Abstract
Neuroblastoma is a common extracranial solid tumor of neural crest (NC) origin that accounts for up to 15% of all pediatric cancer deaths. The disease arises from a transient population of NC cells that undergo an epithelial-mesenchymal transition (EMT) and generate diverse cell-types and tissues. Patients with neuroblastoma are characterized by their extreme heterogeneity ranging from spontaneous regression to malignant progression. More than half of newly diagnosed patients present highly metastatic tumors and are stratified into a high-risk group with dismal outcome. As many as 20% of high-risk patients have residual disease that is refractory or progressive during induction chemotherapy. Although a majority of high-risk patients achieve remission, larger part of those patients has minimal residual disease (MRD) that causes relapse even after additional consolidation therapy. MRD is composed of drug-resistant tumor cells and dynamically presented as cancer stem cells (CSCs) in residual tumors, circulating tumor cells (CTCs) in peripheral blood (PB), and disseminated tumor cells (DTCs) in bone marrow (BM) and other metastatic sites. EMT appears to be a key mechanism for cancer cells to acquire MRD phenotypes and malignant aggressiveness. Due to the restricted availability of residual tumors, PB and BM have been used to isolate and analyze CTCs and DTCs to evaluate MRD in cancer patients. In addition, recent technical advances make it possible to use circulating tumor DNA (ctDNA) shed from tumor cells into PB for MRD evaluation. Because MRD can be detected by tumor-specific antigens, genetic or epigenetic changes, and mRNAs, numerous assays using different methods and samples have been reported to detect MRD in cancer patients. In contrast to the tumor-specific gene-rearrangement-positive acute lymphoblastic leukemia (ALL) and the oncogenic fusion-gene-positive chronic myelogenous leukemia (CML) and several solid tumors, the clinical significance of MRD remains to be established in neuroblastoma. Given the extreme heterogeneity of neuroblastoma, dynamics of MRD in neuroblastoma patients will hold a key to the clinical validation. In this review, we summarize the biology and detection methods of cancer MRD in general and evaluate the available assays and clinical significance of neuroblastoma MRD to clarify its dynamics in neuroblastoma patients.
Highlights
Neuroblastoma is a common extracranial solid tumor in children and accounts for ∼15% of all pediatric cancer-associated mortalities
Current intensive multimodal therapies eliminate the bulk population of tumor cells while sparing the minor subpopulations of minimal residual disease (MRD) that is dynamically presented as cancer stem cells (CSCs), circulating tumor cells (CTCs), and disseminated tumor cells (DTCs) in cancer patients
QPCR of tumorassociated mRNAs in bone marrow (BM) and peripheral blood (PB) samples have detected clinically relevant tumor cells in many hematopoietic and solid tumors, current quantitative RT-PCR (qPCR)-based assays for neuroblastoma MRD detection use different neuroblastoma-associated mRNAs and will require the prospective qualitycontrolled clinical studies that evaluate the clinical significance of these qPCR-based assays
Summary
Neuroblastoma is a common extracranial solid tumor in children and accounts for ∼15% of all pediatric cancer-associated mortalities. Tumor-associated genetic and epigenetic changes such as point mutations, genomic rearrangements, copy number variation (CNV), microsatellite instability (MSI), loss of heterozygosity (LOH), and DNA methylation have been detected in ctDNA These changes warrant a distinction between ctDNA and remaining cell-free DNA, and allow the use of ctDNA as potential biomarkers for determining tumor state, tumor metastasis and relapse, and treatment response [27]. MRD, minimal residual disease; CSC, cancer stem cell; CTC, circulating tumor cell; DTC, disseminating tumor cell; ctDNA, circulating tumor DNA; PB, peripheral blood; PBSC, peripheral blood stem cell; BM, bone marrow; IC, immunocytology; FCM, flow cytometry; PCR, polymerase chain reaction; aCGH, array comparative genomic hybridization; MPS, massively paralleled sequencing; RT-PCR, reverse transcriptase-PCR. The reliability of tumor cell detection and quantification by IC had been controversial, IC detection of neuroblastoma cells was standardized in BM aspirates by using fixed cytospins and anti GD2-antibody [63] and recommended for single-cell based sensitive MRD detection in BM, PB, and PBSC samples by the International Neuroblastoma Risk Group (INRG) [66] (Figures 4, 5, Table 1)
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