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

Murray, Aoife
Groet, Jürgen
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Published in Nature Communications. 2014, vol. 5, 4654
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
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Article (Published version) (363 Kb) - public document Free access
Research group Pathologie Moléculaire de la Trisomie 21 et le Génome Humain (248)
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NIKOLAEV, Sergey Igorievich et al. Frequent cases of RAS-mutated Down syndrome acute lymphoblastic leukaemia lack JAK2 mutations. In: Nature communications, 2014, vol. 5, p. 4654. doi: 10.1038/ncomms5654 https://archive-ouverte.unige.ch/unige:42301

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Deposited on : 2014-12-01

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