Clonal diversity predicts adverse outcome in chronic lymphocytic leukemia Journal Article

Authors: Leeksma, A. C.; Taylor, J.; Wu, B.; Gardner, J. R.; He, J.; Nahas, M.; Gonen, M.; Alemayehu, W. G.; te Raa, D.; Walther, T.; Hüllein, J.; Dietrich, S.; Claus, R.; de Boer, F.; de Heer, K.; Dubois, J.; Dampmann, M.; Dürig, J.; van Oers, M. H. J.; Geisler, C. H.; Eldering, E.; Levine, R. L.; Miller, V.; Mughal, T.; Lamanna, N.; Frattini, M. G.; Heaney, M. L.; Zelenetz, A.; Zenz, T.; Abdel-Wahab, O.; Kater, A. P.
Article Title: Clonal diversity predicts adverse outcome in chronic lymphocytic leukemia
Abstract: 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. © 2018, Springer Nature Limited.
Journal Title: Leukemia
Volume: 33
Issue: 2
ISSN: 0887-6924
Publisher: Nature Publishing Group  
Date Published: 2019-02-01
Start Page: 390
End Page: 402
Language: English
DOI: 10.1038/s41375-018-0215-9
PUBMED: 30038380
PROVIDER: scopus
Notes: Article -- Export Date: 1 March 2019 -- Source: Scopus
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MSK Authors
  1. Mithat Gonen
    713 Gonen
  2. Andrew D Zelenetz
    554 Zelenetz
  3. Ross Levine
    489 Levine
  4. Jeffrey Gardner
    33 Gardner
  5. Justin   Taylor
    22 Taylor