Genetic abnormalities in adolescents and young adults with neuroblastoma: A report from the Italian Neuroblastoma Group

Mazzocco, Katia; Defferrari, Raffaella; Sementa, Angela Rita; Garaventa, Alberto; Longo, Luca; Mariano, Marilena De; Esposito, Maria Rosaria; Negri, Francesca; Ircolò, Davide; Viscardi, Elisabetta; Luksch, Roberto; D’Angelo, Paolo; Prete, Arcangelo; Castellano, Aurora; Massirio, Paolo; Erminio, Giovanni; Gigliotti, Anna Rita; Tonini, Gian Paolo; Conte, Massimo

doi:10.1002/pbc.25552

Cited by 31 publications

(47 citation statements)

References 37 publications

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“…Similar to other reports on adult-onset NB 7, 18, 19, 21 , none of our patients had MYCN -amplified NB. (Table 1) This is in contrast to pediatric NB where 20–25% of patients have MYCN -amplified NB 5, 22 .…”

Section: Discussionsupporting

confidence: 92%

“…Pediatric solid tumors in general, and NB in particular have a low frequency of mutations, 38 but genetic testing on tumors in adults yielded a significantly different pattern of genomic aberrations. Similar to other reports on adult-onset NB, 7,18,19,21 none of our patients had MYCN-amplified NB ( Table 1). This is in contrast to pediatric NB where 20-25% of patients have MYCN-amplified NB.…”

Section: Discussionsupporting

confidence: 92%

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Treatment and outcome of adult‐onset neuroblastoma

Suzuki

Kushner

Krämer

et al. 2018

Intl Journal of Cancer

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Adult-onset neuroblastoma is rare and little is known about its biology and clinical course. There is no established therapy for adult-onset neuroblastoma. Anti-GD2 immunotherapy is now standard therapy in children with high-risk neuroblastoma; however, its use has not been reported in adults. Forty-four adults (18-71 years old) diagnosed with neuroblastoma between 1979 and 2015 were treated at Memorial Sloan Kettering Cancer Center. Five, 1, 5 and 33 patients had INSS stage 1, 2, 3 and 4 diseases, respectively. Genetic abnormalities included somatic ATRX (58%) and ALK mutations (42%) but not MYCN-amplification. In the 11 patients with locoregional disease, 10-year progression-free (PFS) and overall survival (OS) was 35.4 ± 16.1% and 61.4 ± 15.3%, respectively. Among 33 adults with stage 4 neuroblastoma, 7 (21%) achieved complete response (CR) after induction chemotherapy and/or surgery. Seven patients with primary refractory neuroblastoma (all with osteomedullary but no soft tissue disease) received anti-GD2 antibodies, mouse or humanized 3F8. Antibody-related adverse events were similar to those in children, response rate being 71.4%. In patients with stage 4 disease at diagnosis, 5-year PFS was 9.7± 5.3% and most patients who were alive with disease at 5 years died of neuroblastoma over the next 5 years, 10-year OS being only 19.0 ± 8.2%. Patients who achieved CR after induction had superior PFS and OS (p = 0.006, p = 0.031, respectively). Adult-onset neuroblastoma appeared to have different biology from pediatric or adolescent NB, and poorer outcome. Complete disease control appeared to improve long-term survival. Anti-GD2 immunotherapy was well tolerated and might be beneficial.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Treatment and outcome of adult‐onset neuroblastoma

Suzuki

Kushner

Krämer

et al. 2018

Intl Journal of Cancer

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“…Our gain-and loss-of-function studies indicated that CUX1 promoted the aerobic glycolysis, growth, and invasiveness of NB cells, suggesting its oncogenic roles in NB progression. Human CUX1 gene locates at chromosome 7q22, a region associated with copy number gain that contributes to multidrug resistance in NB (Mazzocco et al, 2015). However, we found no alteration of copy number or genetic variants of CUX1 in NB cohorts, indicating other mechanisms facilitating its over-expression.…”

Section: Discussioncontrasting

confidence: 57%

“…Human CUX1 gene locates at chromosome 7q22, a region associated with copy number gain that contributes to multidrug resistance in NB (Mazzocco et al , ). However, we found no alteration of copy number or genetic variants of CUX1 in NB cohorts, indicating other mechanisms facilitating its over‐expression.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic targeting of circ‐ CUX 1 / EWSR 1/ MAZ axis inhibits glycolysis and neuroblastoma progression

Yang

et al. 2019

EMBO Mol Med

116

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Aerobic glycolysis is a hallmark of metabolic reprogramming in tumor progression. However, the mechanisms regulating glycolytic gene expression remain elusive in neuroblastoma (NB), the most common extracranial malignancy in childhood. Herein, we identify that CUT‐like homeobox 1 (CUX1) and CUX1‐generated circular RNA (circ‐CUX1) contribute to aerobic glycolysis and NB progression. Mechanistically, p110 CUX1, a transcription factor generated by proteolytic processing of p200 CUX1, promotes the expression of enolase 1, glucose‐6‐phosphate isomerase, and phosphoglycerate kinase 1, while circ‐CUX1 binds to EWS RNA‐binding protein 1 (EWSR1) to facilitate its interaction with MYC‐associated zinc finger protein (MAZ), resulting in transactivation of MAZ and transcriptional alteration of CUX1 and other genes associated with tumor progression. Administration of an inhibitory peptide blocking circ‐CUX1‐EWSR1 interaction or lentivirus mediating circ‐CUX1 knockdown suppresses aerobic glycolysis, growth, and aggressiveness of NB cells. In clinical NB cases, CUX1 is an independent prognostic factor for unfavorable outcome, and patients with high circ‐CUX1 expression have lower survival probability. These results indicate circ‐CUX1/EWSR1/MAZ axis as a therapeutic target for aerobic glycolysis and NB progression.

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“…In the particular subgroup of NBs occurring in adolescent and young adults [30], representing less than 5% of NBs and characterized by a high prevalence of SCA (35–85%) and very low incidence of MNA, the prevalence of 11q loss is high, ranging between 30 to 60% [37–39]. In this particular subgroup where ALK and ATRX alterations are also more frequent and the outcome very poor [37–40], ATRX mutated NBs showed a higher number of SCA including 11q deletions (Fig.…”

Section: Introductionmentioning

confidence: 99%

11q deletion in neuroblastoma: a review of biological and clinical implications

et al. 2017

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Deletion of the long arm of chromosome 11 (11q deletion) is one of the most frequent events that occur during the development of aggressive neuroblastoma. Clinically, 11q deletion is associated with higher disease stage and decreased survival probability. During the last 25 years, extensive efforts have been invested to identify the precise frequency of 11q aberrations in neuroblastoma, the recurrently involved genes, and to understand the molecular mechanisms of 11q deletion, but definitive answers are still unclear. In this review, it is our intent to compile and review the evidence acquired to date on 11q deletion in neuroblastoma.

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Genetic abnormalities in adolescents and young adults with neuroblastoma: A report from the Italian Neuroblastoma Group

Cited by 31 publications

References 37 publications

Treatment and outcome of adult‐onset neuroblastoma

Treatment and outcome of adult‐onset neuroblastoma

Therapeutic targeting of circ‐ CUX 1 / EWSR 1/ MAZ axis inhibits glycolysis and neuroblastoma progression

11q deletion in neuroblastoma: a review of biological and clinical implications

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