Complex patterns of chromosome 11 aberrations in myeloid malignancies target CBL, MLL, DDB1 and LMO2.

PLoS One 2013 16;8(10):e77819. Epub 2013 Oct 16.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

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.

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0077819PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797696PMC
June 2014
42 Reads

Publication Analysis

Top Keywords

myeloid malignancies
20
exome sequencing
12
chromosome
9
patient 11qupd
8
somatic mutations
8
tumor suppressor
8
mutations cbl
8
chromosomal aberrations
8
813 samples
8
upds chromosome
8
aberrations myeloid
8
myeloid
6
malignancies
5
chromosome 11q
4
defects gains
4
64% chromosome
4
samples 64%
4
gains losses
4
gene ddb1
4
chromosome 813
4

References

(Supplied by CrossRef)
WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues
S Sverdlow et al.
2008
MLL fusions: pathways to leukemia
H Liu et al.
Cancer Biol Ther 2009
ALL-1 partial duplication in acute leukemia
SA Schichman et al.
Proc Natl Acad Sci U S A 1994
Partial tandem duplication of ALL1 as a recurrent molecular defect in acute myeloid leukemia with trisomy 11
MA Caligiuri et al.
Cancer Res 1996
11q deletions in hematological malignancies
O Monni et al.
Leuk Lymphoma 2001

Similar Publications