RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia

被引：281

作者：

Papaemmanuil, Elli ^{[1
]}

Rapado, Inmaculada ^{[2
]}

Li, Yilong ^{[1
]}

Potter, Nicola E. ^{[3
]}

Wedge, David C. ^{[1
]}

Tubio, Jose ^{[1
]}

Alexandrov, Ludmil B. ^{[1
]}

Van Loo, Peter ^{[1
,4
,5
]}

Cooke, Susanna L. ^{[1
]}

Marshall, John ^{[1
]}

Martincorena, Inigo ^{[1
]}

Hinton, Jonathan ^{[1
]}

Gundem, Gunes ^{[1
]}

van Delft, Frederik W. ^{[3
,6
]}

Nik-Zainal, Serena ^{[1
]}

Jones, David R. ^{[1
]}

Ramakrishna, Manasa ^{[1
]}

Titley, Ian ^{[3
]}

Stebbings, Lucy ^{[1
]}

Leroy, Catherine ^{[1
]}

Menzies, Andrew ^{[1
]}

Gamble, John ^{[1
]}

Robinson, Ben ^{[1
]}

Mudie, Laura ^{[1
]}

Raine, Keiran ^{[1
]}

O'Meara, Sarah ^{[1
]}

Teague, Jon W. ^{[1
]}

Butler, Adam P. ^{[1
]}

Cazzaniga, Giovanni ^{[7
]}

Biondi, Andrea ^{[7
]}

Zuna, Jan ^{[8
,9
]}

Kempski, Helena ^{[10
,11
]}

Muschen, Markus ^{[12
]}

Ford, Anthony M. ^{[3
]}

Stratton, Michael R. ^{[1
]}

Greaves, Mel ^{[3
]}

Campbell, Peter J. ^{[1
,13
,14
]}

机构：

[1] Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton, England

[2] Hosp Univ 12 Octubre, Madrid, Spain

[3] Inst Canc Res, London SW3 6JB, England

[4] VIB, Dept Human Genet, Louvain, Belgium

[5] Univ Leuven, Louvain, Belgium

[6] Univ Newcastle, Northern Inst Canc Res, Newcastle Upon Tyne, Tyne & Wear, England

[7] Hosp San Gerardo, Ctr Ric Tettamanti, Monza, Italy

[8] Charles Univ Prague, Fac Med 2, Dept Paediat Haematol & Oncol, Prague, Czech Republic

[9] Univ Hosp Motol, Prague, Czech Republic

[10] Great Ormond St Hosp Sick Children, Camelia Botnar Labs, Mol Haematol & Canc Biol Unit, Paediat Malignancy Unit, London WC1N 3JH, England

[11] UCL, Inst Child Hlth, London, England

[12] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA

[13] Addenbrookes Natl Hlth Serv NHS Fdn Trust, Cambridge, England

[14] Univ Cambridge, Dept Haematol, Cambridge, England

来源：

NATURE GENETICS | 2014年 / 46卷 / 02期

基金：

英国惠康基金;

关键词：

CHROMOSOME TRANSLOCATIONS; MUTATIONAL PROCESSES; V(D)J RECOMBINATION; GENETIC ALTERATIONS; CLONAL ORIGINS; DNA; COMPLEX; SIGNATURES; DELETIONS; CHILDREN;

D O I：

10.1038/ng.2874

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia ( ALL) cases, is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, characterized by recombination signal sequence motifs near breakpoints, incorporation of non-templated sequence at junctions, similar to 30-fold enrichment at promoters and enhancers of genes actively transcribed in B cell development and an unexpectedly high ratio of recurrent to non-recurrent structural variants. Single-cell tracking shows that this mechanism is active throughout leukemic evolution, with evidence of localized clustering and reiterated deletions. Integration of data on point mutations and rearrangements identifies ATF7IP and MGA as two new tumor-suppressor genes in ALL. Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1-positive lymphoblasts, targeting the promoters, enhancers and first exons of genes that normally regulate B cell differentiation.

引用

页码：116 / +

页数：13

共 56 条

[1] Signatures of mutational processes in human cancer [J].

Alexandrov, Ludmil B. ;

Nik-Zainal, Serena ;

Wedge, David C. ;

Aparicio, Samuel A. J. R. ;

Behjati, Sam ;

Biankin, Andrew V. ;

Bignell, Graham R. ;

Bolli, Niccolo ;

Borg, Ake ;

Borresen-Dale, Anne-Lise ;

Boyault, Sandrine ;

Burkhardt, Birgit ;

Butler, Adam P. ;

Caldas, Carlos ;

Davies, Helen R. ;

Desmedt, Christine ;

Eils, Roland ;

Eyfjord, Jorunn Erla ;

Foekens, John A. ;

Greaves, Mel ;

Hosoda, Fumie ;

Hutter, Barbara ;

Ilicic, Tomislav ;

Imbeaud, Sandrine ;

Imielinsk, Marcin ;

Jaeger, Natalie ;

Jones, David T. W. ;

Jones, David ;

Knappskog, Stian ;

Kool, Marcel ;

Lakhani, Sunil R. ;

Lopez-Otin, Carlos ;

Martin, Sancha ;

Munshi, Nikhil C. ;

Nakamura, Hiromi ;

Northcott, Paul A. ;

Pajic, Marina ;

Papaemmanuil, Elli ;

Paradiso, Angelo ;

Pearson, John V. ;

Puente, Xose S. ;

Raine, Keiran ;

Ramakrishna, Manasa ;

Richardson, Andrea L. ;

Richter, Julia ;

Rosenstiel, Philip ;

Schlesner, Matthias ;

Schumacher, Ton N. ;

Span, Paul N. ;

Teague, Jon W. .

