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Nat Commun. 2014 Aug 8;5:4654. doi: 10.1038/ncomms5654.

Frequent cases of RAS-mutated Down syndrome acute lymphoblastic leukaemia lack JAK2 mutations.

Author information

1
1] Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland [2].
2
Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland.
3
1] Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland [2] Geneva University Hospitals-HUG, Service of Genetic Medicine, 4 Rue Gabrielle-Perret-Gentil, Geneva 1211, Switzerland.
4
Geneva University Hospitals-HUG, Service of Genetic Medicine, 4 Rue Gabrielle-Perret-Gentil, Geneva 1211, Switzerland.
5
1] The Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK [2] LonDownS Consortium, The Wellcome Trust, London NW1 2BE, UK.
6
Dipartimento di Salute della Donna e del Bambino, University of Padua, IRP-Istituto di Ricerca Pediatrica-Fondazione Città della Speranza, Via N. Giustiniani 3, 35129 Padua, Italy.
7
1] The Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK [2] LonDownS Consortium, The Wellcome Trust, London NW1 2BE, UK [3] Lee Kong Chian School of Medicine, Nanyang Technological University, Unit 04-11, Proteos Building, 61 Biopolis Drive, Singapore 138673, Singapore [4].
8
1] Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland [2] IGE3 institute of Genetics and Genomics of Geneva, 1 rue Michel Servet, Geneva 1211, Switzerland [3].

Abstract

Children with Down syndrome (DS) and acute lymphoblastic leukaemia (ALL) have poorer survival and more relapses than non-DS children with ALL, highlighting an urgent need for deeper mechanistic understanding of DS-ALL. Here, using full-exome or cancer genes-targeted sequencing of 42 ALL samples from 39 DS patients, we uncover driver mutations in RAS, (KRAS and NRAS) recurring to a similar extent (15/42) as JAK2 (12/42) mutations or P2RY8-CRLF2 fusions (14/42). RAS mutations are almost completely mutually exclusive with JAK2 mutations (P=0.016), driving a combined total of two-thirds of analysed cases. Clonal architecture analysis reveals that both RAS and JAK2 drove sub-clonal expansions primarily initiated by CRLF2 rearrangements, and/or mutations in chromatin remodellers and lymphocyte differentiation factors. Remarkably, in 2/3 relapsed cases, there is a switch from a primary JAK2- or PTPN11-mutated sub-clone to a RAS-mutated sub-clone in relapse. These results provide important new insights informing the patient stratification strategies for targeted therapeutic approaches for DS-ALL.

PMID:
25105841
PMCID:
PMC4665216
DOI:
10.1038/ncomms5654
[Indexed for MEDLINE]
Free PMC Article

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