Genetics and biology of childhood cancers

Olivier Delattre, directeur de l'unité Génétique et biologie des cancers - Institut Curie / Inserm U830.

Olivier Delattre Genetics and biology of childhood cancers

Childhood cancers represent the second cause of death in children in developed countries. Most of these tumours develop from embryonal tissues and constitute, at the difference of adult tumours, accidents of development rather than of tissue renewal or aging. Other differences with adult cancers include the limited exposure of children to environmental mutagenic factors and the likely limited role of genetic instability. The link between oncogenesis and embryogenesis is highlighted by the frequent association of paediatric cancers with developmental abnormalities.

Our objectives are to define the molecular lesions that characterize paediatric tumours.

These molecular lesions constitute the starting point to achieve a better understanding of the specific processes that underlie paediatric tumour development as well as to elaborate new tools for diagnosis and prognosis and to propose new therapeutic options. In this process the construction of biochemical, cellular and animal models constitute critical steps. We are currently mainly working on three specific tumour types: Ewing’s sarcoma, malignant rhabdoid tumors and neuroblastoma.

Figure 1 : Knockdown of EWS-FLI1 expression allow Ewing cells to recover the phenotype of their mesenchymal cell progenitor.
Figure 1 : Knockdown of EWS-FLI1 expression allow Ewing cells to recover the phenotype of their mesenchymal cell progenitor.

Ewing’s sarcoma is characterized in almost all cases by gene fusion between EWS that encodes an RNA binding protein of unknown function and members of the ETS family of transcription factor. Our main focus now is to decipher EWS-FLI1 downstream pathways and in particular to identify genes that are direct targets of EWS-FLI1 and that may account for the oncogenic properties of this chimeric protein. In malignant rhabdoid tumor, which is one of the most aggressive paediatric cancers, we identified the allelic inactivation of SMARCB1 as being critical to the tumoral development. SMARCB1 encodes a member of the chromatin SWI/SNF remodeling complex and the loss of function of SMARCB1 is thought to impair the initiation of various differentiation programs. Importantly, alteration of subunits of the SWI/SNF complex is a frequent event in human cancers as shown by recent results from NGS studies. Neuroblastoma is a tumor derived from the sympathetic neural crest cells. It can occur in the context of PHOX2B or ALK mutation. Its aggressiveness can range from spontaneously regressing tumors to highly invasive and treatment resistant tumors. It is highly dependent upon the type of genetic alteration that characterizes tumor cells, being very low in case of numerical chromosome alterations only and high when segmental chromosome abnormalities are present. The recent finding that ALK can be mutated in both familial and sporadic cases opens new avenues to the understanding of neuroblastoma development.

Our project aims at:

  • elucidating the nature of the progenitor cells which give rise to these cancers and the relationships between the normal and cancer stem cells with respect to the mechanisms of self-renewal and differentiation,

  • understanding the individual susceptibility to develop these cancers. In neuroblastoma and rhadoid tumors strong predisposition is linked to the presence of germline ALK or SMARCB1 mutations, respectively.

No such strong predisposition has been observed in Ewing sarcoma. Yet, this tumor is mostly observed in populations of European descent and much rarer in populations of African or Asian descents suggesting that the occurrence of this tumor is at least partly determined by genetic susceptibility factors. Indeed, three loci were recently linked to the development of Ewing sarcoma. Further investigation of these loci is in progress and should enable to decipher the mechanisms underlying the genetic susceptibility; iii) developing relevant animal models of these cancers. Genetically modified mouse models that recapitulate the human disease have been generated for neuroblastoma and rhabdoid tumors; iv) understanding the mechanisms of tumor progression through the analysis of clonal evolution of tumors taking advantage of next generation sequencing approaches; v) identifying some key fragilities of these cancers that could be at the basis of new therapeutic approaches.

Key publications

Year of publication 2017

Boeva, V., Louis-Brennetot, C., Peltier, A., Durand, S., Pierre-Eugène, C., Raynal, V., Etchevers, H.C., Thomas, S., Lermine, A., Daudigeos-Dubus, E., Geoerger, B., Orth, M.F., Grünewald, T.G.P., Diaz, E., Ducos, B., Surdez, D., Carcaboso, A.M., Medvedeva, I., Deller, T., Combaret, V., Lapouble, E., Pierron, G., Grossetête-Lalami, S., Baulande, S., Schleiermacher, G., Barillot, E., Rohrer, H., Delattre, O., and Janoueix-Lerosey, I. (2017 Sep 1)

Heterogeneity of neuroblastoma cell identity defined by transcriptional circuitries.

