Abstract
Purpose: Neuroblastoma (NB) is a heterogeneous disease characterized by distinct clinical features and by the presence of typical copy-number alterations (CNAs). Given the strong association of these CNA profiles with prognosis, analysis of the CNA profile at diagnosis is mandatory. Therefore, we tested whether the analysis of circulating cell-free DNA (cfDNA) present in plasma samples of patients with NB could offer a valuable alternative to primary tumor DNA for CNA profiling.Experimental Design: In 37 patients with NB, cfDNA analysis using shallow whole genome sequencing (sWGS) was compared with arrayCGH analysis of primary tumor tissue.Results: Comparison of CNA profiles on cfDNA showed highly concordant patterns, particularly in high-stage patients. Numerical chromosome imbalances as well as large and focal structural aberrations including MYCN and LIN28B amplification and ATRX deletion could be readily detected with sWGS using a low input of cfDNA.Conclusions: In conclusion, sWGS analysis on cfDNA offers a cost-effective, noninvasive, rapid, robust and sensitive alternative for tumor DNA copy-number profiling in most patients with NB. Clin Cancer Res; 23(20); 6305-14. ©2017 AACR.
Highlights
Neuroblastoma (NB) is the most common extracranial solid tumor of childhood and is characterized by a remarkable biological and clinical heterogeneity ranging from spontaneous regression to overt metastasis [1, 2]
Numerical chromosome imbalances as well as large and focal structural aberrations including MYCN and LIN28B amplification and ATRX deletion could be readily detected with shallow whole genome sequencing (sWGS) using a low input of cell-free DNA (cfDNA)
We report on the first successful application of shallow whole genome sequencing for the detection of copy-number alterations (CNAs) in cfDNA of 37 patients with NB
Summary
Neuroblastoma (NB) is the most common extracranial solid tumor of childhood and is characterized by a remarkable biological and clinical heterogeneity ranging from spontaneous regression (stage 4s) to overt metastasis [1, 2]. Hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), arrayCGH, or SNParray was used [8, 9]. All these methods depend on the availability of primary tumor tissue at diagnosis, which can be obtained only through an invasive procedure. Open surgical biopsies are preferred, but often diagnosis relies on tru-cut or fine-needle biopsies. These small biopsies only provide a genomic view of one particular small area of a primary tumor, while NB tumors are known to demonstrate intratumoral, spatial, and temporal heterogeneity [10,11,12,13]
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