title: Excess congenital non-synonymous variation in leukemia-associated genes in MLL- infant leukemia: a Children's Oncology Group report.
abstract: Infant leukemia (IL) is a rare sporadic cancer with a grim prognosis. Although most cases are accompanied by MLL rearrangements and harbor very few somatic mutations, less is known about the genetics of the cases without MLL translocations. We performed the largest exome-sequencing study to date on matched non-cancer DNA from pairs of mothers and IL patients to characterize congenital variation that may contribute to early leukemogenesis. Using the COSMIC database to define acute leukemia-associated candidate genes, we find a significant enrichment of rare, potentially functional congenital variation in IL patients compared with randomly selected genes within the same patients and unaffected pediatric controls. IL acute myeloid leukemia (AML) patients had more overall variation than IL acute lymphocytic leukemia (ALL) patients, but less of that variation was inherited from mothers. Of our candidate genes, we found that MLL3 was a compound heterozygote in every infant who developed AML and 50% of infants who developed ALL. These data suggest a model by which known genetic mechanisms for leukemogenesis could be disrupted without an abundance of somatic mutation or chromosomal rearrangements. This model would be consistent with existing models for the establishment of leukemia clones in utero and the high rate of IL concordance in monozygotic twins.
authors.affiliation: 1] Department of Genetics, Washington University School of Medicine, St Louis, MO, USA [2] Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Valentine
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Linabery
authors.affiliation: 1] Department of Genetics, Washington University School of Medicine, St Louis, MO, USA [2] Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chasnoff
authors.affiliation: 1] Department of Genetics, Washington University School of Medicine, St Louis, MO, USA [2] Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: A E O
authors.initials: AE
authors.lastname: Hughes
authors.affiliation: Department of Genetics, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: C
authors.initials: C
authors.lastname: Mallaney
authors.affiliation: Department of Genetics, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: N
authors.initials: N
authors.lastname: Sanchez
authors.affiliation: 1] Department of Genetics, Washington University School of Medicine, St Louis, MO, USA [2] Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: J
authors.initials: J
authors.lastname: Giacalone
authors.affiliation: Department of Pathology, Ohio State University, Columbus, OH, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Heerema
authors.affiliation: Department of Oncology/Hematology, Peyton Manning Children's Hospital at St Vincent, Indianapolis, IN, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Hilden
authors.affiliation: 1] Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA [2] Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
authors.forename: L G
authors.initials: LG
authors.lastname: Spector
authors.affiliation: 1] Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA [2] Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Ross
authors.affiliation: 1] Department of Genetics, Washington University School of Medicine, St Louis, MO, USA [2] Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: T E
authors.identifier: 0000000232457561
authors.initials: TE
authors.lastname: Druley
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D005260:Female; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000151:congenital / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000151:congenital / Q000235:genetics*; D011379:Prognosis; D015996:Survival Rate; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C497422:KMT2A protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase