Liquid biopsy in hematological malignancies: current and future applications

Abstract

The assessment of the cancer mutational profile is crucial for patient management, stratification, and therapeutic decisions. At present, in hematological malignancies with a solid mass, such as lymphomas, tumor genomic profiling is generally performed on the tissue biopsy, but the tumor may harbor genetic lesions that are unique to other anatomical compartments. The analysis of circulating tumor DNA (ctDNA) on the liquid biopsy is an emerging approach that allows genotyping and monitoring of the disease during therapy and follow-up. This review presents the different methods for ctDNA analysis and describes the application of liquid biopsy in different hematological malignancies. In diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL), ctDNA analysis on the liquid biopsy recapitulates the mutational profile of the tissue biopsy and can identify mutations otherwise absent on the tissue biopsy. In addition, changes in the ctDNA amount after one or two courses of chemotherapy significantly predict patient outcomes. ctDNA analysis has also been tested in myeloid neoplasms with promising results. In addition to mutational analysis, liquid biopsy also carries potential future applications of ctDNA, including the analysis of ctDNA fragmentation and epigenetic patterns. On these grounds, several clinical trials aiming at incorporating ctDNA analysis for treatment tailoring are currently ongoing in hematological malignancies.

Analysis of 3760 hematologic malignancies reveals rare transcriptomic aberrations of driver genes

“…Consequently, NPM1 was not prioritized by our driver gene prediction model. We have not characterized circulating DNA specifically, which has the potential to detect driver genes in hematologic malignancies [ 120 ] because its applicability varies within the different leukemia entities and is often limited due to its sensitivity [ 121 ]. Additionally, we did not include gene fusion and copy number variation calls, which are frequent causes of hematologic malignancies, into the driver gene prediction model, as we found them to have very high false positive rates during preliminary investigations.…”

Non-invasive prenatal test identifies circulating cell-free DNA chromosomal abnormalities derived from clonal hematopoiesis in aggressive hematological malignancies

“…Moreover, accurate MRD monitoring, an important prognostic marker, is challenging, because it relies on sensibility and specificity of used method and disease burden [ 29 , 30 ]. Liquid biopsy from cfDNA is a sensitive method for tumor genotyping, prognostic definition, and disease monitoring, and its utility is increasingly studying in hematological malignancies [ 4 ]. Here, we investigated clinical utility of NIPT-based liquid biopsy in plasma cell dyscrasias, B-cell lymphomas for identification of chromosomal abnormalities and correlation with clinical outcomes, showing a comparable sensitivity of NIPT to standard routinary used methods, such as FISH and karyotyping.…”

“…Plasma cfDNA is predominantly of hematopoietic origin with approximately 55% from white blood cells and 30% from erythrocyte progenitors [ 32 ]. In solid tumors or hematological malignancies, cfDNA comprises of nucleic acids derived from both hematopoietic and tumor cells, known as circulating tumor DNA (ctDNA), and its levels vary across clinical entities, disease stage, and tumor burden [ 4 ]. Therefore, cfDNA can be used as a surrogate sample for detection of tumor-related genomic alterations, and quantification of circulating mutation frequency highly mirrors disease burden [ 33 ].…”

“…Therefore, cfDNA can be used as a surrogate sample for detection of tumor-related genomic alterations, and quantification of circulating mutation frequency highly mirrors disease burden [ 33 ]. Cancer personalized profiling by deep sequencing (CAPP-Seq) and PhasED-seq is highly accurate technologies for identification of somatic mutations and for disease monitoring in DLBCL and HL; however, these methodologies are time consuming, expensive, require high specialized personnel, and are low reproducible across laboratories [ 4 ]. Moreover, data normalization, assay standardization, and validation of liquid biopsy methodologies are still challenging, because of several technical issues, including choice of housekeeping genes, normalization methods, nucleic acid degradation rate, or small amounts of ctDNA, especially in those subjects with low tumor burden [ 12 ].…”

“…Liquid biopsy is a minimally invasive procedure that allows detection of various circulating tumor-associated components, such as cell-free nucleic acids or exosomes [ 2 , 3 ], for somatic mutation screening in cancer-associated genes and monitoring of minimal residual disease (MRD) [ 4 , 5 ]. Circulating cell-free DNA (cfDNA) is shed by apoptotic or necrotic cells, such as highly proliferating cancer cells, and released into the bloodstream, thus being extremely representative of tumor tissue genomic heterogeneity, such as during Hodgkin (HL) and non-Hodgkin B-cell lymphomas [ 6 – 8 ].…”