Institut Curie

The web supplement to
Franck Bourdeaut et al. 2011


ALK germline mutations in patients with neuroblastoma: a rare and weakly penetrant syndrome
Franck Bourdeaut1,2,3, Sandrine Ferrand4 , Laurence Brugières5, Marjorie Hilber6 , Agnès Ribeiro4, Ludovic Lacroix7, Jean Bénard7, Valérie Combaret8, Jean Michon1, Dominique Valteau-Couanet5, Bertrand Isidor9, Xavier Rialland10, Maryline Poirée11, Anne-Sophie Defachelles12, Michel Peuchmaur13, Gudrun Schleiermacher1,2, Gaelle Pierron4, Marion Gauthier-Villars14, Isabelle Janoueix-Lerosey2, Olivier Delattre2,4 on the behalf of the Comité Neuroblastome of the Société Francaise de Cancérologie de l'Enfant

1Institut Curie, Département de pédiatrie, Paris France. 2INSERM U830, Laboratoire de Génétique et Biologie des Cancers, Institut Curie, Paris, France. 3CHU Nantes, Service d'hémato-oncologie pédiatrique, Nantes, France. 4Institut Curie, Unité de Génétique Somatique, Paris, France. 5Institut Gustave Roussy, Département de pédiatrie, Villejuif, France. 6Université de Bordeaux & CHU de Bordeaux, Service d'hémato-oncologie pédiatrique, Bordeaux, France. 7Institut Gustave Roussy, Département de Biologie et Pathologie Médicales, Villejuif, France. 8Centre Léon Bérard, Laboratoire, Lyon, France. 9CHU Nantes, Service de génétique médicale, Nantes, France. 10CHU Angers, Service d'hémato-oncologie pédiatrique, Angers, France. 11CHU Nice, Service d'hémato-oncologie pédiatrique, Nice, France. 12Centre Oscar Lambret, Département d'oncologie pédiatrique, Lille, France . 13 Université Paris 6 & Hopital Robert Debré, Service d'anatomie pathologique, Paris, France. 14Institut Curie, Département d'oncogénétique, Paris, France.


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 (pre-birth and <1 month of age, among which 10 were multifocal), 16 multifocal post-natal (>1 months) cases, three pairs of affected relatives and eight patients with multiple malignancies. The whole coding sequences of the 2 genes were analysed in tumour and/or constitutional DNAs. We found 3 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.

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September 14 2011 09:49:43