Germline PHOX2B Mutation in Hereditary Neuroblastoma

Mossé, Yaël P.; Laudenslager, Marci; Khazi, Deepa; Carlisle, Alex J.; Winter, Cynthia; Rappaport, Eric; Maris, John M.

doi:10.1086/424530

Cited by 239 publications

(191 citation statements)

References 30 publications

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“…Cases of familial neuroblastoma often present with multifocal or bilateral adrenal primary tumors and are diagnosed at a median of 9 months of age. Neuroblastoma also occurs in patients with neurocristopathies such as Hirschsprung disease and central hypoventilation syndrome (CHS), and although the underlying etiologies of these associations are not clear, mutations in the PHOX2B gene that are associated with Hirschsprung disease and central hypoventilation have also been detected in some cases of familial neuroblastoma [15][16][17]. Furthermore, although there have been a number of reported cases of neuroblastoma in patients with neurofibromatosis, the role of germline NF1 mutations in the etiology of neuroblastoma remains unclear [18].…”

Section: Epidemiology and Geneticsmentioning

confidence: 99%

Overview and recent advances in the treatment of neuroblastoma

Whittle

Smith

Doherty

et al. 2017

Expert Review of Anticancer Therapy

311

258

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Introduction: Children with neuroblastoma have widely divergent outcomes, ranging from cure in >90% of patients with low risk disease to <50% for those with high risk disease. Recent research has shed light on the biology of neuroblastoma, allowing for more accurate risk stratification and treatment reduction in many cases, although newer treatment strategies for children with high-risk and relapsed neuroblastoma are needed to improve outcomes. Areas covered: Neuroblastoma epidemiology, diagnosis, risk stratification, and recent advances in treatment of both newly diagnosed and relapsed neuroblastoma. Expert commentary: The identification of newer tumor targets and of novel cell-mediated immunotherapy agents may lead to novel therapeutic approaches, and clinical trials for regimens designed to target individual genetic aberrations in tumors are underway. A combination of therapeutic modalities will likely be required to improve survival and cure rates for patients with high-risk neuroblastoma.ARTICLE HISTORY

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Section: Epidemiology and Geneticsmentioning

confidence: 99%

Overview and recent advances in the treatment of neuroblastoma

Whittle

Smith

Doherty

et al. 2017

Expert Review of Anticancer Therapy

311

258

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“…[75][76][77][78]. These clinical observations suggested that a gene or genes implicated in the genesis of Hirschsprung disease or CCHS may confer a predisposition to develop NB (79,80). PHOX2B is a homeobox gene that is a master regulator of autonomic nervous system development.…”

Section: Inactivating Mutations In Phox2bmentioning

confidence: 99%

Retinoblastoma and Neuroblastoma Predisposition and Surveillance

Kamihara

Bourdeaut

Foulkes

et al. 2017

Clinical Cancer Research

184

137

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Retinoblastoma (RB) is the most common intraocular malignancy in childhood. Approximately 40% of retinoblastomas are hereditary and due to germline mutations in the RB1 gene. Children with hereditary RB are also at risk for developing a midline intracranial tumor, most commonly pineoblastoma. We recommend intensive ocular screening for patients with germline RB1 mutations for retinoblastoma as well as neuroimaging for pineoblastoma surveillance. There is an approximately 20% risk of developing second primary cancers among individuals with hereditary RB, higher among those who received radiotherapy for their primary RB tumors. However, there is not yet a clear consensus on what, if any, screening protocol would be most appropriate and effective. Neuroblastoma (NB), an embryonal tumor of the sympathetic nervous system, accounts for 15% of pediatric cancer deaths. Prior studies suggest that about 2% of patients with NB have an underlying genetic predisposition that may have contributed to the development of NB. Germline mutations in ALK and PHOX2B account for most familial NB cases. However, other cancer predisposition syndromes, such as Li-Fraumeni syndrome, RASopathies, and others, may be associated with an increased risk for NB. No established protocols for NB surveillance currently exist. Here, we describe consensus recommendations on hereditary RB and NB from the AACR Childhood Cancer Predisposition Workshop.

