Integrative Genomic Analysis Implicates Gain of PIK3CA at 3q26 and MYC at 8q24 in Chronic Lymphocytic Leukemia

被引：72

作者：

Brown, Jennifer R. ^{[1
,7
]}

Hanna, Megan ^{[3
,8
,9
]}

Tesar, Bethany ^{[1
]}

Werner, Lillian ^{[2
]}

Pochet, Nathalie ^{[8
,9
,11
]}

Asara, John M. ^{[5
,7
]}

Wang, Yaoyu E. ^{[4
]}

dal Cin, Paola ^{[6
]}

Fernandes, Stacey M. ^{[1
]}

Thompson, Christina ^{[1
]}

MacConaill, Laura ^{[3
,6
]}

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

Van de Peer, Yves ^{[11
]}

Correll, Mick ^{[4
]}

Regev, Aviv ^{[8
,9
,10
]}

Neuberg, Donna ^{[2
]}

Freedman, Arnold S. ^{[1
,7
]}

机构：

[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[2] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA

[3] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02215 USA

[4] Dana Farber Canc Inst, Ctr Canc Computat Biol, Boston, MA 02215 USA

[5] Beth Israel Deaconess Med Ctr, Boston, MA USA

[6] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

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

[8] Broad Inst Harvard, Boston, MA USA

[9] MIT, Cambridge, MA 02139 USA

[10] MIT, Dept Biol, Howard Hughes Med Inst, Cambridge, MA USA

[11] Univ Ghent, Dept Plant Syst Biol, VIB, Dept Biotechnol & Genet, B-9000 Ghent, Belgium

来源：

CLINICAL CANCER RESEARCH | 2012年 / 18卷 / 14期

关键词：

B-CELL; EMBRYONIC STEM; C-MYC; 13Q14; DELETIONS; CANCER; SURVIVAL; GENE; ABERRATIONS; ASSOCIATION; COMPLEXITY;

D O I：

10.1158/1078-0432.CCR-11-2342

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: The disease course of chronic lymphocytic leukemia (CLL) varies significantly within cytogenetic groups. We hypothesized that high-resolution genomic analysis of CLL would identify additional recurrent abnormalities associated with short time-to-first therapy (TTFT). Experimental Design: We undertook high-resolution genomic analysis of 161 prospectively enrolled CLLs using Affymetrix 6.0 SNP arrays, and integrated analysis of this data set with gene expression profiles. Results: Copy number analysis (CNA) of nonprogressive CLL reveals a stable genotype, with a median of only 1 somatic CNA per sample. Progressive CLL with 13q deletion was associated with additional somatic CNAs, and a greater number of CNAs was predictive of TTFT. We identified other recurrent CNAs associated with short TTFT: 8q24 amplification focused on the cancer susceptibility locus near MYC in 3.7%; 3q26 amplifications focused on PIK3CA in 5.6%; and 8p deletions in 5% of patients. Sequencing of MYC further identified somatic mutations in two CLLs. We determined which catalytic subunits of phosphoinositide 3-kinase (PI3K) were in active complex with the p85 regulatory subunit and showed enrichment for the a subunit in three CLLs carrying PIK3CA amplification. Conclusions: Our findings implicate amplifications of 3q26 focused on PIK3CA and 8q24 focused on MYC in CLL. Clin Cancer Res; 18(14); 3791-802. (C)2012 AACR.

引用

页码：3791 / 3802

页数：12

共 50 条

[1] A label-free quantification method by MS/MS TIC compared to SILAC and spectral counting in a proteomics screen [J].

Asara, John M. ;

Christofk, Heather R. ;

Freimark, Lisa M. ;

Cantley, Lewis C. .

PROTEOMICS, 2008, 8 (05) :994-999

[2] An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors [J].

Ben-Porath, Ittai ;

Thomson, Matthew W. ;

Carey, Vincent J. ;

Ge, Ruping ;

Bell, George W. ;

Regev, Aviv ;

Weinberg, Robert A. .

NATURE GENETICS, 2008, 40 (05) :499-507

[3] Assessing the significance of chromosomal aberrations in cancer: Methodology and application to glioma [J].

Beroukhim, Rameen ;

Getz, Gad ;

Nghiemphu, Leia ;

Barretina, Jordi ;

Hsueh, Teli ;

Linhart, David ;

Vivanco, Igor ;

Lee, Jeffrey C. ;

Huang, Julie H. ;

Alexander, Sethu ;

Du, Jinyan ;

Kau, Tweeny ;

Thomas, Roman K. ;

Shah, Kinial ;

Soto, Horacio ;

Perner, Sven ;

Prensner, John ;

Debiasi, Ralph M. ;

Demichelis, Francesca ;

Hatton, Charlie ;

Rubin, Mark A. ;

Garraway, Levi A. ;

Nelson, Stan F. ;

Liau, Linda ;

Mischel, Paul S. ;

Cloughesy, Tim F. ;

Meyerson, Matthew ;

Golub, Todd A. ;

Lander, Eric S. ;

Mellinghoff, Ingo K. ;

Sellers, William R. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (50) :20007-20012

[4] The landscape of somatic copy-number alteration across human cancers [J].

