Circulating tumor DNA as a liquid biopsy in plasma cell dyscrasias

Gerber, Bernhard; Manzoni, Martina; Spina, Valeria; Bruscaggin, Alessio; Lionetti, Marta; Fabris, Sonia; Barbieri, Marzia; Ciceri, Gabriella; Pompa, Alessandra; Forestieri, Gabriela; Lerch, Erika; Servida, Paolo; Bertoni, Francesco; Zucca, Emanuele; Ghielmini, Michele; Cortelezzi, Agostino; Cavalli, Franco; Stüssi, Georg; Baldini, Luca; Rossi, Davide; Neri, Antonino

doi:10.3324/haematol.2017.184358

Cited by 34 publications

(39 citation statements)

References 14 publications

(4 reference statements)

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“…Novel diagnostic approaches that make use of cell free tumour DNA (liquid biopsy) are increasingly incorporating sequencing strategies. Several studies have successfully shown the detection of recurrent somatic mutations and copy number variations in MM patients by analysing cell free myeloma DNA [46][47][48] . We provide a validated sequencing approach, including the detection of recurrent translocations, that will increase the diagnostic value of such techniques.…”

Section: Discussionmentioning

confidence: 99%

The combination of WGS and RNA-Seq is superior to conventional diagnostic tests in multiple myeloma: Ready for prime time?

et al. 2020

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The diagnosis and risk stratification of multiple myeloma (MM) is based on clinical and cytogenetic tests. Magnetic CD138 enrichment followed by interphase FISH (fluorescence in situ hybridisation) is the gold standard to identify prognostic translocations and copy number alterations (CNA). Although clinical implications of gene expression profiling (GEP) or panel based sequencing results are evident, those tests have not yet reached routine clinical application. We set up a single workflow to analyse MM of 211 patients at first diagnosis by whole genome sequencing (WGS) and RNA-Seq and validate the results by FISH analysis. We observed a 96% concordance of FISH and WGS results when assessing translocations involving the IGH locus and an overall concordance of FISH and WGS of 92% when assessing CNA. WGS analysis resulted in the identification of 17 additional MYC-translocations that were missed by FISH analysis. RNA-Seq followed by supervised clustering grouped patients in their expected genetically defined subgroup and prompted the assessment of WGS data in cases that were not congruent with FISH. This allowed the identification of additional IGH-translocations and hyperdiploid cases. We show the reliability of WGS an RNA-Seq in a clinical setting, which is a prerequisite for a novel routine diagnostic test.

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Section: Discussionmentioning

confidence: 99%

The combination of WGS and RNA-Seq is superior to conventional diagnostic tests in multiple myeloma: Ready for prime time?

et al. 2020

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“…A wide range of biological and physiological factors, including tumor burden, disease stage or even half‐life of cfDNA can influence release and clearance of tumor‐specific fraction of total cfDNA and play a role in this variability . As a result, scarce amounts of cfDNA are isolated in some cases in which target molecules may be under‐represented causing false‐negative results . This at least partially explains why some patients were found cfDNA negative at diagnosis and put emphasis on standardization of preanalytical factors which can be influenced.…”

Section: Discussionmentioning

confidence: 99%

“…42 As a result, scarce amounts of cfDNA are isolated in some cases in which target molecules may be under-represented causing false-negative results. 6,43 This at least partially explains why some patients were found cfDNA negative at diagnosis and put emphasis on standardization of preanalytical factors which can be influenced. Regardless of these issues, our results…”

Section: Discussionmentioning

confidence: 99%

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

Vrábel

Sedlaříková

Besse

et al. 2019

European J of Haematology

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Objectives Progress in multiple myeloma treatment allows patients to achieve deeper responses, for which the assessment of minimal residual disease (MRD) is critical. Typically, bone marrow samples are used for this purpose; however, this approach is site‐limited. Liquid biopsy represents a minimally invasive and more comprehensive technique that is not site‐limited, but equally challenging. Methods While majority of current data comes from short‐term studies, we present a long‐term study on blood‐based MRD monitoring using tumor‐specific cell‐free DNA detection by ASO‐qPCR. One hundred and twelve patients were enrolled into the study, but long‐term sampling and analysis were feasible only in 45 patients. Results We found a significant correlation of quantity of tumor‐specific cell‐free DNA levels with clinically meaningful events [induction therapy (P = .004); ASCT (P = .012)]. Moreover, length of cfDNA fragments is associated with better treatment response of patients. Conclusions These results support the concept of tumor‐specific cell‐free DNA as a prognostic marker.

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“…Consequently, gene mutations are thought to be late events that contribute to MM heterogeneity and impact disease progression more than its initiation (4). In fact, NGS analysis of sample series has shown variable degrees of spontaneous evolution of genes mutations, cytogenetic lesions and mutational signatures (26)(27)(28)(29)(30)(31)(32)(33). This suggests that MM evolves in discrete steps not just clinically but also from a molecular point of view, with the acquisition of subsequent genomic lesions that underlie an increasingly aggressive clinical behavior.…”

Section: Molecular Pathogenesis Of Multiple Myeloma and Related Monocmentioning

confidence: 99%

Next-Generation Sequencing for Clinical Management of Multiple Myeloma: Ready for Prime Time?

et al. 2020

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Personalized treatment is an attractive strategy that promises increased efficacy with reduced side effects in cancer. The feasibility of such an approach has been greatly boosted by next-generation sequencing (NGS) techniques, which can return detailed information on the genome and on the transcriptome of each patient's tumor, thus highlighting biomarkers of response or druggable targets that may differ from case to case. However, while the number of cancers sequenced is growing exponentially, much fewer cases are amenable to a molecularly-guided treatment outside of clinical trials to date. In multiple myeloma, genomic analysis shows a variety of gene mutations, aneuploidies, segmental copy-number changes, translocations that are extremely heterogeneous, and more numerous than other hematological malignancies. Currently, in routine clinical practice we employ reduced FISH panels that only capture three high-risk features as part of the R-ISS. On the contrary, recent advances have suggested that extending genomic analysis to the full spectrum of recurrent mutations and structural abnormalities in multiple myeloma may have biological and clinical implications. Furthermore, increased efficacy of novel treatments can now produce deeper responses, and standard methods do not have enough sensitivity to stratify patients in complete biochemical remission. Consequently, NGS techniques have been developed to monitor the size of the clone to a sensitivity of up to a cell in a million after treatment. However, even these techniques are not within reach of standard laboratories. In this review we will recapitulate recent advances in multiple myeloma genomics, with special focus on the ones that may have immediate translational impact. We will analyze the benefits and pitfalls of NGS-based diagnostics, highlighting crucial aspects that will need to be taken into account before this can be implemented in most laboratories. We will make the point that a new era in myeloma diagnostics and minimal residual disease monitoring is close and conventional genetic testing will not be able to return the required information. This will mandate that even in routine practice NGS should soon be adopted owing to a higher informative potential with increasing clinical benefits.

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Circulating tumor DNA as a liquid biopsy in plasma cell dyscrasias

Cited by 34 publications

References 14 publications

The combination of WGS and RNA-Seq is superior to conventional diagnostic tests in multiple myeloma: Ready for prime time?

The combination of WGS and RNA-Seq is superior to conventional diagnostic tests in multiple myeloma: Ready for prime time?

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

Next-Generation Sequencing for Clinical Management of Multiple Myeloma: Ready for Prime Time?

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