Level of Seven Neuroblastoma-Associated mRNAs Detected by Droplet Digital PCR Is Associated with Tumor Relapse/Regrowth of High-Risk Neuroblastoma Patients

Thwin, Khin Kyae Mon; Ishida, Toshiaki; Uemura, Suguru; Yamamoto, Nobuyuki; Lin, Kyaw San; Tamura, Akihiro; Kozaki, Aiko; Saito, Atsuro; Kishimoto, Kenji; Mori, Takeshi; Hasegawa, Daiichiro; Kosaka, Yoshiyuki; Nino, Nanako; Takafuji, Satoru; Iijima, Kazumoto; Nishimura, Noriyuki

doi:10.1016/j.jmoldx.2019.10.012

Cited by 22 publications

(66 citation statements)

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“…In another approach, droplet digital PCR was used to identify levels of seven different NB-associated mRNAs in bone marrow and blood. Results indicated that the values were significantly higher in patients that relapsed than in those who did not and provided a better prognosis than qPCR [ 140 ]. As our understanding improves about what the genetic modifications found in NBs mean in terms of proteins expressed and how they interact with other proteins and cell gangliosides it is anticipated that “personalized” medicine will be used to identify the most effective treatment modality for the patient.…”

Section: Examples Of Additional Prognostic Markers and How They Mamentioning

confidence: 99%

Gangliosides and Neuroblastomas

Schengrund

2020

IJMS

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The focus of this review is the ganglio-series of glycosphingolipids found in neuroblastoma (NB) and the myriad of unanswered questions associated with their possible role(s) in this cancer. NB is one of the more common solid malignancies of children. Five-year survival for those diagnosed with low risk NB is 90–95%, while that for children with high-risk NB is around 40–50%. Much of the survival rate reflects age of diagnosis with children under a year having a much better prognosis than those over two. Identification of expression of GD2 on the surface of most NB cells led to studies of the effectiveness and subsequent approval of anti-GD2 antibodies as a treatment modality. Despite much success, a subset of patients, possibly those whose tumors fail to express concentrations of gangliosides such as GD1b and GT1b found in tumors from patients with a good prognosis, have tumors refractory to treatment. These observations support discussion of what is known about control of ganglioside synthesis, and their actual functions in NB, as well as their possible relationship to treatment response.

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Section: Examples Of Additional Prognostic Markers and How They Mamentioning

confidence: 99%

Gangliosides and Neuroblastomas

Schengrund

2020

IJMS

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“…Disease evaluation. Disease evaluation was conducted as described previously (32). Briefly, evaluation was conducted at every collection time point in accordance with the INRC based on the available medical records (13,34).…”

Section: Methodsmentioning

confidence: 99%

“…MRD in BM and PB. BM and PB sample preparation and 7NB-mRNA ddPCR assays were performed as described previously (32). Briefly, all BM and PB samples were separated using Mono-Poly resolving medium (DS Pharma Biomedical), and nucleated cells were collected.…”

Section: Methodsmentioning

confidence: 99%

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Limited correlation between tumor markers and minimal residual disease detected by seven neuroblastoma‑associated mRNAs in high‑risk neuroblastoma patients

et al. 2021

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Vanillylmandelic acid (VMA), homovanillic acid (HVA), neuron-specific enolase (NSE) and lactate dehydrogenase (LDH) are classical tumor markers and are used as standard clinical evaluations for patients with neuroblastoma (NB). Minimal residual disease (MRD) can be monitored by quantifying several sets of NB-associated mRNAs in the bone marrow (BM) and peripheral blood (PB) of patients with NB. Although MRD in BM and PB has been revealed to be a strong prognostic factor that is independent of standard clinical evaluations, its interrelation with tumor markers remains uncharacterized. The present study determined the levels of tumor markers (VMA, HVA, NSE and LDH) and MRD (BM-MRD and PB-MRD) in 133 pairs of concurrently collected BM, PB and urine samples from 19 patients with high-risk NB. The patients were evaluated during the entire course of treatment, which included 10 diagnoses, 32 treatments, 36 post-treatment, 9 relapses and 46 post-relapse sample pairs. The level of BM-MRD and PB-MRD was determined by quantifying 7 NB-mRNAs (collapsin response mediator protein 1, dopamine beta-hydroxylase, dopa decarboxylase, growth-associated protein 43, ISL LIM homeobox 1, pairedlike homeobox 2b and tyrosine hydroxylase) using droplet digital PCR. In overall sample pairs, tumor markers (VMA, HVA, NSE and LDH) demonstrated weak but significant correlations (P<0.011) with BM-MRD and PB-MRD.In subgroups according to each patient evaluation, the degree of correlation between tumor markers and MRD became stronger in patients with adrenal gland tumors, BM metastasis at diagnosis and relapse/regrowth compared with overall sample pairs. In contrast, tumor markers demonstrated variable correlations with MRD in subgroups according to each sample evaluation (BM infiltration at sampling, collection time point and disease status). The results suggested that tumor markers may demonstrate limited correlation with MRD in patients with high-risk NB.

