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

Andersson, Anna LU ; Ma, Jing; Wang, Jianmin; Chen, Xiang; Gedman, Amanda Larson; Dang, Jinjun; Nakitandwe, Joy; Holmfeldt, Linda; Parker, Matthew and Easton, John, et al. (2015) In Nature Genetics 47(4). p.192-330
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... (More)
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. (Less)
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Nature Genetics
volume
47
issue
4
pages
192 - 330
publisher
Nature Publishing Group
external identifiers
  • pmid:25730765
  • wos:000351922900007
  • scopus:84925841593
ISSN
1546-1718
DOI
10.1038/ng.3230
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English
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yes
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f7c9026b-837f-4cd9-a961-79c808db376f (old id 5265548)
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http://www.ncbi.nlm.nih.gov/pubmed/25730765?dopt=Abstract
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2015-04-01 17:44:45
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@article{f7c9026b-837f-4cd9-a961-79c808db376f,
  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.},
  author       = {Andersson, Anna and Ma, Jing and Wang, Jianmin and Chen, Xiang and Gedman, Amanda Larson and Dang, Jinjun and Nakitandwe, Joy and Holmfeldt, Linda and Parker, Matthew and Easton, John and Huether, Robert and Kriwacki, Richard and Rusch, Michael and Wu, Gang and Li, Yongjin and Mulder, Heather and Raimondi, Susana and Pounds, Stanley and Kang, Guolian and Shi, Lei and Becksfort, Jared and Gupta, Pankaj and Payne-Turner, Debbie and Vadodaria, Bhavin and Boggs, Kristy and Yergeau, Donald and Manne, Jayanthi and Song, Guangchun and Edmonson, Michael and Nagahawatte, Panduka and Wei, Lei and Cheng, Cheng and Pei, Deqing and Sutton, Rosemary and Venn, Nicola C and Chetcuti, Albert and Rush, Amanda and Catchpoole, Daniel and Heldrup, Jesper and Fioretos, Thoas and Lu, Charles and Ding, Li and Pui, Ching-Hon and Shurtleff, Sheila and Mullighan, Charles G and Mardis, Elaine R and Wilson, Richard K and Gruber, Tanja A and Zhang, Jinghui and Downing, James R},
  issn         = {1546-1718},
  language     = {eng},
  number       = {4},
  pages        = {192--330},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.},
  url          = {http://dx.doi.org/10.1038/ng.3230},
  volume       = {47},
  year         = {2015},
}