Andersson, A.Ma, J.Wang, J.Chen, X.Gedman, A.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.et al.2017-06-192017-06-192015Nature Genetics, 2015; 47(4):330-3371061-40361546-1718http://hdl.handle.net/2440/106072Includes 3 unnumbered pages at the end of the article. Published online 2 March 2015Infant 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.en© 2015 Nature America, Inc. All rights reserved.Acute lymphocytic leukaemiaJournal article003006120410.1038/ng.32300003519229000072-s2.0-84925841593277141Mullighan, C. [0000-0002-1871-1850]