Beroukhim, Rameen ;

Mermel, Craig H. ;

Porter, Dale ;

Wei, Guo ;

Raychaudhuri, Soumya ;

Donovan, Jerry ;

Barretina, Jordi ;

Boehm, Jesse S. ;

Dobson, Jennifer ;

Urashima, Mitsuyoshi ;

Mc Henry, Kevin T. ;

Pinchback, Reid M. ;

Ligon, Azra H. ;

Cho, Yoon-Jae ;

Haery, Leila ;

Greulich, Heidi ;

Reich, Michael ;

Winckler, Wendy ;

Lawrence, Michael S. ;

Weir, Barbara A. ;

Tanaka, Kumiko E. ;

Chiang, Derek Y. ;

Bass, Adam J. ;

Loo, Alice ;

Hoffman, Carter ;

Prensner, John ;

Liefeld, Ted ;

Gao, Qing ;

Yecies, Derek ;

Signoretti, Sabina ;

Maher, Elizabeth ;

Kaye, Frederic J. ;

Sasaki, Hidefumi ;

Tepper, Joel E. ;

Fletcher, Jonathan A. ;

Tabernero, Josep ;

Baselga, Jose ;

Tsao, Ming-Sound ;

Demichelis, Francesca ;

Rubin, Mark A. ;

Janne, Pasi A. ;

Daly, Mark J. ;

Nucera, Carmelo ;

Levine, Ross L. ;

Ebert, Benjamin L. ;

Gabriel, Stacey ;

Rustgi, Anil K. ;

Antonescu, Cristina R. ;

Ladanyi, Marc ;

Letai, Anthony .

NATURE, 2010, 463 (7283) :899-905

[5] The c-myc transactivation domain is a direct modulator of apoptotic versus proliferative signals [J].

Chang, DW ;

Claassen, GF ;

Hann, SR ;

Cole, MD .

MOLECULAR AND CELLULAR BIOLOGY, 2000, 20 (12) :4309-4319

[6] Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk [J].

Crowther-Swanepoel, Dalemari ;

Broderick, Peter ;

Di Bernardo, Maria Chiara ;

Dobbins, Sara E. ;

Torres, Maria ;

Mansouri, Mahmoud ;

Ruiz-Ponte, Clara ;

Enjuanes, Anna ;

Rosenquist, Richard ;

Carracedo, Angel ;

Jurlander, Jesper ;

Campo, Elias ;

Juliusson, Gunnar ;

Montserrat, Emilio ;

Smedby, Karin E. ;

Dyer, Martin J. S. ;

Matutes, Estella ;

Dearden, Claire ;

Sunter, Nicola J. ;

Hall, Andrew G. ;

Mainou-Fowler, Tryfonia ;

Jackson, Graham H. ;

Summerfield, Geoffrey ;

Harris, Robert J. ;

Pettitt, Andrew R. ;

Allsup, David J. ;

Bailey, James R. ;

Pratt, Guy ;

Pepper, Chris ;

Fegan, Chris ;

Parker, Anton ;

Oscier, David ;

Allan, James M. ;

Catovsky, Daniel ;

Houlston, Richard S. .

NATURE GENETICS, 2010, 42 (02) :132-U59

[7] A sustained activation of PI3K/NF-κB pathway is critical for the survival of chronic lymphocytic leukemia B cells [J].

Cuní, S ;

Pérez-Aciego, P ;

Pérez-Chacón, G ;

Vargas, JA ;

Sánchez, A ;

Martín-Saavedra, FM ;

Ballester, S ;

García-Marco, J ;

Jordá, J ;

Durántez, A .

LEUKEMIA, 2004, 18 (08) :1391-1400

[8] A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia [J].

Di Bernardo, Maria Chiara ;

Crowther-Swanepoel, Dalemari ;

Broderick, Peter ;

Webb, Emily ;

Sellick, Gabrielle ;

Wild, Ruth ;

Sullivan, Kate ;

Vijayakrishnan, Jayaram ;

Wang, Yufei ;

Pittman, Alan M. ;

Sunter, Nicola J. ;

Hall, Andrew G. ;

Dyer, Martin J. S. ;

Matutes, Estella ;

Dearden, Claire ;

Mainou-Fowler, Tryfonia ;

Jackson, Graham H. ;

Summerfield, Geoffrey ;

Harris, Robert J. ;

Pettitt, Andrew R. ;

Hillmen, Peter ;

Allsup, David J. ;

Bailey, James R. ;

Pratt, Guy ;

Pepper, Chris ;

Fegan, Chris ;

Allan, James M. ;

Catovsky, Daniel ;

Houlston, Richard S. .

NATURE GENETICS, 2008, 40 (10) :1204-1210

[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] Genome-wide DNA analysis identifies recurrent imbalances predicting outcome in chronic lymphocytic leukaemia with 17p deletion [J].

Forconi, Francesco ;

Rinaldi, Andrea ;

Kwee, Ivo ;

Sozzi, Elisa ;

Raspadori, Donatella ;

Rancoita, Paola M. V. ;

Scandurra, Marta ;

Rossi, Davide ;

Deambrogi, Clara ;

Capello, Daniela ;

Zucca, Emanuele ;

Marconi, Daniela ;

Bomben, Riccardo ;

Gattei, Valter ;

Lauria, Francesco ;

Gaidano, Gianluca ;

Bertoni, Francesco .

BRITISH JOURNAL OF HAEMATOLOGY, 2008, 143 (04) :532-536

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