The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.
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 × 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.
1] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Clinical Genetics, Lund University, Lund, Sweden.
Anna K
AK
Andersson
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Jing
J
Ma
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Jianmin
J
Wang
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Xiang
X
Chen
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Amanda Larson
AL
Gedman
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Jinjun
J
Dang
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Joy
J
Nakitandwe
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Linda
0000000341403423
L
Holmfeldt
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Matthew
M
Parker
Pediatric Cancer Genome Project Laboratory, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
John
J
Easton
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Robert
0000000170777470
R
Huether
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Richard
R
Kriwacki
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Michael
M
Rusch
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Gang
0000000216785864
G
Wu
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Yongjin
Y
Li
Pediatric Cancer Genome Project Laboratory, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Heather
H
Mulder
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Susana
S
Raimondi
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Stanley
0000000291672114
S
Pounds
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Guolian
G
Kang
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Lei
L
Shi
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Jared
J
Becksfort
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Pankaj
P
Gupta
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Debbie
D
Payne-Turner
Pediatric Cancer Genome Project Laboratory, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Bhavin
B
Vadodaria
Pediatric Cancer Genome Project Laboratory, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Kristy
K
Boggs
Pediatric Cancer Genome Project Laboratory, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Donald
D
Yergeau
Pediatric Cancer Genome Project Laboratory, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Jayanthi
J
Manne
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Guangchun
G
Song
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Michael
M
Edmonson
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Panduka
P
Nagahawatte
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Lei
L
Wei
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Cheng
C
Cheng
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Deqing
D
Pei
Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales, Australia.
Rosemary
R
Sutton
Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales, Australia.
Nicola C
NC
Venn
Tumor Bank, Children's Cancer Research Unit, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
Albert
A
Chetcuti
Tumor Bank, Children's Cancer Research Unit, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
Amanda
A
Rush
Tumor Bank, Children's Cancer Research Unit, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
Daniel
D
Catchpoole
Department of Pediatrics, Skåne University Hospital, Lund, Sweden.
Jesper
J
Heldrup
Department of Clinical Genetics, Lund University, Lund, Sweden.
Thoas
T
Fioretos
1] Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA. [2] Genome Institute, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA.
Charles
C
Lu
1] Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA. [2] Genome Institute, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA.
Li
L
Ding
1] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Ching-Hon
CH
Pui
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Sheila
S
Shurtleff
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Charles G
0000000218711850
CG
Mullighan
1] Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA. [2] Genome Institute, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA.
Elaine R
ER
Mardis
1] Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA. [2] Genome Institute, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA.
Richard K
RK
Wilson
1] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Tanja A
TA
Gruber
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Jinghui
J
Zhang
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
James R
JR
Downing
D022981:Allelic Imbalance / Q000235:genetics; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005787:Gene Frequency; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000453:epidemiology / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
C497422:KMT2A protein, human; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D018631:ras Proteins