title: Complex patterns of chromosome 11 aberrations in myeloid malignancies target CBL, MLL, DDB1 and LMO2.
abstract: Exome sequencing of primary tumors identifies complex somatic mutation patterns. Assignment of relevance of individual somatic mutations is difficult and poses the next challenge for interpretation of next generation sequencing data. Here we present an approach how exome sequencing in combination with SNP microarray data may identify targets of chromosomal aberrations in myeloid malignancies. The rationale of this approach is that hotspots of chromosomal aberrations might also harbor point mutations in the target genes of deletions, gains or uniparental disomies (UPDs). Chromosome 11 is a frequent target of lesions in myeloid malignancies. Therefore, we studied chromosome 11 in a total of 813 samples from 773 individual patients with different myeloid malignancies by SNP microarrays and complemented the data with exome sequencing in selected cases exhibiting chromosome 11 defects. We found gains, losses and UPDs of chromosome 11 in 52 of the 813 samples (6.4%). Chromosome 11q UPDs frequently associated with mutations of CBL. In one patient the 11qUPD amplified somatic mutations in both CBL and the DNA repair gene DDB1. A duplication within MLL exon 3 was detected in another patient with 11qUPD. We identified several common deleted regions (CDR) on chromosome 11. One of the CDRs associated with de novo acute myeloid leukemia (P=0.013). One patient with a deletion at the LMO2 locus harbored an additional point mutation on the other allele indicating that LMO2 might be a tumor suppressor frequently targeted by 11p deletions. Our chromosome-centered analysis indicates that chromosome 11 contains a number of tumor suppressor genes and that the role of this chromosome in myeloid malignancies is more complex than previously recognized.
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Klampfl
authors.forename: Jelena D
authors.initials: JD
authors.lastname: Milosevic
authors.forename: Ana
authors.initials: A
authors.lastname: Puda
authors.forename: Andreas
authors.initials: A
authors.lastname: Schönegger
authors.forename: Klaudia
authors.initials: K
authors.lastname: Bagienski
authors.forename: Tiina
authors.initials: T
authors.lastname: Berg
authors.forename: Ashot S
authors.initials: AS
authors.lastname: Harutyunyan
authors.forename: Bettina
authors.initials: B
authors.lastname: Gisslinger
authors.forename: Elisa
authors.initials: E
authors.lastname: Rumi
authors.forename: Luca
authors.initials: L
authors.lastname: Malcovati
authors.forename: Daniela
authors.initials: D
authors.lastname: Pietra
authors.forename: Chiara
authors.initials: C
authors.lastname: Elena
authors.forename: Matteo Giovanni
authors.initials: MG
authors.lastname: Della Porta
authors.forename: Lisa
authors.initials: L
authors.lastname: Pieri
authors.forename: Paola
authors.initials: P
authors.lastname: Guglielmelli
authors.forename: Christoph
authors.initials: C
authors.lastname: Bock
authors.forename: Michael
authors.initials: M
authors.lastname: Doubek
authors.forename: Dana
authors.initials: D
authors.lastname: Dvorakova
authors.forename: Nada
authors.initials: N
authors.lastname: Suvajdzic
authors.forename: Dragica
authors.initials: D
authors.lastname: Tomin
authors.forename: Natasa
authors.initials: N
authors.lastname: Tosic
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Racil
authors.forename: Michael
authors.initials: M
authors.lastname: Steurer
authors.forename: Sonja
authors.initials: S
authors.lastname: Pavlovic
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Vannucchi
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.forename: Heinz
authors.initials: H
authors.lastname: Gisslinger
authors.forename: Robert
authors.initials: R
authors.lastname: Kralovics
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D002869:Chromosome Aberrations; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D059472:Exome / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D009190:Myelodysplastic Syndromes / Q000235:genetics; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D011087:Polycythemia Vera / Q000235:genetics; D016133:Polymerase Chain Reaction; D055728:Primary Myelofibrosis / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics; D013922:Thrombocytosis / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; D011518:Proto-Oncogene Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D050721:Proto-Oncogene Proteins c-cbl; C067419:CBL protein, human