Molecular map of chronic lymphocytic leukemia and its impact on outcome

被引：75

作者：

Knisbacher, Binyamin A. ^{[1
]}

Lin, Ziao ^{[1
,2
]}

Hahn, Cynthia K. ^{[1
,3
]}

Nadeu, Ferran ^{[4
,5
]}

Duran-Ferrer, Marti ^{[4
,5
]}

Stevenson, Kristen E. ^{[6
]}

Tausch, Eugen ^{[7
]}

Delgado, Julio ^{[4
,5
,8
]}

Barbera-Mourelle, Alex ^{[1
,9
]}

Taylor-Weiner, Amaro ^{[1
]}

Bousquets-Munoz, Pablo ^{[10
]}

Diaz-Navarro, Ander ^{[10
]}

Dunford, Andrew ^{[1
]}

Anand, Shankara ^{[1
]}

Kretzmer, Helene ^{[11
]}

Gutierrez-Abril, Jesus ^{[12
]}

Lopez-Tamargo, Sara ^{[10
]}

Fernandes, Stacey M. ^{[3
]}

Sun, Clare ^{[13
]}

Sivina, Mariela ^{[14
]}

Rassenti, Laura Z. ^{[15
]}

Schneider, Christof ^{[7
]}

Li, Shuqiang ^{[1
,3
,16
]}

Parida, Laxmi ^{[17
]}

Meissner, Alexander ^{[1
,11
,18
]}

Aguet, Francois ^{[1
]}

Burger, Jan A. ^{[14
]}

Wiestner, Adrian ^{[13
]}

Kipps, Thomas J. ^{[15
]}

Brown, Jennifer R. ^{[3
,19
]}

Hallek, Michael ^{[20
,21
,22
]}

Stewart, Chip ^{[1
]}

Neuberg, Donna S. ^{[6
]}

Martin-Subero, Jose, I ^{[4
,5
,23
,24
]}

Puente, Xose S. ^{[5
,10
]}

Stilgenbauer, Stephan ^{[7
]}

Wu, Catherine J. ^{[1
,3
,19
,25
]}

Campo, Elias ^{[2
,4
,5
,26
]}

Getz, Gad ^{[1
,9
,19
,27
]}

机构：

[1] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[2] Harvard Univ, Cambridge, MA 02138 USA

[3] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[4] Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain

[5] Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain

[6] Dana Farber Canc Inst, Dept Data Sci, Boston, MA 02115 USA

[7] Ulm Univ, Dept Internal Med 3, Ulm, Germany

[8] IDIBAPS, Hosp Clin, Serv Hematol, Barcelona, Spain

[9] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA

[10] Univ Oviedo, Inst Univ Oncol, Dept Bioquim & Biol Mol, Oviedo, Spain

[11] Max Planck Inst Mol Genet, Dept Genome Regulat, Berlin, Germany

[12] Mem Sloan Kettering Canc Ctr, Computat Oncol Serv, Dept Pediat, 1275 York Ave, New York, NY 10021 USA

[13] NHLBI, Lab Lymphoid Malignancies, NIH, Bldg 10, Bethesda, MD 20892 USA

[14] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA

[15] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA

[16] Dana Farber Canc Inst, Translat Immunogen Lab, Boston, MA 02115 USA

[17] IBM Res, Yorktown Hts, NY USA

[18] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

[19] Harvard Med Sch, Boston, MA 02115 USA

[20] Ctr Mol Med, Cologne, Germany

[21] Univ Cologne, Dept Internal Med 1, Ctr Integrated Oncol, Aachen Bonn Cologne Duesseldorf & German CLL Stud, Cologne, Germany

[22] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, Cologne, Germany

[23] Inst Catalana Recerca & Estudis Avancats ICREA, Barcelona, Spain

[24] Univ Barcelona, Fac Med, Dept Fonaments Clin, Barcelona, Spain

[25] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA

[26] Hosp Clin Barcelona, Hematopathol Sect, Lab Pathol, Barcelona, Spain

[27] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

来源：

NATURE GENETICS | 2022年 / 54卷 / 11期

基金：

欧洲研究理事会; 美国国家卫生研究院;

关键词：

CANCER GENES; RNA-BINDING; MUTATIONS; DISCOVERY; PROTEIN; MECHANISMS; EVOLUTION; REVEALS; SAMPLES; FAMILY;

D O I：

10.1038/s41588-022-01140-w

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：1664 / +

页数：31

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