title: Frequent cases of RAS-mutated Down syndrome acute lymphoblastic leukaemia lack JAK2 mutations.
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.
authors.affiliation: 1] Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland [2].
authors.forename: Sergey I
authors.initials: SI
authors.lastname: Nikolaev
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Garieri
authors.affiliation: 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.
authors.forename: Federico
authors.initials: F
authors.lastname: Santoni
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland.
authors.forename: Emilie
authors.initials: E
authors.lastname: Falconnet
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue Michel Servet, Geneva 1211, Switzerland.
authors.forename: Pascale
authors.initials: P
authors.lastname: Ribaux
authors.affiliation: Geneva University Hospitals-HUG, Service of Genetic Medicine, 4 Rue Gabrielle-Perret-Gentil, Geneva 1211, Switzerland.
authors.forename: Michel
authors.initials: M
authors.lastname: Guipponi
authors.affiliation: 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.
authors.forename: Aoife
authors.initials: A
authors.lastname: Murray
authors.affiliation: 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.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Groet
authors.affiliation: 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.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Giarin
authors.affiliation: 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.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.affiliation: 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].
authors.forename: Dean
authors.initials: D
authors.lastname: Nizetic
authors.affiliation: 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].
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
mesh_terms: D002648:Child; D002843:Chromatin / Q000737:chemistry; D004252:DNA Mutational Analysis; D004314:Down Syndrome / Q000235:genetics* / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D008214:Lymphocytes / Q000166:cytology; D008297:Male; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D018121:Receptors, Cytokine / Q000235:genetics; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C498762:CRLF2 protein, human; D002843:Chromatin; D018121:Receptors, Cytokine; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D018631:ras Proteins
references.citation: Blood. 2013 Jul 25;122(4):554-61
references.pmid: 23733339
references.citation: Leukemia. 2013 Sep;27(9):1933-6
references.pmid: 23535558
references.citation: Nature. 2013 May 30;497(7451):577-8
references.pmid: 23698372
references.citation: Cancer Res. 2008 Aug 15;68(16):6803-9
references.pmid: 18701506
references.citation: Nature. 2014 Jan 23;505(7484):495-501
references.pmid: 24390350
references.citation: Blood. 2012 Dec 20;120(26):5134-42
references.pmid: 23091296
references.citation: Blood. 2009 Jan 15;113(3):646-8
references.pmid: 18927438
references.citation: Nat Genet. 2009 Nov;41(11):1243-6
references.pmid: 19838194
references.citation: Leukemia. 2013 Jan;27(1):251-2
references.pmid: 22868968
references.citation: Lancet. 2013 Jun 1;381(9881):1943-55
references.pmid: 23523389
references.citation: Lancet. 2003 May 10;361(9369):1617-20
references.pmid: 12747884
references.citation: Blood. 2011 Sep 15;118(11):3080-7
references.pmid: 21680795
references.citation: Nat Genet. 2014 Feb;46(2):116-25
references.pmid: 24413735
references.citation: Blood. 2014 Jan 2;123(1):70-7
references.pmid: 24222333
references.citation: Cancer Res. 2012 Dec 1;72(23):6279-89
references.pmid: 23204322
references.citation: Nat Genet. 2013 Nov;45(11):1293-9
references.pmid: 24056718
references.citation: Blood. 2010 Feb 4;115(5):1006-17
references.pmid: 19965641
references.citation: Cell. 2012 Jul 20;150(2):264-78
references.pmid: 22817890
references.citation: Pediatr Hematol Oncol. 1992 Apr-Jun;9(2):139-49
references.pmid: 1388043
references.citation: Leukemia. 2003 Feb;17(2):277-82
references.pmid: 12592323
references.citation: Science. 2013 Mar 29;339(6127):1546-58
references.pmid: 23539594
references.citation: Lancet. 2000 Jan 15;355(9199):165-9
references.pmid: 10675114
references.citation: Lancet. 2008 Mar 22;371(9617):1030-43
references.pmid: 18358930
references.citation: Blood. 2010 Aug 19;116(7):1045-50
references.pmid: 20442364
references.citation: Nat Genet. 2013 Mar;45(3):242-52
references.pmid: 23334668
references.citation: AMA J Dis Child. 1957 Sep;94(3):289-93
references.pmid: 13457660
references.citation: Nat Rev Cancer. 2012 Oct;12(10):721-32
references.pmid: 22996602
references.citation: Blood. 2009 Mar 19;113(12):2619-28
references.pmid: 19139078
references.citation: Lancet. 2008 Oct 25;372(9648):1484-92
references.pmid: 18805579
references.citation: Nat Rev Cancer. 2007 Apr;7(4):295-308
references.pmid: 17384584
references.citation: Nat Genet. 2002 Sep;32(1):148-52
references.pmid: 12172547
references.citation: Blood. 2002 Jan 1;99(1):245-51
references.pmid: 11756178