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Clonal diversity predicts adverse outcome in chronic lymphocytic leukemia

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  • Alexander C Leeksma
  • Justin Taylor
  • Bian Wu
  • Jeffrey R Gardner
  • Jie He
  • Michelle Nahas
  • Mithat Gonen
  • Wendimagegn G Alemayehu
  • Doreen Te Raa
  • Tatjana Walther
  • Jennifer Hüllein
  • Sascha Dietrich
  • Rainer Claus
  • Fransien de Boer
  • Koen de Heer
  • Julie Dubois
  • Maria Dampmann
  • Jan Dürig
  • Marinus H J van Oers
  • Christian H Geisler
  • Eric Eldering
  • Ross L Levine
  • Vincent Miller
  • Tariq Mughal
  • Nicole Lamanna
  • Mark G Frattini
  • Mark L Heaney
  • Andrew Zelenetz
  • Thorsten Zenz
  • Omar Abdel-Wahab
  • Arnon P Kater
Vis graf over relationer

Genomic analyses of chronic lymphocytic leukemia (CLL) identified somatic mutations and associations of clonal diversity with adverse outcomes. Clonal evolution likely has therapeutic implications but its dynamic is less well studied. We studied clonal composition and prognostic value of seven recurrently mutated driver genes using targeted next-generation sequencing in 643 CLL patients and found higher frequencies of mutations in TP53 (35 vs. 12%, p < 0.001) and SF3B1 (20 vs. 11%, p < 0.05) and increased number of (sub)clonal (p < 0.0001) mutations in treated patients. We next performed an in-depth evaluation of clonal evolution on untreated CLL patients (50 "progressors" and 17 matched "non-progressors") using a 404 gene-sequencing panel and identified novel mutated genes such as AXIN1, SDHA, SUZ12, and FOXO3. Progressors carried more mutations at initial presentation (2.5 vs. 1, p < 0.0001). Mutations in specific genes were associated with increased (SF3B1, ATM, and FBXW7) or decreased progression risk (AXIN1 and MYD88). Mutations affecting specific signaling pathways, such as Notch and MAP kinase pathway were enriched in progressive relative to non-progressive patients. These data extend earlier findings that specific genomic alterations and diversity of subclones are associated with disease progression and persistence of disease in CLL and identify novel recurrently mutated genes and associated outcomes.

OriginalsprogEngelsk
TidsskriftLeukemia
Vol/bind33
Udgave nummer2
Sider (fra-til)390-402
ISSN0887-6924
DOI
StatusUdgivet - 2019

ID: 55722655