title: Oncologic Phenotype of Peripheral Neuroblastic Tumors Associated With PHOX2B Non-Polyalanine Repeat Expansion Mutations.
abstract: BACKGROUND
  Germline non-polyalanine repeat expansion mutations in PHOX2B (PHOX2B NPARM) predispose to peripheral neuroblastic tumors (PNT), frequently in association with other neurocristopathies: Hirschsprung disease (HSCR) or congenital central hypoventilation syndrome (CCHS). Although PHOX2B polyalanine repeat expansions predispose to a low incidence of benign PNTs, the oncologic phenotype associated with PHOX2B NPARM is still not known in detail.
  
  
  METHODS
  We analyzed prognostic factors, treatment toxicity, and outcome of patients with PNT and PHOX2B NPARM.
  
  
  RESULTS
  Thirteen patients were identified, six of whom also had CCHS and/or HSCR, one also had late-onset hypoventilation with hypothalamic dysfunction (LO-CHS/HD), and six had no other neurocristopathy. Four tumours were "poorly differentiated," and nine were differentiated, including five ganglioneuromas, three ganglioneuroblastomas, and one differentiating neuroblastoma, hence illustrating that PHOX2B NPARM are predominantly associated with differentiating tumors. Nevertheless, three patients had stage 4 and one patient had stage 3 disease. Segmental chromosomal alterations, correlating with poor prognosis, were found in all the six tumors analyzed by array-comparative genomic hybridization. One patient died of tumor progression, one is on palliative care, one died of hypoventilation, and 10 patients are still alive, with median follow-up of 5 years.
  
  
  CONCLUSIONS
  Based on histological phenotype, our series suggests that heterozygous PHOX2B NPARM do not fully preclude ganglion cell differentiation in tumors. However, this tumor predisposition syndrome may also be associated with poorly differentiated tumors with unfavorable genomic profiles and clinically aggressive behaviors. The intrafamilial variability and the unpredictable tumor prognosis should be considered in genetic counseling.
authors.affiliation: Service de Pathologie, Hôpital Robert Debré, APHP, Paris, France.
authors.forename: Solveig
authors.initials: S
authors.lastname: Heide
authors.affiliation: INSERM U830, Génétique et Biologie des Cancers, Institut Curie, Paris, France.|Institut Curie, Unité de Génétique Somatique, Institut Curie, Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Masliah-Planchon
authors.affiliation: Service de Génétique Clinique, Centre Hospitalier Universitaire de Nantes, Nantes, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Isidor
authors.affiliation: INSERM UMR 1163, Institut Imagine, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Guimier
authors.affiliation: Unité d'Onco-Hématologie, Centre Hospitalier Universitaire de Caen, Caen, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Bodet
authors.affiliation: Service d'Oncologie Pédiatrique, Hôpital de la Timone, Centre Hospitalier Universitaire de Marseille, Marseille, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Coze
authors.affiliation: Service d'Onco-Hématologie Pédiatrique, Centre Hospitalier Universitaire de Nice, Nice, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Deville
authors.affiliation: Service d'Onco-Hématologie Pédiatrique, Centre Hospitalier Universitaire de Nantes, Nantes, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Thebault
authors.affiliation: Service d'Anatomie Pathologique, Centre Hospitalier Universitaire de Caen, Caen, France.
authors.forename: Corinne Jeanne
authors.initials: CJ
authors.lastname: Pasquier
authors.affiliation: Service d'Anatomie Et Cytologie Pathologiques, Centre Hospitalier Universitaire de Nantes, Nantes, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Cassagnau
authors.affiliation: Institut Curie, Unité de Génétique Somatique, Institut Curie, Paris, France.
authors.forename: Gaelle
authors.initials: G
authors.lastname: Pierron
authors.affiliation: Institut Curie, Unité de Génétique Somatique, Institut Curie, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Clément
authors.affiliation: INSERM U830, Génétique et Biologie des Cancers, Institut Curie, Paris, France.|Institut Curie, Unité de Génétique Somatique, Institut Curie, Paris, France.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Schleiermacher
authors.affiliation: INSERM UMR 1163, Institut Imagine, Paris, France.|Sorbonne Paris Cite, Université Paris Descartes, Paris, France.|Service de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.affiliation: INSERM U830, Génétique et Biologie des Cancers, Institut Curie, Paris, France.|Institut Curie, Unité de Génétique Somatique, Institut Curie, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.affiliation: Service de Pathologie, Hôpital Robert Debré, APHP, Paris, France.|Sorbonne Paris Cite, Université Paris Diderot, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Peuchmaur
authors.affiliation: INSERM U830, Génétique et Biologie des Cancers, Institut Curie, Paris, France.|Institut Curie, Département de pédiatrie-adolescent-jeunes adultes, Institut Curie, Paris, France.|Site de Recherche Intégrée en Cancérologie, Recherche Translationnelle en Oncologie Pédiatrique, Institut Curie, Paris, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Bourdeaut
mesh_terms: D000328:Adult; D015984:Causality; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D042622:DNA Repeat Expansion; D018305:Ganglioneuroblastoma / Q000235:genetics / Q000473:pathology; D005729:Ganglioneuroma / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007027:Hypothalamic Diseases / Q000235:genetics / Q000473:pathology; D007040:Hypoventilation / Q000151:congenital / Q000235:genetics / Q000473:pathology; D007223:Infant; D009154:Mutation; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D009693:Nucleic Acid Hybridization; D010524:Peripheral Nervous System Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D010641:Phenotype; D011379:Prognosis; D020182:Sleep Apnea, Central / Q000235:genetics / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D018398:Homeodomain Proteins; C109220:NBPhox protein; D014157:Transcription Factors
keywords: PHOX2B; neuroblastoma; neurocristopathy; predisposition