title: Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing.
abstract: Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, which is associated with clonal evolution at the cytogenetic level. To determine the mutational spectrum associated with relapse, we sequenced the primary tumour and relapse genomes from eight AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to define clonality and clonal evolution patterns precisely at relapse. In addition to discovering novel, recurrently mutated genes (for example, WAC, SMC3, DIS3, DDX41 and DAXX) in AML, we also found two major clonal evolution patterns during AML relapse: (1) the founding clone in the primary tumour gained mutations and evolved into the relapse clone, or (2) a subclone of the founding clone survived initial therapy, gained additional mutations and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific versus primary tumour mutations in all eight cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. These data demonstrate that AML relapse is associated with the addition of new mutations and clonal evolution, which is shaped, in part, by the chemotherapy that the patients receive to establish and maintain remissions.
authors.affiliation: The Genome Institute, Washington University, St Louis, Missouri 63108, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ley
authors.forename: David E
authors.initials: DE
authors.lastname: Larson
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Miller
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Koboldt
authors.forename: John S
authors.initials: JS
authors.lastname: Welch
authors.forename: Julie K
authors.initials: JK
authors.lastname: Ritchey
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Young
authors.forename: Tamara
authors.initials: T
authors.lastname: Lamprecht
authors.forename: Michael D
authors.initials: MD
authors.lastname: McLellan
authors.forename: Joshua F
authors.initials: JF
authors.lastname: McMichael
authors.forename: John W
authors.initials: JW
authors.lastname: Wallis
authors.forename: Charles
authors.initials: C
authors.lastname: Lu
authors.forename: Dong
authors.initials: D
authors.lastname: Shen
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Harris
authors.forename: David J
authors.initials: DJ
authors.lastname: Dooling
authors.forename: Robert S
authors.initials: RS
authors.lastname: Fulton
authors.forename: Lucinda L
authors.initials: LL
authors.lastname: Fulton
authors.forename: Ken
authors.initials: K
authors.lastname: Chen
authors.forename: Heather
authors.initials: H
authors.lastname: Schmidt
authors.forename: Joelle
authors.initials: J
authors.lastname: Kalicki-Veizer
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Magrini
authors.forename: Lisa
authors.initials: L
authors.lastname: Cook
authors.forename: Sean D
authors.initials: SD
authors.lastname: McGrath
authors.forename: Tammi L
authors.initials: TL
authors.lastname: Vickery
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wendl
authors.forename: Sharon
authors.initials: S
authors.lastname: Heath
authors.forename: Mark A
authors.initials: MA
authors.lastname: Watson
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Link
authors.forename: Michael H
authors.initials: MH
authors.lastname: Tomasson
authors.forename: William D
authors.initials: WD
authors.lastname: Shannon
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: Payton
authors.forename: Shashikant
authors.initials: S
authors.lastname: Kulkarni
authors.forename: Peter
authors.initials: P
authors.lastname: Westervelt
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Walter
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Graubert
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.forename: John F
authors.initials: JF
authors.lastname: DiPersio
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D060965:Clonal Evolution / Q000235:genetics*; D002999:Clone Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects; D004252:DNA Mutational Analysis; D052138:Genes, Neoplasm / Q000235:genetics; D015894:Genome, Human / Q000187:drug effects / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D016296:Mutagenesis / Q000187:drug effects / Q000235:genetics; D012008:Recurrence; D015203:Reproducibility of Results
chemical_list: D000970:Antineoplastic Agents