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“…Patients with CCHS have a predisposition for developing tumors of the SNS, such as neuroblastoma, ganglioneuroma and ganglioneuroblastoma (43). Soon after the discovery of the role of PHOX2B in CCHS, four independent studies revealed heterozygous missense and frame-shift mutations in the PHOX2B gene, both in hereditary and sporadic neuroblastoma (44)(45)(46)(47). These mutations were rare in all four studies indicating locus heterogeneity for predisposition of inherited disease, but still demonstrated the importance of the PHOX2B gene in neuroblastoma oncogenesis and initiation (Fig.…”

Section: Neural Crest and Development Of The Sympathetic Nervous Systemmentioning

confidence: 99%

Neuroblastoma aggressiveness in relation to sympathetic neuronal differentiation stage

Mohlin

Wigerup

Påhlman

2011

Seminars in Cancer Biology

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Neuroblastoma aggressiveness in relation to sympathetic neuronal differentiation stage.Mohlin, Sofie; Wigerup, Caroline; Påhlman, Sven Link to publication Citation for published version (APA): Mohlin, S., Wigerup, C., & Påhlman, S. (2011). Neuroblastoma aggressiveness in relation to sympathetic neuronal differentiation stage. Seminars in Cancer Biology, 21(4), 276-282. DOI: 10.1016276-282. DOI: 10. /j.semcancer.2011 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Neural crest and development of the sympathetic nervous systemThe sympathetic nervous system (SNS) originates from the neural crest, an ephemeral structure during vertebrate development. Located along the neural fold, cells on the neural tube in the ectoderm give rise to the neural crest, in turn generating different derivatives, such as the cranial, hindbrain, vagal and trunk neural crest (reviewed in (9)). Trunk neural crest cells migrate from the neural tube along two defined routes, with one group of cells migrating early along a ventral pathway, giving rise to glial cells and neurons, whereas a later migrating group of cells follows a lateral pathway and gives rise to melanocytes in the skin (10, 11). These mutations were rare in all four studies indicating locus heterogeneity for predisposition of inherited disease, but still demonstrated the importance of the PHOX2B gene in neuroblastoma oncogenesis and initiation (Fig. 1) (58), and Fig. 1). Neuroblastoma differentiation stage and clinical outcomeThere is a well-documented difference in aggressive behavior between the morphologically undifferentiated (neuroblastoma proper) and the differentiated (ganglioneuroblastoma, Cellular adaptation to hypoxiaThe biological consequences of hypoxia involve induced angiogenesis, a switch in glucose metabolism and increased invasion and migration capacities, changes that stimulate tumor progression. The hypoxic response is mainly mediated by stabilization of the hypoxia inducible factor (HIF) proteins. HIFs are heterodimeric transcription factors composed of an oxygen sensitive  subunit and a constitutively expressed  subunit. At physiological oxygen levels, the  subunit is hydroxylated by the oxygen-dependent prolyl hydroxylases (PHDs), leading to interaction with the von Hippel Lindau-ubiquitin ligase complex, followed by ubiquitination and proteasomal degradation. At hypoxia, the PHDs are inactive leading to the 9 stabilization of the HIF- subunits, and by dimerization with the  subunit the comple...

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Germline PHOX2B Mutation in Hereditary Neuroblastoma

Abstract: Merlin-rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30:97-101 Cordell HJ (2004) Bias toward the null hypothesis in modelfree linkage analysis is highly dependent on the test statistic used.

Cited by 239 publications

References 30 publications

Overview and recent advances in the treatment of neuroblastoma

Overview and recent advances in the treatment of neuroblastoma

Retinoblastoma and Neuroblastoma Predisposition and Surveillance

Neuroblastoma aggressiveness in relation to sympathetic neuronal differentiation stage

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