SF3B1 and Other Novel Cancer Genes in Chronic Lymphocytic Leukemia

被引：855

作者：

Wang, Lili ^{[1
,2
]}

Lawrence, Michael S.

Wan, Youzhong ^{[1
,2
]}

Stojanov, Petar

Sougnez, Carrie

Stevenson, Kristen ^{[3
]}

Werner, Lillian ^{[3
]}

Sivachenko, Andrey

DeLuca, David S.

Zhang, Li ^{[1
,2
]}

Zhang, Wandi ^{[1
,2
]}

Vartanov, Alexander R. ^{[2
]}

Fernandes, Stacey M. ^{[2
]}

Goldstein, Natalie R. ^{[2
]}

Folco, Eric G. ^{[4
,5
]}

Cibulskis, Kristian

Tesar, Bethany ^{[2
]}

Sievers, Quinlan L. ^{[1
,2
]}

Shefler, Erica

Gabriel, Stacey

Hacohen, Nir ^{[7
]}

Reed, Robin ^{[4
,5
]}

Meyerson, Matthew ^{[2
]}

Golub, Todd R. ^{[4
,5
]}

Lander, Eric S.

Neuberg, Donna ^{[3
]}

Brown, Jennifer R. ^{[2
,6
,8
]}

Getz, Gad

Wu, Catherine J. ^{[1
,2
,6
,8
]}

机构：

[1] Harvard Inst Med, 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] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA

[6] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

[7] Massachusetts Gen Hosp, Dept Med, Div Allergy Immunol & Rheumatol, Boston, MA 02114 USA

[8] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2011年 / 365卷 / 26期

基金：

美国国家卫生研究院;

关键词：

PRE-MESSENGER-RNA; MUTATION STATUS; IN-VITRO; GENOME; ACTIVATION; SURVIVAL; PATHWAYS; CELLS; SPLICEOSTATIN; REVEALS;

D O I：

10.1056/NEJMoa1109016

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND The somatic genetic basis of chronic lymphocytic leukemia, a common and clinically heterogeneous leukemia occurring in adults, remains poorly understood. METHODS We obtained DNA samples from leukemia cells in 91 patients with chronic lymphocytic leukemia and performed massively parallel sequencing of 88 whole exomes and whole genomes, together with sequencing of matched germline DNA, to characterize the spectrum of somatic mutations in this disease. RESULTS Nine genes that are mutated at significant frequencies were identified, including four with established roles in chronic lymphocytic leukemia (TP53 in 15% of patients, ATM in 9%, MYD88 in 10%, and NOTCH1 in 4%) and five with unestablished roles (SF3B1, ZMYM3, MAPK1, FBXW7, and DDX3X). SF3B1, which functions at the catalytic core of the spliceosome, was the second most frequently mutated gene (with mutations occurring in 15% of patients). SF3B1 mutations occurred primarily in tumors with deletions in chromosome 11q, which are associated with a poor prognosis in patients with chronic lymphocytic leukemia. We further discovered that tumor samples with mutations in SF3B1 had alterations in pre-messenger RNA (mRNA) splicing. CONCLUSIONS Our study defines the landscape of somatic mutations in chronic lymphocytic leukemia and highlights pre-mRNA splicing as a critical cellular process contributing to chronic lymphocytic leukemia.

引用

页码：2497 / 2506

页数：10

共 35 条

[1] Mutations in the ATM gene lead to impaired overall and treatment-free survival that is independent of IGVH mutation status in patients with B-CLL [J].

Austen, B ;

Powell, JE ;

Alvi, A ;

Edwards, I ;

Hooper, L ;

Starczynski, J ;

Taylor, AMR ;

Fegan, C ;

Moss, P ;

Stankovic, T .

BLOOD, 2005, 106 (09) :3175-3182

[2] FBXW7 influences murine intestinal homeostasis and cancer, targeting Notch, Jun, and DEK for degradation [J].

Babaei-Jadidi, Roya ;

Li, Ningning ;

Saadeddin, Anas ;

Spencer-Dene, Bradley ;

Jandke, Anett ;

Muhammad, Belal ;

Ibrahim, ElSayed E. ;

Muraleedharan, Ranjithmenon ;

Abuzinadah, Mohammed ;

Davis, Hayley ;

Lewis, Annabelle ;

Watson, Susan ;

Behrens, Axel ;

Tomlinson, Ian ;

Nateri, Abdolrahman Shams .

