Download Leukaemia Section del (13q) Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Leukaemia Section
Review
del (13q)
Edmond SK Ma, Thomas SK Wan
Hematology Division, Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Hong
Kong, P.R. China (ESKM, TSKW)
Published in Atlas Database: March 2004
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/del13qID1310.html
DOI: 10.4267/2042/38080
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Partial karyotype in 2 cases of AML with del(13q): Left panel: Relapsed AML in a 17-year old man; Right panel: Acute monoblastic
leukaemia in a 31-year old woman at diagnosis. G-banding with trypsin / Giemsa.
also detected in post-polycythaemic myelo-fibrosis. A
high prevalence of chromosome 13q deletion or
translocation was reported as a second aberration in
chronic myeloid leukaemia (CML) with persistent or
relapsed disease after bone marrow transplantation. In 6
such CML patients, a common region of deletion at 13q
12-14 was identified by fluorescence in-situ
hybridization (FISH) with a panel of 13q YAC clones.
Interestingly, del(13q) was detected in aplastic anaemia
and these patients showed hypoplastic bone marrow
without morphological dysplasia.
Clinics and pathology
Disease
Myeloid disorder
Among myeloid malignancies, deletion 13q is
encountered in myelodysplastic syndrome (MDS),
acute
myeloid
leukaemia
(AML)
and
myeloproloferative disorders (MPD). The deletion is
described as interstitial in most cases although a few
cases of terminal deletion are reported.
A survey of 640 patients with primary MDS showed
that del(13q) was rare, and existed as the sole
abnormality in 2 cases of refractory anaemia. Besides
de novo MDS and AML, del(13q) was also reported in
therapy-related MDS. In a series of 137 cases of
therapy-related MDS and AML, del(13q) was detected
in 3 cases of the former group but not the latter.
Moreover, del(13q) was detected in 2 out of 55 patients
with unexplained cytopenia and clonal cytogenetic
abnormalities in bone marrow cells but without definite
morphological evidence of dysplasia, which might be a
harbinger of MDS.
With respect to MPD, del(13q) appeared to be more
common in chronic idiopathic myelofibrosis, and was
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(2)
Cytogenetics
Morphological Cytogenetics: Characterization of
del(13q) in 20 patients with myeloid malignancies,
including MPD, AML and MDS patients, showed that
the deletions consistently involved region 13q 14 - 21
by conventional G-banding assessment.
Molecular alterations of 13q may be more common
than is suggested by conventional cytogenetics.
First, loss of heterozygosity (LOH) at the RB1 locus,
which maps to 13q14, has been observed in 15 out of
39 (38%) of BCR-ABL negative MPD patients, with an
over-representation in chronic idiopathic myelofibrosis.
Second, 13q14 deletion can be demonstrated by FISH
108
del (13q)
Ma ESK, Wan TSK
in chronic idiopathic myelofibrosis and polycythaemia
vera patients without 13q abnormality on conventional
cytogenetics. These show that 13q deletions may occur
as a sub-microscopic lesion only detectable with
molecular techniques such as LOH study and FISH.
Molecular Cytogenetics: In a series 20 patients with
myeloid malignancies, FISH analysis with a panel of
DNA probes for 13q13.1-14.3 delineated a common
deleted region that was flanked by YAC 833A2 and
YAC 854D4. Subsequent study on one case of 13q
translocation with accompanying cryptic 13q deletion
allowed the genomic segment to be narrowed down to
around 4 cM that included YAC 937C7, RB1 and YAC
745E3. This overlaps with the critical deleted segment
in CLL which is limited by RB1 and D13S25 markers.
A number of genes lie within this region and include
RB1, CHCIL and RFP2. Despite initial report of RB1
abnormality in MDS and AML, subsequent reports
failed to shows RB1 rearrangement in myeloid
malignancies. In one series involving 39 cases of BCRABL negative MPD, the RB1 gene displayed a
germline configuration in all, suggesting that 13q
deletions most probably affect a tumour suppressor
locus distinct from RB1. No mutations in candidate
genes have been identified in any of the lymphoid
neoplasms as well.
associated with the longest median survival time of 133
months.
Subsequent investigations showed the presence of
del(13q) in other non-Hodgkin's lymphoma (NHL),
including both low grade and aggressive lymphoma. A
preferential association with mantle cell lymphoma was
suggested. It was also reported in 37 out of 74 cases
(50%) of splenic lymphoma with villous lymphocytes
in one study.
More recently, del(13q) was recognized as a common
genetic lesion in multiple myeloma. Cytogenetics and
FISH studies detected the presence of del(13q) in 20 86% of myeloma, usually within the 13q14 region. The
deletion may occur as an early event in the
development of monoclonal gammopathies and
possibly be involved in evolution of monoclonal
gammopathy of uncertain significance (MGUS) into
overt myeloma. A long-term follow up study on MGUS
showed presence of deletion 13q14 as detected by
FISH in 5 out of 18 cases, and all progressed to
myeloma within 6 - 12 months after identification of
the cytogenetics abnormality.
Cytogenetics
Morphological Cytogenetics: The deletion in CLL,
NHL and myeloma uniformly involves 13q14.
Commonly used FISH probes to detect the deletion in
the lymphoid disorders are chromosome 13q14
specific, including RB1, D13S319 and D13S25.
Molecular Cytogenetics: The most commonly deleted
marker in CLL and NHL initially reported was
D13S319, between the retinoblastoma locus and
D13S25 locus. The 13q14 deletions usually do not lead
to inactivation of the RB1 gene, and del(13q) is
associated with the presence of one intact RB1 gene on
the homologous chromosome, implying the role of an
adjacent locus that may harbour important tumour
suppressor gene(s). However, the pathogenesis of
splenic lymphoma with villous lymphocytes may be
different. In one study, 13q14 deletion was identified in
50% of SLVL cases, in which 47% showed monoallelic
loss of RB1, 12% showed hemizygous D13S25
deletion, and cases that displayed both RB1 and
D13S25 deletion. It follows therefore that allelic loss of
RB1 may indeed play a role in the patho-genesis of
SLVL.
