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

Anna Andersson, Tanja Gruber, James Downing and colleagues report a genomic analysis of infant acute lymphoblastic leukemias with MLL rearrangements. They identify recurrent activating mutations in tyrosine kinase, phosphatidylinositol 3-kinase and RAS pathway genes but find that these mutations wer...

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Veröffentlicht in:	Nature genetics Jg. 47; H. 4; S. 330 - 337
Hauptverfasser:	Andersson, Anna K, Ma, Jing, Wang, Jianmin, Chen, Xiang, Gedman, Amanda Larson, Dang, Jinjun, Nakitandwe, Joy, Holmfeldt, Linda, Parker, Matthew, Easton, John, Huether, Robert, Kriwacki, Richard, Rusch, Michael, Wu, Gang, Li, Yongjin, Mulder, Heather, Raimondi, Susana, Pounds, Stanley, Kang, Guolian, Shi, Lei, Becksfort, Jared, Gupta, Pankaj, Payne-Turner, Debbie, Vadodaria, Bhavin, Boggs, Kristy, Yergeau, Donald, Manne, Jayanthi, Song, Guangchun, Edmonson, Michael, Nagahawatte, Panduka, Wei, Lei, Cheng, Cheng, Pei, Deqing, Sutton, Rosemary, Venn, Nicola C, Chetcuti, Albert, Rush, Amanda, Catchpoole, Daniel, Heldrup, Jesper, Fioretos, Thoas, Lu, Charles, Ding, Li, Pui, Ching-Hon, Shurtleff, Sheila, Mullighan, Charles G, Mardis, Elaine R, Wilson, Richard K, Gruber, Tanja A, Zhang, Jinghui, Downing, James R
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	New York Nature Publishing Group US 01.04.2015 Nature Publishing Group
Schlagworte:	38 38/23 38/47 38/90 38/91 45 45/22 45/23 631/208/212 692/308/575 692/699/67/1990/283/2125 Acute lymphocytic leukemia Agriculture Allelic Imbalance - genetics Animal Genetics and Genomics Babies Basic Medicine Bioinformatics Biomedicine Cancer Cancer Research Children & youth Cohort Studies Development and progression DNA Mutational Analysis Gene Frequency Gene Function Gene mutations Genes Genetic aspects Genetic engineering Genomes Health aspects Histone-Lysine N-Methyltransferase Hospitals Human Genetics Humans Hypotheses Identification and classification Infant Infants Laboratories Leukemia Medical and Health Sciences Medical Genetics and Genomics (including Gene Therapy) Medicin och hälsovetenskap Medicinsk genetik och genomik (Här ingår: Genterapi) Medicinska och farmaceutiska grundvetenskaper Mutation Myeloid-Lymphoid Leukemia Protein - genetics Oncogene Proteins, Fusion - genetics Pediatrics Phosphatidylinositol 3-Kinases - genetics Phosphatidylinositol 3-Kinases - metabolism Precursor Cell Lymphoblastic Leukemia-Lymphoma - epidemiology Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics Protein-Tyrosine Kinases - genetics Protein-Tyrosine Kinases - metabolism Proteins ras Proteins - genetics ras Proteins - metabolism Signal Transduction - genetics
ISSN:	1061-4036, 1546-1718, 1546-1718
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Zusammenfassung:	Anna Andersson, Tanja Gruber, James Downing and colleagues report a genomic analysis of infant acute lymphoblastic leukemias with MLL rearrangements. They identify recurrent activating mutations in tyrosine kinase, phosphatidylinositol 3-kinase and RAS pathway genes but find that these mutations were often present in minor subclones and lost at the time of relapse. 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.
Bibliographie:	SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 A list of contributing authors appears in the Supplementary Note. These authors contributed equally to the work.
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/ng.3230