JOURNAL OF EXPERIMENTAL MEDICINE, 2011, 208 (02) :295-312

[3] Integrated genomic analyses of ovarian carcinoma [J].

Bell, D. ;

Berchuck, A. ;

Birrer, M. ;

Chien, J. ;

Cramer, D. W. ;

Dao, F. ;

Dhir, R. ;

DiSaia, P. ;

Gabra, H. ;

Glenn, P. ;

Godwin, A. K. ;

Gross, J. ;

Hartmann, L. ;

Huang, M. ;

Huntsman, D. G. ;

Iacocca, M. ;

Imielinski, M. ;

Kalloger, S. ;

Karlan, B. Y. ;

Levine, D. A. ;

Mills, G. B. ;

Morrison, C. ;

Mutch, D. ;

Olvera, N. ;

Orsulic, S. ;

Park, K. ;

Petrelli, N. ;

Rabeno, B. ;

Rader, J. S. ;

Sikic, B. I. ;

Smith-McCune, K. ;

Sood, A. K. ;

Bowtell, D. ;

Penny, R. ;

Testa, J. R. ;

Chang, K. ;

Dinh, H. H. ;

Drummond, J. A. ;

Fowler, G. ;

Gunaratne, P. ;

Hawes, A. C. ;

Kovar, C. L. ;

Lewis, L. R. ;

Morgan, M. B. ;

Newsham, I. F. ;

Santibanez, J. ;

Reid, J. G. ;

Trevino, L. R. ;

Wu, Y. -Q. ;

Wang, M. .

NATURE, 2011, 474 (7353) :609-615

[4] The genomic complexity of primary human prostate cancer [J].

Berger, Michael F. ;

Lawrence, Michael S. ;

Demichelis, Francesca ;

Drier, Yotam ;

Cibulskis, Kristian ;

Sivachenko, Andrey Y. ;

Sboner, Andrea ;

Esgueva, Raquel ;

Pflueger, Dorothee ;

Sougnez, Carrie ;

Onofrio, Robert ;

Carter, Scott L. ;

Park, Kyung ;

Habegger, Lukas ;

Ambrogio, Lauren ;

Fennell, Timothy ;

Parkin, Melissa ;

Saksena, Gordon ;

Voet, Douglas ;

Ramos, Alex H. ;

Pugh, Trevor J. ;

Wilkinson, Jane ;

Fisher, Sheila ;

Winckler, Wendy ;

Mahan, Scott ;

Ardlie, Kristin ;

Baldwin, Jennifer ;

Simons, Jonathan W. ;

Kitabayashi, Naoki ;

MacDonald, Theresa Y. ;

Kantoff, Philip W. ;

Chin, Lynda ;

Gabriel, Stacey B. ;

Gerstein, Mark B. ;

Golub, Todd R. ;

Meyerson, Matthew ;

Tewari, Ashutosh ;

Lander, Eric S. ;

Getz, Gad ;

Rubin, Mark A. ;

Garraway, Levi A. .

NATURE, 2011, 470 (7333) :214-220

[5] Initial genome sequencing and analysis of multiple myeloma [J].

Chapman, Michael A. ;

Lawrence, Michael S. ;

Keats, Jonathan J. ;

Cibulskis, Kristian ;

Sougnez, Carrie ;

Schinzel, Anna C. ;

Harview, Christina L. ;

Brunet, Jean-Philippe ;

Ahmann, Gregory J. ;

Adli, Mazhar ;

Anderson, Kenneth C. ;

Ardlie, Kristin G. ;

Auclair, Daniel ;

Baker, Angela ;

Bergsagel, P. Leif ;

Bernstein, Bradley E. ;

Drier, Yotam ;

Fonseca, Rafael ;

Gabriel, Stacey B. ;

Hofmeister, Craig C. ;

Jagannath, Sundar ;

Jakubowiak, Andrzej J. ;

Krishnan, Amrita ;

Levy, Joan ;

Liefeld, Ted ;

Lonial, Sagar ;

Mahan, Scott ;

Mfuko, Bunmi ;

Monti, Stefano ;

Perkins, Louise M. ;

Onofrio, Robb ;

Pugh, Trevor J. ;

Rajkumar, S. Vincent ;

Ramos, Alex H. ;

Siegel, David S. ;

Sivachenko, Andrey ;

Stewart, A. Keith ;

Trudel, Suzanne ;

Vij, Ravi ;

Voet, Douglas ;

Winckler, Wendy ;

Zimmerman, Todd ;

Carpten, John ;

Trent, Jeff ;

Hahn, William C. ;

Garraway, Levi A. ;

Meyerson, Matthew ;

Lander, Eric S. ;

Getz, Gad ;

Golub, Todd R. .

