Evolution and Impact of Subclonal Mutations in Chronic Lymphocytic Leukemia

被引：1102

作者：

Landau, Dan A. ^{[1
,2
,4
,5
,6
]}

Carter, Scott L. ^{[4
]}

Stojanov, Petar ^{[2
,4
]}

McKenna, Aaron ^{[4
]}

Stevenson, Kristen ^{[3
]}

Lawrence, Michael S. ^{[4
]}

Sougnez, Carrie ^{[4
]}

Stewart, Chip ^{[4
]}

Sivachenko, Andrey ^{[4
]}

Wang, Lili ^{[1
,2
]}

Wan, Youzhong ^{[1
,2
]}

Zhang, Wandi ^{[1
,2
]}

Shukla, Sachet A. ^{[1
,4
]}

Vartanov, Alexander ^{[2
]}

Fernandes, Stacey M. ^{[2
]}

Saksena, Gordon ^{[4
]}

Cibulskis, Kristian ^{[4
]}

Tesar, Bethany ^{[2
]}

Gabriel, Stacey ^{[4
]}

Hacohen, Nir ^{[4
,8
]}

Meyerson, Matthew ^{[4
]}

Lander, Eric S. ^{[4
]}

Neuberg, Donna ^{[3
]}

Brown, Jennifer R. ^{[2
,7
]}

Getz, Gad ^{[4
,9
,10
]}

Wu, Catherine J. ^{[1
,2
,7
]}

机构：

[1] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA

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

[3] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA

[4] Broad Inst, Cambridge, MA 02139 USA

[5] Yale Canc Ctr, Dept Hematol, New Haven, CT 06510 USA

[6] Univ Paris Diderot, F-75013 Paris, France

[7] Harvard Univ, Brigham & Womens Hosp, Dept Med, Sch Med, Boston, MA 02115 USA

[8] Harvard Univ, Div Allergy Immunol & Rheumatol, Dept Med, Massachusetts Gen Hosp,Med Sch, Boston, MA 02114 USA

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

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

来源：

CELL | 2013年 / 152卷 / 04期

关键词：

ACUTE MYELOID-LEUKEMIA; COPY-NUMBER ALTERATION; B-CELL LYMPHOMA; CLONAL EVOLUTION; SOMATIC MUTATIONS; GENOMIC ABERRATIONS; MULTIPLE-MYELOMA; CANCER GENES; PROGRESSION; HETEROGENEITY;

D O I：

10.1016/j.cell.2013.01.019

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Clonal evolution is a key feature of cancer progression and relapse. We studied intratumoral heterogeneity in 149 chronic lymphocytic leukemia (CLL) cases by integrating whole-exome sequence and copy number to measure the fraction of cancer cells harboring each somatic mutation. We identified driver mutations as predominantly clonal (e.g., MYD88, trisomy 12, and del(13q)) or subclonal (e.g., SF3B1 and TP53), corresponding to earlier and later events in CLL evolution. We sampled leukemia cells from 18 patients at two time points. Ten of twelve CLL cases treated with chemotherapy (but only one of six without treatment) underwent clonal evolution, predominantly involving subclones with driver mutations (e.g., SF3B1 and TP53) that expanded over time. Furthermore, presence of a subclonal driver mutation was an independent risk factor for rapid disease progression. Our study thus uncovers patterns of clonal evolution in CLL, providing insights into its stepwise transformation, and links the presence of subclones with adverse clinical outcomes.

引用

页码：714 / 726

页数：13

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