A recent study on critically deleted region (CDR) at
13q14 in with three probes for 13q14 (RB1, D13S319,
and D13S25) showed deletions in 29 out of 82 (35.4%)
cases. Subsequently, contiguous YACs, PACs, and a
BAC spanning the 13q14-q21 region were employed
for deletion mapping in addition to a 13q telomere
probe. Large deletions extending to the 13q34 region
were found in 55% of the deleted cases, whereas an
additional 13.8% showed loss of both 13q34 and 13q14
regions with retention of 13q21. A CDR of
approximately 350 kb was identified at 13q14 with the
proximal border approximately 120 kb centromeric
Prognosis
Unlike the lymphoproliferative disorders in which
del(13q) shows prognostic significance, for example
associating with the longest survival in chronic
lymphocytic leukaemia when compared with other
chromosomal changes, no data are yet available for the
prognostic outcome of del(13q) in the myeloid
disorders. Aplastic anaemia with del(13q) appears to be
clinically benign. In a series of 9 cases, 6 responded to
immunosuppressive therapy while the other 3 improved
with steroids. None of these patients developed acute
leukaemia. These findings indicated that aplastic
anaemia with del(13q) resembled bone marrow failure
syndrome without cytogenetic abnormalities rather than
preleukaemia. Concurrent with this notation was the
report of spontaneous clinical and cytogenetic
remission in an aplastic anaemia patient with del(13q).
Disease
Lymphoid disorder
Del(13q) involving the band q14 occurs frequently in
B-cell chronic lymphocytic leukaemia (CLL), being
detectable in 8 - 10% of patients by conventional
cytogenetics and up to 40 - 50% of patients by FISH.
The deletion may occur in isolation or associated with
other recurrent cytogenetics abnormalities including
+12, del(11q), del(6q) and del(17p). In a large survey
of 325 patients with CLL by FISH, del(13q) was the
commonest genetic aberration, detected in 55% of
cases, and correlated with the longest survival of 92
months. The subcategory of isolated del(13q) was also
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(2)
109
del (13q)
Ma ESK, Wan TSK
García-Marco JA, Nouel A, Navarro B, Matutes E, Oscier D,
Price CM, Catovsky D. Molecular cytogenetic analysis in
splenic lymphoma with villous lymphocytes: frequent allelic
imbalance of the RB1 gene but not the D13S25 locus on
chromosome 13q14. Cancer Res. 1998 Apr 15;58(8):1736-40
from D13S319, encompassing an area rich in expressed
sequence tagged sites and containing DLEU1, DLEU2,
and RFP2 genes. While direct sequencing of the RFP2
gene revealed no mutations in six patients and four
myeloma cell lines harboring deletions of the CDR, a
role for RFP2 in the pathogenesis of myeloma cannot
yet be excluded.
La Starza R, Wlodarska I, Aventin A, Falzetti D, Crescenzi B,
Martelli MF, Van den Berghe H, Mecucci C. Molecular
delineation of 13q deletion boundaries in 20 patients with
myeloid malignancies. Blood. 1998 Jan 1;91(1):231-7
Prognosis
Cuneo A, Bigoni R, Rigolin GM, Roberti MG, Bardi A,
Campioni D, Minotto C, Agostini P, Milani R, Bullrich F, Negrini
M, Croce C, Castoldi G. 13q14 deletion in non-Hodgkin's
lymphoma: correlation with clinicopathologic features.
Haematologica. 1999 Jul;84(7):589-93
Sole deletion of 13q14 is associated with a more
favourable clinical outcome in CLL, with a reported
median survival time of 133 months for this particular
cytogenetics subgroup. However, among NHL in
general, del(13q) is associated with presence of
splenomegaly, peripheral blood dissemination, lower
probability of attaining complete remission and a
shorter survival. In myeloma, deletion of 13q14 also
predicts an adverse prognosis. A recent FISH study on
myeloma showed deletion of Rb gene in 48 out of 104
patients (46.2%), and deletion of D13S319 locus in 28
out of 72 patients (38.9%). Myeloma patients with
13q14 deletion were more likely to have stage III
disease, high serum levels of b2-microglobulin, and a
higher percentage of bone marrow plasma cells than
patients with normal 13q14 status on FISH study. The
presence of 13q14 deletion on FISH analysis was
associated with a significantly lower rate of response to
conventional-dose chemotherapy and a shorter overall
survival than in patients without the deletion.
Wada M, Okamura T, Okada M, Teramura M, Masuda M,
Motoji T, Mizoguchi H. Frequent chromosome arm 13q deletion
in aggressive non-Hodgkin's lymphoma. Leukemia. 1999
May;13(5):792-8
Chase A, Pickard J, Szydlo R, Coulthard S, Goldman JM,
Cross NC. Non-random involvement of chromosome 13 in
patients with persistent or relapsed disease after bone-marrow
transplantation for chronic myeloid leukemia. Genes
Chromosomes Cancer. 2000 Mar;27(3):278-84
Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A,
Bullinger L, Döhner K, Bentz M, Lichter P. Genomic
aberrations and survival in chronic lymphocytic leukemia. N
Engl J Med. 2000 Dec 28;343(26):1910-6
Solé F, Espinet B, Sanz GF, Cervera J, Calasanz MJ, Luño E,
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This article should be referenced as such:
Ma ESK, Wan TSK. del (13q). Atlas Genet Cytogenet Oncol
Haematol. 2004; 8(2):108-111.
111