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

Anna K Andersson; Jing Ma; Jianmin Wang; Xiang Chen; Amanda Larson Gedman; Jinjun Dang; Joy Nakitandwe; Linda Holmfeldt; Matthew Parker; John Easton; Robert Huether; Richard Kriwacki; Michael Rusch; Gang Wu; Yongjin Li; Heather Mulder; Susana Raimondi; Stanley Pounds; Guolian Kang; Lei Shi; Jared Becksfort; Pankaj Kumar Gupta; Debbie Payne-Turner; Bhavin Vadodaria; Kristy Boggs; Donald Yergeau; Jayanthi Manne; Guangchun Song; Michael Edmonson; Panduka Nagahawatte; Lei Wei; Cheng Cheng; Deqing Pei; Rosemary Sutton; Nicola C Venn; Albert Chetcuti; Amanda Rush; Daniel Catchpoole; Jesper Heldrup; Thoas Fioretos; Charles Lu; Li Ding; Ching-Hon Pui; Sheila Shurtleff; Charles G Mullighan; Elaine R Mardis; James Richard Wilson; Tanja A Gruber; Jinghui Zhang; James R Downing; St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project

doi:10.1038/ng.3230

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

Anna K Andersson, Jing Ma, Jianmin Wang, Xiang Chen, Amanda Larson Gedman, Jinjun Dang, Joy Nakitandwe, Linda Holmfeldt, Matthew Parker, John Easton, Robert Huether, Richard Kriwacki, Michael Rusch, Gang Wu, Yongjin Li, Heather Mulder, Susana Raimondi, Stanley Pounds, Guolian Kang, Lei ShiJared Becksfort, Pankaj Kumar Gupta, Debbie Payne-Turner, Bhavin Vadodaria, Kristy Boggs, Donald Yergeau, Jayanthi Manne, Guangchun Song, Michael Edmonson, Panduka Nagahawatte, Lei Wei, Cheng Cheng, Deqing Pei, Rosemary Sutton, Nicola C Venn, Albert Chetcuti, Amanda Rush, Daniel Catchpoole, Jesper Heldrup, Thoas Fioretos, Charles Lu, Li Ding, Ching-Hon Pui, Sheila Shurtleff, Charles G Mullighan, Elaine R Mardis, James Richard Wilson, Tanja A Gruber, Jinghui Zhang, James R Downing, St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project

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388 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	47
Udgave nummer	4
Sider (fra-til)	330-7
Antal sider	8
ISSN	1061-4036
DOI	https://doi.org/10.1038/ng.3230
Status	Udgivet - apr. 2015

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10.1038/ng.3230

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Andersson, A. K., Ma, J., Wang, J., Chen, X., Gedman, A. L., Dang, J., Nakitandwe, J., Holmfeldt, L., Parker, M., Easton, J., Huether, R., Kriwacki, R., Rusch, M., Wu, G., Li, Y., Mulder, H., Raimondi, S., Pounds, S., Kang, G., ... St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project (2015). The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias. Nature Genetics, 47(4), 330-7. https://doi.org/10.1038/ng.3230

Andersson, AK, Ma, J, Wang, J, Chen, X, Gedman, AL, Dang, J, Nakitandwe, J, Holmfeldt, L, Parker, M, Easton, J, Huether, R, Kriwacki, R, Rusch, M, Wu, G, Li, Y, Mulder, H, Raimondi, S, Pounds, S, Kang, G, Shi, L, Becksfort, J, Gupta, PK, Payne-Turner, D, Vadodaria, B, Boggs, K, Yergeau, D, Manne, J, Song, G, Edmonson, M, Nagahawatte, P, Wei, L, Cheng, C, Pei, D, Sutton, R, Venn, NC, Chetcuti, A, Rush, A, Catchpoole, D, Heldrup, J, Fioretos, T, Lu, C, Ding, L, Pui, C-H, Shurtleff, S, Mullighan, CG, Mardis, ER, Wilson, JR, Gruber, TA, Zhang, J, Downing, JR & St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project 2015, 'The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias', Nature Genetics, bind 47, nr. 4, s. 330-7. https://doi.org/10.1038/ng.3230

