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.
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ACL is supported by the van der Laan foundation. JT is supported by an American Society of Hematology (ASH) Research Training Award for Fellows, an ASCO Young Investigator Award, and the ASH and Harold Amos Medical Faculty Development Program of the Robert Wood Johnson Foundation. JG was supported by the Vogelstein Fund at MSKCC. OAW is supported by NIH/NCI R01 (1R01HL128239-01 and 1R01 CA201247-01) and support from the Cycle for Survival. This work was also supported by the Peter Solomon Fund at MSKCC. TZ was supported by a Mildred Scheel Professorship, the “Monique Dornonville de la Cour Stiftung” and the Transcan project. Many thanks go to the participating patients and we would like to acknowledge all participating institutions in the HOVON68 CLL trial, the data managers and statisticians of the HOVON data center, as well as the HOVON68 CLL study funding sources, the participating German centers and MSKCC.
ACL, JT, BW, JRG, MN, JH, MG, OAW, TZ, and APK were responsible for conception and design of the study. ACL, BW, JT, JRG, RLL, VM, and TM were involved in analysis and interpretation of data. MN, JH, MH, DR, WGA, TW, JH, FB, KH, JD, NL, MGF, SD, RC, JD, CHG, MHJO, MLH, and AZ, TZ, OAW, and APK were involved in acquisition of patient materials. ACL, BW, JRG, and MG perfomed statistical analyses. ACL, BW, and JRG made the figures. ACL, JT, TZ, OAW, and APK wrote the first draft; and all authors were involved in revising the manuscript and approved the final version.
Conflict of interest
MN, JH, VM, and TM are employees of Foundation Medicine. RLL and OAW are consultants for Foundation Medicine. The remaining authors declare that they have no conflict of interest.
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Leeksma, A.C., Taylor, J., Wu, B. et al. Clonal diversity predicts adverse outcome in chronic lymphocytic leukemia. Leukemia 33, 390–402 (2019) doi:10.1038/s41375-018-0215-9
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