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

Sergey I. Nikolaev (), Marco Garieri, Federico Santoni, Emilie Falconnet, Pascale Ribaux, Michel Guipponi, Aoife Murray, Jürgen Groet, Emanuela Giarin, Giuseppe Basso, Dean Nizetic () and Stylianos E. Antonarakis ()
Additional contact information
Sergey I. Nikolaev: University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland
Marco Garieri: University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland
Federico Santoni: University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland
Emilie Falconnet: University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland
Pascale Ribaux: University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland
Michel Guipponi: Geneva University Hospitals—HUG, Service of Genetic Medicine, 4 Rue Gabrielle-Perret-Gentil, Geneva 1211, Switzerland
Aoife Murray: The Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London
Jürgen Groet: The Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London
Emanuela Giarin: University of Padua, IRP—Istituto di Ricerca Pediatrica—Fondazione Città della Speranza
Giuseppe Basso: University of Padua, IRP—Istituto di Ricerca Pediatrica—Fondazione Città della Speranza
Dean Nizetic: The Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London
Stylianos E. Antonarakis: University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland

Nature Communications, 2014, vol. 5, issue 1, 1-6

Abstract: 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.

Date: 2014
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/ncomms5654 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5654

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms5654

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().