to therapy in multiple myeloma patients

“…It provides non‐ or minimally invasive alternative to diagnosis, treatment monitoring and MRD monitoring from body fluids . One of the most promising target molecules in liquid biopsies are cell‐free DNA (cfDNA), short double‐stranded DNA molecules circulating in various body fluids . Low levels of these molecules can be found even in healthy individuals; however, levels of cfDNA were found to be considerably elevated in various pathological conditions .…”

“…One of the most promising target molecules in liquid biopsies are cell‐free DNA (cfDNA), short double‐stranded DNA molecules circulating in various body fluids . Low levels of these molecules can be found even in healthy individuals; however, levels of cfDNA were found to be considerably elevated in various pathological conditions . The use of cfDNA for MRD evaluation in various hematological malignancies was described several times as having promising results .…”

“…9,10 Low levels of these molecules can be found even in healthy individuals; however, levels of cfDNA were found to be considerably elevated in various pathological conditions. 9 The use of cfDNA for MRD evaluation in various hematological malignancies was described several times as having promising results. [11][12][13] Moreover, cheap, reliable, and sensitive method of detection of these molecules and MRD in general is one of the top priorities in the field.…”

Evaluation of minimal residual disease in childhoodALL

“…Although not yet implemented for childhood ALL, the development of new methods using circulating DNA could provide less invasive approaches . Indeed, these techniques use a small amount of plasma in which abnormal DNA issued from the tumor cells is amplified and characterized.…”

Circulating exosomal long noncoding RNA PRINS—First findings in monoclonal gammopathies

“…Liquid biopsies (biopsies of peripheral blood) represent a real promise for such diseases since circulating molecules detectable in peripheral blood (PB) mirror the complex heterogeneity of MG and can serve as potential diagnostic, prognostic, and predictive markers. We and others showed that these molecules include cell‐free DNA and noncoding RNA (ncRNA), especially microRNA (miRNA) and long noncoding RNA (lncRNA) . LncRNA expression is tissue specific and implicated in diverse biological functions .…”