title: ALK germline mutations in patients with neuroblastoma: a rare and weakly penetrant syndrome.
abstract: Neuroblastic tumours may occur in a predisposition context. Two main genes are involved: PHOX2B, observed in familial cases and frequently associated with other neurocristopathies (Ondine's and Hirschsprung's disease); and ALK, mostly in familial tumours. We have assessed the frequency of mutations of these two genes in patients with a presumable higher risk of predisposition. We sequenced both genes in 26 perinatal cases (prebirth and <1 month of age, among which 10 were multifocal), 16 multifocal postnatal (>1 month) cases, 3 pairs of affected relatives and 8 patients with multiple malignancies. The whole coding sequences of the two genes were analysed in tumour and/or constitutional DNAs. We found three ALK germline mutations, all in a context of multifocal tumours. Two mutations (T1151R and R1192P) were inherited and shared by several unaffected patients, thus illustrating an incomplete penetrance. Younger age at tumour onset did not seem to offer a relevant selection criterion for ALK analyses. Conversely, multifocal tumours might be the most to benefit from the genetic screening. Finally, no PHOX2B germline mutation was found in this series. In conclusion, ALK deleterious mutations are rare events in patients with a high probability of predisposition. Other predisposing genes remain to be discovered.
authors.affiliation: Institut Curie, Département de pédiatrie, Paris, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Bourdeaut
authors.forename: Sandrine
authors.initials: S
authors.lastname: Ferrand
authors.forename: Laurence
authors.initials: L
authors.lastname: Brugières
authors.forename: Marjorie
authors.initials: M
authors.lastname: Hilbert
authors.forename: Agnès
authors.initials: A
authors.lastname: Ribeiro
authors.forename: Ludovic
authors.initials: L
authors.lastname: Lacroix
authors.forename: Jean
authors.initials: J
authors.lastname: Bénard
authors.forename: Valérie
authors.initials: V
authors.lastname: Combaret
authors.forename: Jean
authors.initials: J
authors.lastname: Michon
authors.forename: Dominique
authors.initials: D
authors.lastname: Valteau-Couanet
authors.forename: Bertrand
authors.initials: B
authors.lastname: Isidor
authors.forename: Xavier
authors.initials: X
authors.lastname: Rialland
authors.forename: Maryline
authors.initials: M
authors.lastname: Poirée
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Defachelles
authors.forename: Michel
authors.initials: M
authors.lastname: Peuchmaur
authors.forename: Gudrun
authors.initials: G
authors.lastname: Schleiermacher
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Pierron
authors.forename: Marion
authors.initials: M
authors.lastname: Gauthier-Villars
authors.forename: Isabelle
authors.initials: I
authors.lastname: Janoueix-Lerosey
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D001483:Base Sequence; D055028:Comparative Genomic Hybridization; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D009378:Neoplasms, Multiple Primary / Q000235:genetics* / Q000473:pathology; D009447:Neuroblastoma / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; C109220:NBPhox protein; D014157:Transcription Factors; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
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