title: Clinical and biological implications of driver mutations in myelodysplastic syndromes.
abstract: Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic hematological malignancies characterized by dysplasia, ineffective hematopoiesis and a variable risk of progression to acute myeloid leukemia. Sequencing of MDS genomes has identified mutations in genes implicated in RNA splicing, DNA modification, chromatin regulation, and cell signaling. We sequenced 111 genes across 738 patients with MDS or closely related neoplasms (including chronic myelomonocytic leukemia and MDS-myeloproliferative neoplasms) to explore the role of acquired mutations in MDS biology and clinical phenotype. Seventy-eight percent of patients had 1 or more oncogenic mutations. We identify complex patterns of pairwise association between genes, indicative of epistatic interactions involving components of the spliceosome machinery and epigenetic modifiers. Coupled with inferences on subclonal mutations, these data suggest a hypothesis of genetic "predestination," in which early driver mutations, typically affecting genes involved in RNA splicing, dictate future trajectories of disease evolution with distinct clinical phenotypes. Driver mutations had equivalent prognostic significance, whether clonal or subclonal, and leukemia-free survival deteriorated steadily as numbers of driver mutations increased. Thus, analysis of oncogenic mutations in large, well-characterized cohorts of patients illustrates the interconnections between the cancer genome and disease biology, with considerable potential for clinical application.
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom;
authors.forename: Elli
authors.initials: E
authors.lastname: Papaemmanuil
authors.forename: Moritz
authors.initials: M
authors.lastname: Gerstung
authors.forename: Luca
authors.initials: L
authors.lastname: Malcovati
authors.forename: Sudhir
authors.initials: S
authors.lastname: Tauro
authors.forename: Gunes
authors.initials: G
authors.lastname: Gundem
authors.forename: Peter
authors.initials: P
authors.lastname: Van Loo
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Yoon
authors.forename: Peter
authors.initials: P
authors.lastname: Ellis
authors.forename: David C
authors.initials: DC
authors.lastname: Wedge
authors.forename: Andrea
authors.initials: A
authors.lastname: Pellagatti
authors.forename: Adam
authors.initials: A
authors.lastname: Shlien
authors.forename: Michael John
authors.initials: MJ
authors.lastname: Groves
authors.forename: Simon A
authors.initials: SA
authors.lastname: Forbes
authors.forename: Keiran
authors.initials: K
authors.lastname: Raine
authors.forename: Jon
authors.initials: J
authors.lastname: Hinton
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Mudie
authors.forename: Stuart
authors.initials: S
authors.lastname: McLaren
authors.forename: Claire
authors.initials: C
authors.lastname: Hardy
authors.forename: Calli
authors.initials: C
authors.lastname: Latimer
authors.forename: Matteo G
authors.initials: MG
authors.lastname: Della Porta
authors.forename: Sarah
authors.initials: S
authors.lastname: O'Meara
authors.forename: Ilaria
authors.initials: I
authors.lastname: Ambaglio
authors.forename: Anna
authors.initials: A
authors.lastname: Galli
authors.forename: Adam P
authors.initials: AP
authors.lastname: Butler
authors.forename: Gunilla
authors.initials: G
authors.lastname: Walldin
authors.forename: Jon W
authors.initials: JW
authors.lastname: Teague
authors.forename: Lynn
authors.initials: L
authors.lastname: Quek
authors.forename: Alex
authors.initials: A
authors.lastname: Sternberg
authors.forename: Carlo
authors.initials: C
authors.lastname: Gambacorti-Passerini
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Green
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Boultwood
authors.forename: Paresh
authors.initials: P
authors.lastname: Vyas
authors.forename: Eva
authors.initials: E
authors.lastname: Hellstrom-Lindberg
authors.forename: David
authors.initials: D
authors.lastname: Bowen