Nature Genetics : DOI : 10.1038/ng.3921
Franzetti GA, Laud-Duval K, van der Ent W, Brisac A, Irondelle M, Aubert S, Dirksen U, Bouvier C, de Pinieux G, Snaar-Jagalska E, Chavrier P, Delattre O, (2017 Jun 22)

Cell-to-cell heterogeneity of EWSR1-FLI1 activity determines proliferation/migration choices in Ewing sarcoma cells.

Oncogene- : DOI : 10.1038/onc.2016.498
Sheffield NC, Pierron G, Klughammer J, Datlinger P, Schönegger A, Schuster M, Hadler J, Surdez D, Guillemot D, Lapouble E, Freneaux P, Champigneulle J, Bouvier R, Walder D, Ambros IM, Hutter C, Sorz E, Amaral AT, de Álava E, Schallmoser K, Strunk D, Rinner B, Liegl-Atzwanger B, Huppertz B, Leithner A, de Pinieux G, Terrier P, Laurence V, Michon J, Ladenstein R, Holter W, Windhager R, Dirksen U, Ambros PF, Delattre O, Kovar H, Bock C, Tomazou EM. (2017 Mar 23)

DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma.

Nature Médecine- : DOI : 10.1038/nm.4273

Year of publication 2016

Zhi-Yan Han, Wilfrid Richer, Paul Fréneaux, Céline Chauvin, Carlo Lucchesi, Delphine Guillemot, Camille Grison, Delphine Lequin, Gaelle Pierron, Julien Masliah-Planchon, André Nicolas, Dominique Ranchère-Vince, Pascale Varlet, Stéphanie Puget, Isabelle Janoueix-Lerosey, Olivier Ayrault, Didier Surdez, Olivier Delattre, Franck Bourdeaut (2016 Jan 29)

The occurrence of intracranial rhabdoid tumours in mice depends on temporal control of Smarcb1 inactivation.

Nature communications : 10421 : DOI : 10.1038/ncomms10421

Year of publication 2015

Angela Bellini, Virginie Bernard, Quentin Leroy, Thomas Rio Frio, Gaelle Pierron, Valérie Combaret, Eve Lapouble, Nathalie Clement, Herve Rubie, Estelle Thebaud, Pascal Chastagner, Anne Sophie Defachelles, Christophe Bergeron, Nimrod Buchbinder, Sophie Taque, Anne Auvrignon, Dominique Valteau-Couanet, Jean Michon, Isabelle Janoueix-Lerosey, Olivier Delattre, Gudrun Schleiermacher (2015 Feb 20)

Deep Sequencing Reveals Occurrence of Subclonal ALK Mutations in Neuroblastoma at Diagnosis.

Clinical cancer research : an official journal of the American Association for Cancer Research : 4913-21 : DOI : 10.1158/1078-0432.CCR-15-0423
Thomas F Eleveld, Derek A Oldridge, Virginie Bernard, Jan Koster, Leo Colmet Daage, Sharon J Diskin, Linda Schild, Nadia Bessoltane Bentahar, Angela Bellini, Mathieu Chicard, Eve Lapouble, Valérie Combaret, Patricia Legoix-Né, Jean Michon, Trevor J Pugh, Lori S Hart, JulieAnn Rader, Edward F Attiyeh, Jun S Wei, Shile Zhang, Arlene Naranjo, Julie M Gastier-Foster, Michael D Hogarty, Shahab Asgharzadeh, Malcolm A Smith, Jaime M Guidry Auvil, Thomas B K Watkins, Danny A Zwijnenburg, Marli E Ebus, Peter van Sluis, Anne Hakkert, Esther van Wezel, C Ellen van der Schoot, Ellen M Westerhout, Johannes H Schulte, Godelieve A Tytgat, M Emmy M Dolman, Isabelle Janoueix-Lerosey, Daniela S Gerhard, Huib N Caron, Olivier Delattre, Javed Khan, Rogier Versteeg, Gudrun Schleiermacher, Jan J Molenaar, John M Maris (2015 Jan 15)

Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations.

Nature genetics : 864-71 : DOI : 10.1038/ng.3333
All publications