4.8 Article

Molecular map of chronic lymphocytic leukemia and its impact on outcome

Journal

NATURE GENETICS
Volume 54, Issue 11, Pages 1664-+

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41588-022-01140-w

Keywords

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Funding

  1. National Institutes of Health (NIH)/National Cancer Institute (NCI) [P01 CA206978]
  2. Broad/IBM Cancer Resistance Research Project
  3. long-term EMBO fellowship [ALTF 14-2018]
  4. NHLBI Training Program in Molecular Hematology [T32HL116324]
  5. American Association for Cancer Research [21-40-11-NADE]
  6. European Hematology Association [RG-202012-00245]
  7. Lady Tata Memorial Trust [LADY_TATA_21_3223]
  8. Deutsche Forschungsgemeinschaft [SFB1074]
  9. Intramural Research Program at NIH/NHLBI
  10. MD Anderson's Moon Shot Program in CLL
  11. CLL Global Research Foundation
  12. MDACC Support Grant [CA016672]
  13. NCI Research Specialist Award [R50CA251956]
  14. NIH [R01 CA 213442]
  15. NIH/NCI [P01 CA206978]
  16. Melton Family Foundation
  17. Spanish Ministerio de Economia y Competitividad [SAF2017-87811-R, PID2020-117185RB-I00]
  18. Department of Education of the Basque Government [PRE_2017_1_0100]
  19. la Caixa Foundation [CLLEvolution- LCF/PR/HR17/52150017, HR17-0022]
  20. European Research Council under the European Union [810287]
  21. Accelerator award CRUK/AIRC/AECC
  22. Generalitat de Catalunya Suport Grups de Recerca [AGAUR 2017-SGR-1142, 2017-SGR-736]
  23. CERCA Programme/Generalitat de Catalunya
  24. European Research Council (ERC) [810287] Funding Source: European Research Council (ERC)

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This study identifies genetic drivers and molecular subtypes associated with clinical outcomes in chronic lymphocytic leukemia (CLL) through genomic, transcriptomic, and epigenomic analysis. The findings provide fresh insights into the oncogenesis and prognostication of CLL.
A genomic, transcriptomic and epigenomic analysis of chronic lymphocytic leukemia identifies genetic drivers and molecular subtypes associated with clinical outcomes. Recent advances in cancer characterization have consistently revealed marked heterogeneity, impeding the completion of integrated molecular and clinical maps for each malignancy. Here, we focus on chronic lymphocytic leukemia (CLL), a B cell neoplasm with variable natural history that is conventionally categorized into two subtypes distinguished by extent of somatic mutations in the heavy-chain variable region of immunoglobulin genes (IGHV). To build the 'CLL map,' we integrated genomic, transcriptomic and epigenomic data from 1,148 patients. We identified 202 candidate genetic drivers of CLL (109 new) and refined the characterization of IGHV subtypes, which revealed distinct genomic landscapes and leukemogenic trajectories. Discovery of new gene expression subtypes further subcategorized this neoplasm and proved to be independent prognostic factors. Clinical outcomes were associated with a combination of genetic, epigenetic and gene expression features, further advancing our prognostic paradigm. Overall, this work reveals fresh insights into CLL oncogenesis and prognostication.

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