Complex Patterns of Chromosome 11 Aberrations in Myeloid Malignancies Target CBL, MLL, DDB1 and LMO2

Thorsten Klampfl, Jelena D. Milosevic, Ana Puda, Andreas Schönegger, Klaudia Bagienski, Tiina Berg, Ashot S. Harutyunyan, Bettina Gisslinger, Elisa Rumi, Luca Malcovati, Daniela Pietra, Chiara Elena, Matteo Giovanni Della Porta, Lisa Pieri, Paola Guglielmelli, Christoph Bock, Michael Doubek, Dana Dvorakova, Nada Suvajdzic, Dragica TominNatasa Tosic, Zdenek Racil, Michael Steurer, Sonja Pavlovic, Alessandro M. Vannucchi, Mario Cazzola, Heinz Gisslinger, Robert Kralovics

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article numbere77819
JournalPLoS One
Volume8
Issue number10
DOIs
Publication statusPublished - Oct 16 2013

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Klampfl, T., Milosevic, J. D., Puda, A., Schönegger, A., Bagienski, K., Berg, T., Harutyunyan, A. S., Gisslinger, B., Rumi, E., Malcovati, L., Pietra, D., Elena, C., Della Porta, M. G., Pieri, L., Guglielmelli, P., Bock, C., Doubek, M., Dvorakova, D., Suvajdzic, N., ... Kralovics, R. (2013). Complex Patterns of Chromosome 11 Aberrations in Myeloid Malignancies Target CBL, MLL, DDB1 and LMO2. PLoS One, 8(10), [e77819]. https://doi.org/10.1371/journal.pone.0077819