The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias

被引：368

作者：

Andersson, Anna K. ^{[1
,2
]}

Ma, Jing ^{[1
]}

Wang, Jianmin ^{[3
]}

Chen, Xiang ^{[3
]}

Gedman, Amanda Larson ^{[1
]}

Dang, Jinjun ^{[1
]}

Nakitandwe, Joy ^{[1
]}

Holmfeldt, Linda ^{[1
]}

Parker, Matthew ^{[3
]}

Easton, John ^{[4
]}

Huether, Robert ^{[3
]}

Kriwacki, Richard ^{[5
]}

Rusch, Michael ^{[3
]}

Wu, Gang ^{[3
]}

Li, Yongjin ^{[3
]}

Mulder, Heather ^{[4
]}

Raimondi, Susana ^{[1
]}

Pounds, Stanley ^{[6
]}

Kang, Guolian ^{[6
]}

Shi, Lei ^{[6
]}

Becksfort, Jared ^{[3
]}

Gupta, Pankaj ^{[3
]}

Payne-Turner, Debbie ^{[1
]}

Vadodaria, Bhavin ^{[4
]}

Boggs, Kristy ^{[4
]}

Yergeau, Donald ^{[4
]}

Manne, Jayanthi ^{[4
]}

Song, Guangchun ^{[1
]}

Edmonson, Michael ^{[3
]}

Nagahawatte, Panduka ^{[3
]}

Wei, Lei ^{[3
]}

Cheng, Cheng ^{[6
]}

Pei, Deqing ^{[6
]}

Sutton, Rosemary ^{[7
]}

Venn, Nicola C. ^{[7
]}

Chetcuti, Albert ^{[8
]}

Rush, Amanda ^{[8
]}

Catchpoole, Daniel ^{[8
]}

Heldrup, Jesper ^{[9
]}

Fioretos, Thoas ^{[2
]}

Lu, Charles ^{[10
,11
]}

Ding, Li ^{[10
,11
]}

Pui, Ching-Hon ^{[1
,12
]}

Shurtleff, Sheila ^{[1
]}

Mullighan, Charles G. ^{[1
]}

Mardis, Elaine R. ^{[10
,11
]}

Wilson, Richard K. ^{[10
,11
]}

Gruber, Tanja A. ^{[1
,12
]}

Zhang, Jinghui ^{[3
]}

Downing, James R. ^{[1
]}

机构：

[1] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA

[2] Lund Univ, Dept Clin Genet, Lund, Sweden

[3] St Jude Childrens Res Hosp, Dept Computat Biol, Memphis, TN 38105 USA

[4] St Jude Childrens Res Hosp, Pediat Canc Genome Project Lab, Memphis, TN 38105 USA

[5] St Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USA

[6] St Jude Childrens Res Hosp, Dept Biostat, Memphis, TN 38105 USA

[7] Univ New S Wales, Lowy Canc Res Ctr, Childrens Canc Inst Australia, Sydney, NSW, Australia

[8] Childrens Hosp Westmead, Tumor Bank, Childrens Canc Res Unit, Sydney, NSW, Australia

[9] Skane Univ Hosp, Dept Pediat, Lund, Sweden

[10] Washington Univ, Sch Med St Louis, Dept Genet, St Louis, MO USA

[11] Washington Univ, Sch Med St Louis, Genome Inst, St Louis, MO USA

[12] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN 38105 USA

来源：

NATURE GENETICS | 2015年 / 47卷 / 04期

基金：

美国国家卫生研究院; 瑞典研究理事会;

关键词：

ACUTE MYELOID-LEUKEMIA; K-RAS MUTATIONS; CHROMOSOMAL TRANSLOCATIONS; GENETIC ALTERATIONS; CANCER; IDENTIFICATION; RESISTANCE; T(4/11); FLT3; BREAKPOINT;

D O I：

10.1038/ng.3230

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases. Surprisingly, these mutations were often subclonal and were frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (mean of 6.5 mutations/case versus 1.3 mutations/case, P = 7.15 x 10(-5)) and had frequent mutations (45%) in epigenetic regulators, a category of genes that, with the exception of MLL, was rarely mutated in infant MLL-R ALL.

引用

页码：330 / U192

页数：11

共 69 条

[1] Clonal variegation and dynamic competition of leukemia-initiating cells in infant acute lymphoblastic leukemia with MLL rearrangement
Bardini, M.
Woll, P. S.
Corral, L.
Luc, S.
Wittmann, L.
Ma, Z.
Lo Nigro, L.
Basso, G.
Biondi, A.
Cazzaniga, G.
Jacobsen, S. E. W.
[J]. LEUKEMIA, 2015, 29 (01) : 38 - 50
[2] Implementation of array based whole-genome high-resolution technologies confirms the absence of secondary copy-number alterations in MLL-AF4-positive infant ALL patients
Bardini, M.
Galbiati, M.
Lettieri, A.
Bungaro, S.
Gorletta, T. A.
Biondi, A.
Cazzaniga, G.
[J]. LEUKEMIA, 2011, 25 (01) : 175 - 178
[3] GenBank
Benson, Dennis A.
Karsch-Mizrachi, Ilene
Lipman, David J.
Ostell, James
Wheeler, David L.
[J]. NUCLEIC ACIDS RESEARCH, 2008, 36 : D25 - D30
[4] GenBank
Benson, Dennis A.
Karsch-Mizrachi, Ilene
Lipman, David J.
Ostell, James
Sayers, Eric W.
[J]. NUCLEIC ACIDS RESEARCH, 2009, 37 : D26 - D31
[5] Activating mutations of the Noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia
Bentires-Alj, M
Paez, JG
David, FS
Keilhack, H
Halmos, B
Naoki, K
Maris, JM
Richardson, A
Bardelli, A
Sugarbaker, DJ
Richards, WG
Du, JY
Girard, L
Minna, JD
Loh, ML
Fisher, DE
Velculescu, VE
Vogelstein, B
Meyerson, M
Sellers, WR
Neel, BG
[J]. CANCER RESEARCH, 2004, 64 (24) : 8816 - 8820
[6] The Protein Data Bank: a historical perspective
Berman, Helen M.
[J]. ACTA CRYSTALLOGRAPHICA A-FOUNDATION AND ADVANCES, 2008, 64 : 88 - 95
[7] Biological and therapeutic aspects of infant leukemia
Biondi, A
Cimino, G
Pieters, R
Pui, CH
[J]. BLOOD, 2000, 96 (01) : 24 - 33
[8] Oncogenic mutations mimic and enhance dynamic events in the natural activation of phosphoinositide 3-kinase p110α (PIK3CA)
Burke, John E.
Perisic, Olga
Masson, Glenn R.
Vadas, Oscar
Williams, Roger L.
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2012, 109 (38) : 15259 - 15264
[9] Identification of somatic and germline mutations using whole exome sequencing of congenital acute lymphoblastic leukemia
Chang, Vivian Y.
Basso, Giuseppe
Sakamoto, Kathleen M.
Nelson, Stanley F.
[J]. BMC CANCER, 2013, 13
[10] Chen K, 2009, NAT METHODS, V6, P677, DOI [10.1038/nmeth.1363, 10.1038/NMETH.1363]

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