NATURE, 2013, 500 (7463) :415-+

[2] Deciphering Signatures of Mutational Processes Operative in Human Cancer [J].

Alexandrov, Ludmil B. ;

Nik-Zainal, Serena ;

Wedge, David C. ;

Campbell, Peter J. ;

Stratton, Michael R. .

CELL REPORTS, 2013, 3 (01) :246-259

[3] Genetic variegation of clonal architecture and propagating cells in leukaemia [J].

Anderson, Kristina ;

Lutz, Christoph ;

van Delft, Frederik W. ;

Bateman, Caroline M. ;

Guo, Yanping ;

Colman, Susan M. ;

Kempski, Helena ;

Moorman, Anthony V. ;

Titley, Ian ;

Swansbury, John ;

Kearney, Lyndal ;

Enver, Tariq ;

Greaves, Mel .

NATURE, 2011, 469 (7330) :356-+

[4] Punctuated Evolution of Prostate Cancer Genomes [J].

Baca, Sylvan C. ;

Prandi, Davide ;

Lawrence, Michael S. ;

Mosquera, Juan Miguel ;

Romanel, Alessandro ;

Drier, Yotam ;

Park, Kyung ;

Kitabayashi, Naoki ;

MacDonald, Theresa Y. ;

Ghandi, Mahmoud ;

Van Allen, Eliezer ;

Kryukov, Gregory V. ;

Sboner, Andrea ;

Theurillat, Jean-Philippe ;

Soong, T. David ;

Nickerson, Elizabeth ;

Auclair, Daniel ;

Tewari, Ashutosh ;

Beltran, Himisha ;

Onofrio, Robert C. ;

Boysen, Gunther ;

Guiducci, Candace ;

Barbieri, Christopher E. ;

Cibulskis, Kristian ;

Sivachenko, Andrey ;

Carter, Scott L. ;

Saksena, Gordon ;

Voet, Douglas ;

Ramos, Alex H. ;

Winckler, Wendy ;

Cipicchio, Michelle ;

Ardlie, Kristin ;

Kantoff, Philip W. ;

Berger, Michael F. ;

Gabriel, Stacey B. ;

Golub, Todd R. ;

Meyerson, Matthew ;

Lander, Eric S. ;

Elemento, Olivier ;

Getz, Gad ;

Demichelis, Francesca ;

Rubin, Mark A. ;

Garraway, Levi A. .

CELL, 2013, 153 (03) :666-677

[5] MEME: discovering and analyzing DNA and protein sequence motifs [J].

Bailey, Timothy L. ;

Williams, Nadya ;

Misleh, Chris ;

Li, Wilfred W. .

NUCLEIC ACIDS RESEARCH, 2006, 34 :W369-W373

[6] Acquisition of genome-wide copy number alterations in monozygotic twins with acute lymphoblastic leukemia [J].

Bateman, Caroline M. ;

Colman, Susan M. ;

Chaplin, Tracy ;

Young, Bryan D. ;

Eden, Tim O. ;

Bhakta, Manoo ;

Gratias, Eric J. ;

van Wering, Elisabeth R. ;

Cazzaniga, Giovanni ;

Harrison, Christine J. ;

Hain, Richard ;

Ancliff, Philip ;

Ford, Anthony M. ;

Kearney, Lyndal ;

Greaves, Mel .

BLOOD, 2010, 115 (17) :3553-3558

[7] 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

[8] ETV6-RUNX1-positive childhood acute lymphoblastic leukemia: improved outcome with contemporary therapy [J].

Bhojwani, D. ;

Pei, D. ;

Sandlund, J. T. ;

Jeha, S. ;

Ribeiro, R. C. ;

Rubnitz, J. E. ;

Raimondi, S. C. ;

Shurtleff, S. ;

Onciu, M. ;

Cheng, C. ;

Coustan-Smith, E. ;

Bowman, W. P. ;

Howard, S. C. ;

Metzger, M. L. ;

Inaba, H. ;

Leung, W. ;

Evans, W. E. ;

Campana, D. ;

Relling, M. V. ;

Pui, C-H .

LEUKEMIA, 2012, 26 (02) :265-270

[9] Terminal deoxynucleotidyl transferase requires KU80 and XRCC4 to promote N-addition at non-V(D)J chromosomal breaks in non-lymphoid cells [J].

Boubakour-Azzouz, Imenne ;

Bertrand, Pascale ;

Claes, Aurelie ;

Lopez, Bernard S. ;

Rougeon, Francois .

NUCLEIC ACIDS RESEARCH, 2012, 40 (17) :8381-8391

[10] The patterns and dynamics of genomic instability in metastatic pancreatic cancer [J].

Campbell, Peter J. ;

Yachida, Shinichi ;

Mudie, Laura J. ;

Stephens, Philip J. ;

Pleasance, Erin D. ;

Stebbings, Lucy A. ;

Morsberger, Laura A. ;

Latimer, Calli ;

McLaren, Stuart ;

Lin, Meng-Lay ;

McBride, David J. ;

Varela, Ignacio ;

Nik-Zainal, Serena A. ;

Leroy, Catherine ;

Jia, Mingming ;

Menzies, Andrew ;

Butler, Adam P. ;

Teague, Jon W. ;

Griffin, Constance A. ;

Burton, John ;

Swerdlow, Harold ;

Quail, Michael A. ;

Stratton, Michael R. ;

Iacobuzio-Donahue, Christine ;

Futreal, P. Andrew .

NATURE, 2010, 467 (7319) :1109-1113

← 1 2 3 4 5 6 →