Pediatric cancer Alteration of a gene causes

16 October 2008
P
R
E
S
S
R
E
L
E
A
S
E
Pediatric cancer
Alteration of a gene causes
neuroblastoma
Olivier Delattre’s team (Inserm Unit 830 “Genetics and Biology of Cancer”) of the Institut Curie
reveal in an article in the 16 October issue of Nature that alteration of the ALK gene is closely
associated with the most frequent solid extracerebral tumor in children—neuroblastoma. By
studying the familial forms of this tumor, the researchers also conclude that ALK is a gene that
predisposes to neuroblastoma. This discovery may allow the development of new treatments in
neuroblastomas. It may also enable the identification in at-risk families of children who carry an
altered ALK gene, so that they can be offered regular checkups. At present, over half of children
diagnosed with neuroblastoma and metastases still die of their disease.
Neuroblastoma is the most frequent solid extracerebral tumor in young children. Some 50% of children
affected—boys and girls alike—are under two years of age. In France, there are about 150 new cases
every year, and one quarter of these are treated at the Institut Curie, a reference center recognized
worldwide for its neuroblastoma research and treatment.
Neuroblastoma develops in the sympathetic nervous system, more specifically in the small round cells
derived from the neural crest, a transient region characteristic of vertebrate embryos. It principally affects
the abdomen, and more rarely the thorax, neck, and lower pelvis.
ALK, a key participant in development of neuroblastoma
At the Institut Curie, Olivier Delattre, Director of Inserm Unit 830 “Genetics and Biology of Cancer”, and his
team have just shown that the ALK gene is involved right from the earliest stages of neuroblastoma
development.
Through a national collaboration with other centers that treat neuroblastoma,
and exemplary exchanges between physicians and researchers at the Institut
Curie, Olivier Delattre and his group “genetically” analyzed 592
neuroblastoma samples. They found that in these tumors the ALK gene was
frequently altered: either there were excess copies or it contained activating
mutations. Now, inhibition of the ALK gene in neuroblastoma cells greatly
reduces cell proliferation.
The researchers have also shown that in the familial forms of
neuroblastoma, mutations of the ALK gene are transmitted to offspring.
Histological section of a
ALK thus acquires the status of neuroblastoma predisposition gene. In a neuroblastoma
study of ten familial forms, an American team confirms this result in the same © I. Janoueix-Lerosey/Institut Curie
issue of Nature1.
1
Identification of ALK as a major familial neuroblastoma predisposition gene Y.P. Mosse, et al. Nature, doi:10.103.
This discovery should also lead to an improved clinical management and follow-up of at risk patients within
neuroblastoma families with ALK mutations. The tight links between the Inserm U830 and Institut Curie
Genetics Department, directed by Prof Dominique Stoppa-Lyonnet, should constitute an asset for these
clinical applications;
Therapeutic applications should soon follow from this discovery, since as Olivier Delattre points out the
“ALK gene is also involved in certain lymphomas and one type of lung cancer, and drugs that can
counteract its effect have already been identified.” ALK encodes a tyrosine kinase receptor on the cell
surface which acts as a switch. Permanently switched on in tumor cells, it tells them to multiply
ceaselessly. Dr Delattre, who is both a researcher and pediatrician, observes that “in other cancers, as for
instance breast cancer, drugs able to block the effect of this type of receptor—Herceptin® to name but
one—are already used routinely.” Preclinical studies should soon be under way to assess whether these
drugs can stop on neuroblastoma growth. This holds out great hope to young patients since, in certain
forms, currently available chemotherapy fails to stop rapid progression of the neuroblastoma.
This study was funded by the Ligue contre le cancer, the Association des Parents et des Amis des Enfants
Soignés à l’Institut Curie (APAESIC), Bagouz à Manon, Association Hubert Gouin, and Les Amis de Claire
et Enfants et Santé.
References
Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma
1,2
1,2
3
4
5
Isabelle Janoueix-Lerosey , Delphine Lequin , Laurence Brugières , Agnès Ribeiro , Loïc de Pontual , Valérie
6
1,2
6,7,8
1,2,9
4
Combaret , Virginie Raynal , Alain Puisieux , Gudrun Schleiermacher , Gaëlle Pierron , Dominique Valteau3
10
9
5
5
1,2,4
Couanet , Thierry Frebourg , Jean Michon , Stanislas Lyonnet , Jeanne Amiel and Olivier Delattre
1
2
3
4
Institut Curie, Centre de Recherche, Paris, Inserm, U830, Paris, Institut Gustave Roussy, Département de pédiatrie, Villejuif,. Institut Curie, unité
5
de Génétique Somatique, Paris, Département de Génétique, Université Paris Descartes, Faculté de Médecine et INSERM-U781, Hôpital Necker6
7
8
Enfants Malades, Paris, Centre Léon Bérard, FNCLCC, Laboratoire de Recherche Translationnelle, Lyon, Inserm, U590, Lyon, Université de
9
10
Lyon, Lyon1, Institut des Sciences Pharmaceutiques et Biologiques, Lyon, Institut Curie, département de Pédiatrie, Paris, Service de Génétique,
CHU de Rouen et Inserm U614, Faculté de Médecine et de Pharmacie, Rouen.
Nature, 16 October, vol. 455 (7215), p. 967-70.
Press contact:
Institut Curie
Céline Giustranti
Tel. 01 56 24 55 24
[email protected]