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D018450:Disease Progression; D004843:Epistasis, Genetic; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D054437:Myelodysplastic-Myeloproliferative Diseases / Q000235:genetics; D009857:Oncogenes; D011379:Prognosis; D012326:RNA Splicing / Q000235:genetics; D017381:Spliceosomes / Q000235:genetics
references.citation: Nature. 2012 May 16;486(7403):400-4
references.pmid: 22722201
references.citation: Ann Hematol. 2013 Jan;92(1):19-24
references.pmid: 22948274
references.citation: Blood. 2009 Jun 11;113(24):6182-92
references.pmid: 19387008
references.citation: Mol Cancer Res. 2013 Aug;11(8):815-27
references.pmid: 23645565
references.citation: Blood. 2012 Apr 5;119(14):3211-8
references.pmid: 22343920
references.citation: N Engl J Med. 2011 Oct 13;365(15):1384-95
references.pmid: 21995386
references.citation: Science. 2013 Mar 29;339(6127):1546-58
references.pmid: 23539594
references.citation: J Clin Oncol. 2013 May 20;31(15):1806-14
references.pmid: 23589557
references.citation: Blood. 2011 Dec 8;118(24):6239-46
references.pmid: 21998214
references.citation: Leukemia. 2011 Jul;25(7):1200-2
references.pmid: 21455215
references.citation: Leukemia. 2013 Jun;27(6):1275-82
references.pmid: 23443460
references.citation: Nat Genet. 2009 Jul;41(7):838-42
references.pmid: 19483684
references.citation: Blood. 2005 Nov 15;106(10):3377-9
references.pmid: 16081687
references.citation: Cell. 2012 Jul 20;150(2):264-78
references.pmid: 22817890
references.citation: N Engl J Med. 2012 Mar 8;366(10):883-892
references.pmid: 22397650
references.citation: Blood. 2002 Oct 1;100(7):2292-302
references.pmid: 12239137
references.citation: Nature. 2010 Apr 15;464(7291):999-1005
references.pmid: 20393555
references.citation: J Clin Oncol. 2012 Sep 20;30(27):3376-82
references.pmid: 22869879
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13081-6
references.pmid: 18723673
references.citation: Blood. 2013 Jul 25;122(4):567-70
references.pmid: 23760614
references.citation: N Engl J Med. 2013 May 30;368(22):2059-74
references.pmid: 23634996
references.citation: N Engl J Med. 2009 Nov 5;361(19):1872-85
references.pmid: 19890130
references.citation: Cancer Cell. 2010 Dec 14;18(6):553-67
references.pmid: 21130701
references.citation: Nucleic Acids Res. 2011 Jan;39(Database issue):D945-50
references.pmid: 20952405
references.citation: N Engl J Med. 2012 Mar 22;366(12):1090-8
references.pmid: 22417201
references.citation: Blood. 2012 Sep 20;120(12):2454-65
references.pmid: 22740453
references.citation: Nature. 2009 Apr 9;458(7239):719-24
references.pmid: 19360079
references.citation: Nature. 2011 Sep 11;478(7367):64-9
references.pmid: 21909114
references.citation: Leukemia. 2010 May;24(5):1062-5
references.pmid: 20182461
references.citation: Cancer Cell. 2012 Aug 14;22(2):180-93
references.pmid: 22897849
references.citation: N Engl J Med. 2006 Oct 5;355(14):1456-65
references.pmid: 17021321
references.citation: N Engl J Med. 2011 Jun 30;364(26):2496-506
references.pmid: 21714648
references.citation: Cell. 2013 Mar 28;153(1):17-37
references.pmid: 23540688
references.citation: Leukemia. 2011 Jul;25(7):1153-8
references.pmid: 21415852
references.citation: Blood. 2013 Feb 7;121(6):975-83
references.pmid: 23212519
references.citation: Blood. 2012 Apr 12;119(15):3578-84
references.pmid: 22389253
references.citation: Blood. 2009 Jul 30;114(5):937-51
references.pmid: 19357394
references.citation: Br J Haematol. 2009 Jun;145(6):788-800
references.pmid: 19388938
references.citation: Nat Genet. 2013 Jan;45(1):18-24
references.pmid: 23222956
references.citation: J Stat Softw. 2011 Mar;39(5):1-13
references.pmid: 27065756
references.citation: N Engl J Med. 2009 May 28;360(22):2289-301
references.pmid: 19474426
references.citation: Cell. 2012 May 25;149(5):994-1007
references.pmid: 22608083
references.citation: Stat Med. 1997 Feb 28;16(4):385-95
references.pmid: 9044528
references.citation: Nat Genet. 2010 Aug;42(8):722-6
references.pmid: 20601953
references.citation: Nature. 2012 Jan 11;481(7382):506-10
references.pmid: 22237025
references.citation: Nat Genet. 2011 Dec 11;44(1):53-7
references.pmid: 22158538