NATURE, 2011, 471 (7339) :467-472

[6] Comprehensive genomic characterization defines human glioblastoma genes and core pathways [J].

Chin, L. ;

Meyerson, M. ;

Aldape, K. ;

Bigner, D. ;

Mikkelsen, T. ;

VandenBerg, S. ;

Kahn, A. ;

Penny, R. ;

Ferguson, M. L. ;

Gerhard, D. S. ;

Getz, G. ;

Brennan, C. ;

Taylor, B. S. ;

Winckler, W. ;

Park, P. ;

Ladanyi, M. ;

Hoadley, K. A. ;

Verhaak, R. G. W. ;

Hayes, D. N. ;

Spellman, Paul T. ;

Absher, D. ;

Weir, B. A. ;

Ding, L. ;

Wheeler, D. ;

Lawrence, M. S. ;

Cibulskis, K. ;

Mardis, E. ;

Zhang, Jinghui ;

Wilson, R. K. ;

Donehower, L. ;

Wheeler, D. A. ;

Purdom, E. ;

Wallis, J. ;

Laird, P. W. ;

Herman, J. G. ;

Schuebel, K. E. ;

Weisenberger, D. J. ;

Baylin, S. B. ;

Schultz, N. ;

Yao, Jun ;

Wiedemeyer, R. ;

Weinstein, J. ;

Sander, C. ;

Gibbs, R. A. ;

Gray, J. ;

Kucherlapati, R. ;

Lander, E. S. ;

Myers, R. M. ;

Perou, C. M. ;

McLendon, Roger .

NATURE, 2008, 455 (7216) :1061-1068

[7] Reduced fidelity of branch point recognition and alternative splicing induced by the anti-tumor drug spliceostatin A [J].

Corrionero, Anna ;

Minana, Belen ;

Valcarcel, Juan .

GENES & DEVELOPMENT, 2011, 25 (05) :445-459

[8] A framework for variation discovery and genotyping using next-generation DNA sequencing data [J].

DePristo, Mark A. ;

Banks, Eric ;

Poplin, Ryan ;

Garimella, Kiran V. ;

Maguire, Jared R. ;

Hartl, Christopher ;

Philippakis, Anthony A. ;

del Angel, Guillermo ;

Rivas, Manuel A. ;

Hanna, Matt ;

McKenna, Aaron ;

Fennell, Tim J. ;

Kernytsky, Andrew M. ;

Sivachenko, Andrey Y. ;

Cibulskis, Kristian ;

Gabriel, Stacey B. ;

Altshuler, David ;

Daly, Mark J. .

NATURE GENETICS, 2011, 43 (05) :491-+

[9] Genomic aberrations and survival in chronic lymphocytic leukemia. [J].

Döhner, H ;

Stilgenbauer, S ;

Benner, A ;

Leupolt, E ;

Kröber, A ;

Bullinger, L ;

Döhner, K ;

Bentz, M ;

Lichter, P .

NEW ENGLAND JOURNAL OF MEDICINE, 2000, 343 (26) :1910-1916

[10] Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation [J].

Fabbri, Giulia ;

Rasi, Silvia ;

Rossi, Davide ;

Trifonov, Vladimir ;

Khiabanian, Hossein ;

Ma, Jing ;

Grunn, Adina ;

Fangazio, Marco ;

Capello, Daniela ;

Monti, Sara ;

Cresta, Stefania ;

Gargiulo, Ernesto ;

Forconi, Francesco ;

Guarini, Anna ;

Arcaini, Luca ;

Paulli, Marco ;

Laurenti, Luca ;

Larocca, Luigi M. ;

Marasca, Roberto ;

Gattei, Valter ;

Oscier, David ;

Bertoni, Francesco ;

Mullighan, Charles G. ;

Foa, Robin ;

Pasqualucci, Laura ;

Rabadan, Raul ;

Dalla-Favera, Riccardo ;

Gaidano, Gianluca .

JOURNAL OF EXPERIMENTAL MEDICINE, 2011, 208 (07) :1389-1401

← 1 2 3 4 →