@article{0c5b82213d5c4e0db161268b3be9b770,

title = "The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias",

abstract = "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.",

keywords = "Allelic Imbalance, Cohort Studies, DNA Mutational Analysis, Gene Frequency, Histone-Lysine N-Methyltransferase, Humans, Infant, Mutation, Myeloid-Lymphoid Leukemia Protein, Oncogene Proteins, Fusion, Phosphatidylinositol 3-Kinases, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Protein-Tyrosine Kinases, Signal Transduction, ras Proteins",

author = "Andersson, {Anna K} and Jing Ma and Jianmin Wang and Xiang Chen and Gedman, {Amanda Larson} and Jinjun Dang and Joy Nakitandwe and Linda Holmfeldt and Matthew Parker and John Easton and Robert Huether and Richard Kriwacki and Michael Rusch and Gang Wu and Yongjin Li and Heather Mulder and Susana Raimondi and Stanley Pounds and Guolian Kang and Lei Shi and Jared Becksfort and Gupta, {Pankaj Kumar} and Debbie Payne-Turner and Bhavin Vadodaria and Kristy Boggs and Donald Yergeau and Jayanthi Manne and Guangchun Song and Michael Edmonson and Panduka Nagahawatte and Lei Wei and Cheng Cheng and Deqing Pei and Rosemary Sutton and Venn, {Nicola C} and Albert Chetcuti and Amanda Rush and Daniel Catchpoole and Jesper Heldrup and Thoas Fioretos and Charles Lu and Li Ding and Ching-Hon Pui and Sheila Shurtleff and Mullighan, {Charles G} and Mardis, {Elaine R} and Wilson, {James Richard} and Gruber, {Tanja A} and Jinghui Zhang and Downing, {James R} and {St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project}",

year = "2015",

month = apr,

doi = "10.1038/ng.3230",

language = "English",

volume = "47",

pages = "330--7",

journal = "Nature Genetics",

issn = "1061-4036",

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TY - JOUR

T1 - The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias

AU - Andersson, Anna K

AU - Ma, Jing

AU - Wang, Jianmin

AU - Chen, Xiang

AU - Gedman, Amanda Larson

AU - Dang, Jinjun

AU - Nakitandwe, Joy

AU - Holmfeldt, Linda

AU - Parker, Matthew

AU - Easton, John

AU - Huether, Robert

AU - Kriwacki, Richard

AU - Rusch, Michael

AU - Wu, Gang

AU - Li, Yongjin

AU - Mulder, Heather

AU - Raimondi, Susana

AU - Pounds, Stanley

AU - Kang, Guolian

AU - Shi, Lei

AU - Becksfort, Jared

AU - Gupta, Pankaj Kumar

AU - Payne-Turner, Debbie

AU - Vadodaria, Bhavin

AU - Boggs, Kristy

AU - Yergeau, Donald

AU - Manne, Jayanthi

AU - Song, Guangchun

AU - Edmonson, Michael

AU - Nagahawatte, Panduka

AU - Wei, Lei

AU - Cheng, Cheng

AU - Pei, Deqing

AU - Sutton, Rosemary

AU - Venn, Nicola C

AU - Chetcuti, Albert

AU - Rush, Amanda

AU - Catchpoole, Daniel

AU - Heldrup, Jesper

AU - Fioretos, Thoas

AU - Lu, Charles

AU - Ding, Li

AU - Pui, Ching-Hon

AU - Shurtleff, Sheila

AU - Mullighan, Charles G

AU - Mardis, Elaine R

AU - Wilson, James Richard

AU - Gruber, Tanja A

AU - Zhang, Jinghui

AU - Downing, James R

AU - St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project

PY - 2015/4

Y1 - 2015/4

N2 - 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.

AB - 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.

KW - Allelic Imbalance

KW - Cohort Studies

KW - DNA Mutational Analysis

KW - Gene Frequency

KW - Histone-Lysine N-Methyltransferase

KW - Humans

KW - Infant

KW - Mutation

KW - Myeloid-Lymphoid Leukemia Protein

KW - Oncogene Proteins, Fusion

KW - Phosphatidylinositol 3-Kinases

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma

KW - Protein-Tyrosine Kinases

KW - Signal Transduction

KW - ras Proteins

U2 - 10.1038/ng.3230

DO - 10.1038/ng.3230

M3 - Journal article

C2 - 25730765

SN - 1061-4036

VL - 47

SP - 330

EP - 337

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -

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

Abstract

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