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“…Among these shared targets are the mRNAs of the following tumor-suppressing genes: XIAP Associated Factor 1 ( XAF I ) ( 71 , 100 , 101 ), whose loss of function mutation causes gastric carcinoma, HRAS-Like-Suppressor4 (or HRASLS4 ) ( 71 , 101 , 102 ), also associated with mutations in gastric cancer, Homeodomain Interacting Protein Kinase 2 ( HIPK2 ) ( 71 , 103 ), mutations in which gene are associated with keratocanthoma (a rare skin cancer), breast cancer, and Thioredoxin Interacting Protein ( TXNIP ) ( 71 , 104 ), associated with exocervical carcinoma. In the opposite direction, TargetScan ( ) analysis of MIR211-5p and MIR204-5p also yields the following common oncogene or oncogene-like genes as high-confidence targets: Ras-Related Protein Rab-22A ( RAB22A ), Paired Like Homeobox 2B ( PHOX2B ) whose high expression is associated with neuroblastoma ( 105 ), and Adaptor Related Protein Complex 1 Subunit Sigma 2 ( AP1S2 ) whose mRNA expression is enhanced in melanoma and is associated with significantly poorer survival of melanoma patients (although confers a better survival probability to ovarian and breast cancer patients). In summary, MIR211 and its paralog MIR204 together regulate a number of genes whose expression are related to both tumor suppressor and oncogenic activities in a number of different cancer types including melanoma.…”

Section: Paralogs Of the Mir211 Familymentioning

confidence: 99%

The Paradoxical Behavior of microRNA-211 in Melanomas and Other Human Cancers

2021

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Cancer initiation, progression, and metastasis leverage many regulatory agents, such as signaling molecules, transcription factors, and regulatory RNA molecules. Among these, regulatory non-coding RNAs have emerged as molecules that control multiple cancer types and their pathologic properties. The human microRNA-211 (MIR211) is one such molecule, which affects several cancer types, including melanoma, glioblastoma, lung adenocarcinomas, breast, ovarian, prostate, and colorectal carcinoma. Previous studies suggested that in certain tumors MIR211 acts as a tumor suppressor while in others it behaves as an oncogenic regulator. Here we summarize the known molecular genetic mechanisms that regulate MIR211 gene expression and molecular pathways that are in turn controlled by MIR211 itself. We discuss how cellular and epigenetic contexts modulate the biological effects of MIR211, which exhibit pleiotropic effects. For example, up-regulation of MIR211 expression down-regulates Warburg effect in melanoma tumor cells associated with an inhibition of the growth of human melanoma cells in vitro, and yet these conditions robustly increase tumor growth in xenografted mice. Signaling through the DUSP6-ERK5 pathway is modulated by MIR211 in BRAFV600E driven melanoma tumors, and this function is involved in the resistance of tumor cells to the BRAF inhibitor, Vemurafenib. We discuss several alternate but testable models, involving stochastic cell-to-cell expression heterogeneity due to multiple equilibria involving feedback circuits, intracellular communication, and genetic variation at miRNA target sties, to reconcile the paradoxical effects of MIR211 on tumorigenesis. Understanding the precise role of this miRNA is crucial to understanding the genetic basis of melanoma as well as the other cancer types where this regulatory molecule has important influences. We hope this review will inspire novel directions in this field.

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Level of Seven Neuroblastoma-Associated mRNAs Detected by Droplet Digital PCR Is Associated with Tumor Relapse/Regrowth of High-Risk Neuroblastoma Patients

Cited by 22 publications

References 35 publications

Gangliosides and Neuroblastomas

Gangliosides and Neuroblastomas

Limited correlation between tumor markers and minimal residual disease detected by seven neuroblastoma‑associated mRNAs in high‑risk neuroblastoma patients

The Paradoxical Behavior of microRNA-211 in Melanomas and Other Human Cancers

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