Germline gain-of-function mutations of ALK disrupt central nervous system development

Pontual, Loïc de; Kettaneh, Dania; Gordon, Christopher T.; Oufadem, Myriam; Boddaert, Nathalie; Lees, Melissa; Balu, Laurent; Lachassinne, E.; Petros, Andy; Mollet, Julie; Wilson, Louise C.; Münnich, Arnold; Brugière, Laurence; Delattre, Olivier; Vekemans, Michel; Etchevers, Heather C.; Lyonnet, Stanislas; Janoueix‐Lerosey, Isabelle; Amiel, Jeanne

doi:10.1002/humu.21442

Cited by 37 publications

(29 citation statements)

References 32 publications

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“…This again illustrates that mutations that most strongly activate the tyrosine kinase domain might not be observed in patients without severe malformative phenotype. 29 Altogether, our results show that germline ALK mutations are rarely involved in sporadic neuroblastomas. Thus, systematic screening may not be proposed in non-familial cases.…”

Section: Discussionsupporting

confidence: 51%

ALK germline mutations in patients with neuroblastoma: a rare and weakly penetrant syndrome

et al. 2011

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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 o1 month of age, among which 10 were multifocal), 16 multifocal postnatal (41 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.

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Section: Discussionsupporting

confidence: 51%

ALK germline mutations in patients with neuroblastoma: a rare and weakly penetrant syndrome

et al. 2011

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“…The ALK gene, located at 2p23, encodes a receptor tyrosine kinase (RTK) that belongs to the insulin-receptor superfamily (4,5). Activating ALK mutations, mainly affecting residues located within the kinase domain, have been identified in sporadic, familial, and syndromic cases of NB (6)(7)(8)(9)(10)(11) and ALK amplifications have also been reported in a subset of sporadic cases (2,12). Furthermore, it has been suggested that the wild-type (WT) ALK receptor may exert oncogenic activity in NB when a critical threshold of expression is achieved (13).…”

Section: Introductionmentioning

confidence: 99%

Characterization of Rearrangements Involving the ALK Gene Reveals a Novel Truncated Form Associated with Tumor Aggressiveness in Neuroblastoma

et al. 2013

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Activating mutations of the ALK gene have been identified in sporadic and familial cases of neuroblastoma (NB), a cancer of the peripheral nervous system, and are thought to be the primary mechanism of oncogenic activation of this receptor in this pediatric neoplasm. To address the possibility that ALK activation may occur through genomic rearrangements as detected in other cancers, we first took advantage of high-resolution arraycomparative genomic hybridization to search for ALK rearrangements in NB samples. Using complementary experiments by capture/paired-end sequencing and FISH experiments, various types of rearrangements were fully characterized, including partial gains or amplifications, in several NB cell lines and primary tumors. In the CLB-Bar cell line, we described a genomic rearrangement associated with an amplification of the ALK locus, leading to the expression of a 170 kDa protein lacking part of the extracellular domain encoded by exons 4 to 11, named ALK D4-11 . Analysis of genomic DNA from the tumor at diagnosis and relapse revealed that the ALK gene was amplified at diagnosis but that the rearranged ALK allele was observed at the relapse stage only, suggesting that it may be implicated in tumor aggressiveness. Consistently, oncogenic and tumorigenic properties of the ALK D4-11 variant were shown after stable expression in NIH3T3 cells. Moreover, we documented an increased constitutive kinase activity of this variant, as well as an impaired maturation and retention into intracellular compartments. These results indicate that genomic rearrangements constitute an alternative mechanism to ALK point mutations resulting in receptor activation. Cancer Res; 73(1); 195-204. Ó2012 AACR.

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“…The syndromic patients with de novo germline activating ALK mutations presented with an enlarged medulla obloganta evidenced by magnetic resonance imaging [9]. We therefore sought to document Alk expression in the brainstem and determine whether KI Alk F1178L mice exhibited abnormalities of this structure.…”

Section: Resultsmentioning

confidence: 99%

“…The observation of missing germline mutations relative to the somatic repertoire suggested that a highest activity of these mutated forms may induce severe effects during embryonic development resulting in embryonal lethality. Yet, a syndromic presentation associating congenital neuroblastoma with severe encephalopathy and abnormal shape of the brainstem has now been described in two sporadic cases harbouring de novo germline F1174V and F1245V ALK mutations [9]. These patients presented with major feeding difficulties, associated with poor sucking and swallowing.…”

Section: Introductionmentioning

confidence: 99%

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Hyperactivation of Alk induces neonatal lethality in knock-in AlkF1178L mice

et al. 2014

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The ALK (Anaplastic Lymphoma Kinase) gene encodes a tyrosine kinase receptor preferentially expressed in the central and peripheral nervous systems. A syndromic presentation associating congenital neuroblastoma with severe encephalopathy and an abnormal shape of the brainstem has been described in patients harbouring de novo germline F1174V and F1245V ALK mutations. Here, we investigated the phenotype of knock-in (KI) mice bearing the AlkF1178L mutation (F1174L in human). Although heterozygous KI mice did not reproduce the severe breathing and feeding difficulties observed in human patients, behavioral tests documented a reduced activity during dark phases and an increased anxiety of mutated mice. Matings of heterozygotes yielded the expected proportions of wild-type, heterozygotes and homozygotes at birth but a high neonatal lethality was noticed for homozygotes. We documented Alk expression in several motor nuclei of the brainstem involved in the control of sucking and swallowing. Evaluation of basic physiological functions 12 hours after birth revealed slightly more apneas but a dramatic reduced milk intake for homozygotes compared to control littermates. Overall, our data demonstrate that Alk activation above a critical threshold is not compatible with survival in mice, in agreement with the extremely severe phenotype of patients carrying aggressive de novo ALK germline mutations.

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Germline gain-of-function mutations of ALK disrupt central nervous system development

Cited by 37 publications

References 32 publications

ALK germline mutations in patients with neuroblastoma: a rare and weakly penetrant syndrome

ALK germline mutations in patients with neuroblastoma: a rare and weakly penetrant syndrome

Characterization of Rearrangements Involving the ALK Gene Reveals a Novel Truncated Form Associated with Tumor Aggressiveness in Neuroblastoma

Hyperactivation of Alk induces neonatal lethality in knock-in AlkF1178L mice

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