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Atlas of Genetics and Cytogenetics
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Leukaemia Section
Mini Review
dic(9;20)(p11-13;q11)
Jon C Strefford
Cancer Genomics Group, Cancer Sciences Division, University of Southampton, UK (JCS)
Published in Atlas Database: October 2009
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/dic920ID1143.html
DOI: 10.4267/2042/44834
This article is an update of :
Gibbons B. dic(9;20)(p11-13;q11). Atlas Genet Cytogenet Oncol Haematol 1999;3(3):144
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Cytogenetics molecular
Clinics and pathology
Even at the cytogenetic level, considerable breakpoint
heterogeneity is apparent on both chromosomes. Arraybased comparative genomic hybridization (aCGH),
with BAC clones at tiling resolution, has shown
clustering of breakpoints within 9p13.2 (genomic
position 37.1-38.7 Mb) and 20q11.2 (29.2-30.8 Mb).
Recent FISH mapping data has confirmed this
heterogeneity in a large series of dic(9;20) patients
(Figure 2).
Disease
Acute lymphoblastic leukaemia (ALL)
Phenotype/cell stem origin
B-cell precursor acute lymphoblastic leukemia (BCPALL).
Prognosis
On a limited series, the median patient age is 3 years,
the female/male ratio of 2.0 has been reported. Risk
group stratification was nonstandard risk in 79%. The
event-free survival and overall survival at 5 years for
the 24 Nordic cases was 0.62 and 0.82, respectively.
Thus, although relapses are quite common, post-relapse
treatment of many patients is successful.
Additional anomalies
Cytogenetics
The dic(9;20) can occur as a sole cytogenetic
abnormality, or in the context of a more complex
karyotype. Gains of chromosome X and 21 are the most
frequency additional findings in these patients.
Diagnostic FISH data shows that the dic(9;20) can
occur in the presence of the BCR-ABL1 and ETV6RUNX1 fusion genes.
Cytogenetics morphological
Genes involved and proteins
Chromosomes 7, 9, 12 and 20 are frequently involved
in the formation of dicentric chromosomes in BCPALL. The dic(9;20)(p11~13;q11) occurs in approx 2%
and approx 0.5% of childhood and adult BCP-ALL,
respectively. FISH has shown that dic(9;20) contains
the centromere of both chromosomes, resulting in loss
of 9p and 20q material. It is a subtle chromosome
abnormality, often appearing as monosomy 20,
sometimes with apparent deletion of 9p; confirmation
of the dic(9;20) translocation is obtained by FISH
(Figure 1).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8)
PAX5
Location
9p13
DNA/RNA
The paired box 5 gene (PAX5) extends over 200 kb of
genomic DNA and contains 10 exons.
800
dic(9;20)(p11-13;q11)
Strefford JC
Figure 1. Top: The left shows a G-banded karyogram of the dic(9;20). Monosomy 20 and the dicentric chromosome are highlighted with
black arrows. The right shows a metaphase from the same patient using paints for chromosomes 9 (green) and 20 (red). The dicentric is
shown by the white arrow - Courtesy Jon C Strefford; Bottom: M-FISH - Courtesy Melanie Zenger and Claudia Haferlach.
Protein
The gene encodes a transcription factor, with a highly
conserved DNA-binding domain, known as a paired
box. PAX5 is a 42 kDa protein of 391 amino acids that
encodes the B-cell lineage specific activator protein
that is expressed at early, but not late stages of B-cell
differentiation. The protein is expressed during B-cell
lineage commitment during early B-cell development
and maintenance.
mechanisms. Breakpoints proximal to PAX5 can be in
euchromatic or heterochromatic regions of the
chromosome and result in deletion of PAX5 in the
majority of cases. Less frequently, breakpoints can
occur within the PAX5 gene and result in aberrant
fusion sequences with regions of chromosome 20.
Breakpoint cloning experiments have shown PAX5
sequence juxtaposed to several genes on 20q including
ASXL1, C20ORF112 and KIF3B (Figure 3).
The genes involved in these fusion sequences are either
in opposing orientation, or in the same orientation and
out-of-frame, suggesting the biological consequence of
these fusion events in loss of function.
Quantitative PCR (qRT-PCR) has confirmed disruption
of PAX5 in the context of the dic(9;20), by showing
deregulated expression of PAX5 and several key
downstream PAX5 target genes, including, BLK, EBF1
and FLT3. In the case of PAX5-C20ORF112, it has
been shown that the C-terminal of the PAX5 protein is
Result of the chromosomal
anomaly
Hybrid gene
Note
FISH analysis has shown that in spite of the breakpoint
heterogeneity, the PAX5 gene is targeted at high
frequencies, by a variety of genetic
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8)
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dic(9;20)(p11-13;q11)
Strefford JC
replaced by that of the partner gene, which does not
change the affinity for the protein to bind to recognition
sites, but does effect the expression of certain
downstream PAX5 target genes. Furthermore,
transfected vectors encoding the PAX5-C20ORF112
are able to suppress the transcriptional activity of wildtype PAX5, leading to the inhibition of B-cell
development. Sequence analysis and genomic
quantitative PCR have also shown that the PAX5 allele
not involved in the translocation can be targeted by
mutations and homozygous deletions.
Further sequence analysis of the dic(9;20) is beginning
to unravel the heterogeneity on chromosome 20, and
identify recurrent targets. It has been suggested that
C20ORF112 may be the recurrent target gene on
chromosome 20, but this has not been supported by
other studies. In addition to C20ORF112, FISH and
molecular investigations have implicated the recurrent
involvement of ASXL1.
Advances in recent years have expanded our
understanding of the dic(9;20), most notably with the
identification of PAX5 on 9p. However, there are
exceptionally rare cases where PAX5 is not deleted or
fused though mutations of deletions beyond the
resolution of FISH cannot be excluded. The key genes
on 20q remain to be fully elucidated.
Figure 2. Breakpoint heterogeneity on chromosome 9 and 20 in the dic(9;20). A partial idiogram for each of the chromosomes is shown
on the left for chromosomes 9 and 20. Each black filled square shows the position of a FISH probe in relation to the gene of interest.
Each column shows an individual patient with the position and extent of the deleted region represented by vertical red bar.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8)
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dic(9;20)(p11-13;q11)
Strefford JC
Figure 3. Schematic of PAX5 fusion sequences. The exons of the PAX5 and partner genes are shown in red and pink respectively. The
gene orientation is shown by the horizontal arrow. Below each schematic is the corresponding predicted protein structure and domains.
Forestier E, Gauffin F, Andersen MK, Autio K, Borgström G, et
al. Clinical and cytogenetic features of pediatric
dic(9;20)(p13.2;q11.2)-positive
B-cell
precursor
acute
lymphoblastic leukemias: a Nordic series of 24 cases and
review of the literature. Genes Chromosomes Cancer. 2008
Feb;47(2):149-58
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This article should be referenced as such:
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8)
Strefford JC. dic(9;20)(p11-13;q11). Atlas Genet Cytogenet
Oncol Haematol. 2010; 14(8):800-803.
803