European Human Genetics Conference 2007 June 16 – 19, 2007 ...

Cancer genetics
ate. Glivec became the therapy of choice in chronic phase CML.
We present some preliminary results of cytogenetic evaluation within a
study aiming the long term Glivec therapy monitoring.
Chromosomal studies were performed on GTG-banded slides obtained
from bone marrow, after short term culture and standard preparation.
FISH studies were done with BCR/ABL probes (Vysis), BAC
FISH probe (8p23.1) and WCP probes (Vysis, Cytocell).
Cytogenetic evaluations were performed at 6, 12, 18 and 24 months.
After more than 2 years of treatment most of the patients were assessed
at 12 months intervals.
Sixty six out of 77 patients (86%) had advanced disease or a history of
long term interferon-alpha and conventional chemotherapy in chronic
phase CML. Eleven patients (14%) received imatinib as first therapeutic
choice in early chronic phase. Among these patients, 2 had additional
pre-treatment chromosomal changes [7q additional material
of unknown origin and translocation t(8;14), respectively], and 2 had
variant t(9;22): t(3;9;22) and t(1;9;22). None of the patients receiving
front line Glivec therapy showed karyotype evolution so far. Instead, 5q
deletion was seen in Ph negative cells of one patient, after 24 months
of therapy.
The evaluation of cellular genome, prior to Glivec therapy, helps the
prediction of response. Monitoring both Ph positive and Ph negative
clones for chromosomal changes allows a better management of CML
patients.
Acknowledgements: The authors gratefully acknowledge to CNCSIS
National Program Board (Project No. 19/2006).
P0528. Cytogenetic evolution patterns in CML post-SCT
K. Karrman 1 , B. Sallerfors 2 , S. Lenhoff 3 , T. Fioretos 1 , B. Johansson 1 ;
1 Department of Clinical Genetics, Lund University Hospital, Sweden, 2 Department
of Medicine, Halmstad Hospital, Sweden, 3 Department of Hematology,
Lund University Hospital, Sweden.
The cytogenetic evolution patterns in CMLs after allogeneic SCT are different
from the ones observed in non-transplanted patients, a phenomenon
suggested to be caused by the conditioning regime. We reviewed
131 CMLs displaying karyotypic evolution after SCT (122 allogeneic, 9
autologous), treated at Lund University Hospital or reported in the literature.
Major route abnormalities (i.e., +8, +Ph, i(17q), +19, +21, +17
and -7) were seen in 14%, balanced aberrations in 61%, hyperdiploidy
in 19%, pseudodiploidy in 79%, divergent clones in 14%, and Ph-negative
clones in 21%. The breakpoints involved in secondary structural
rearrangements clustered at 1q21, 1q32, 7q22, 9q34, 11q13, 11q23,
12q24, 13q14, 17q10, and 22q11. Cytogenetic abnormalities common
in AML after genotoxic exposure, i.e., der(1;7)(q10;p10), del(3p), -5,
del(5q), -7, -17, der(17p), -18, and -21, were only rarely seen post-
SCT. Comparing the cytogenetic features in relation to type of SCT
revealed that balanced aberrations were significantly more common
after allogeneic than after autologous SCT (64% and 22%, respectively,
P = 0.03). In addition, there was a trend as regards hyperdiploidy
being more common after autologous (P = 0.07) and pseudodiploidy
being more frequent after allogeneic SCT (P = 0.09).
P0529. Classification of chromosomal aberrations in a group of
patients with chronic myeloproliferative disorders
T. Tuncali, H. G. Karabulut, H. I. Ruhi, N. Y. Kutlay, F. Sadeghi, A. Ibrahim, B.
Saglam, A. Vicdan, K. Yararbas, A. Tukun;
Ankara University Faculty of Medicine, Ankara, Turkey.
Chronic myeloproliferative disorders (CMPD) are thought to be clonal
disorders arising in a multipotent hematopoietic progenitor cell. The diagnosis
of an CMPD other than chronic myelogenous leukemia (CML)
can be problematic due to a lack of clinically applicable clonal markers.
It’s suggested that in patients with classical CMPD phenotype, the
hematopoietic stem cells appear to be polyclonal, suggesting that the
chronic CMPD other than CML may actually be a genetically heterogeneous
group of disorders. Here, we present the results of a retrospective
data mining study for CMPD patients refered to our department for
cytogenetic analysis to seek the clonality. We followed the the most
established criteria for CMPD released by the WHO and Polycthemia
Study Group for inclusions. The data was obtained from results of the
bone marrow and peripheral blood samples of 274 patients diagnosed
or suspected as CMPD between May 1998 and January 2007 analyzed
with conventional /FISH cytogenetic methods. The cohorts were
formed as CMPD?, ET, PV, CMML, IMF, and HES. The existence of Ph
1 2
chromosome in conventional analysis and/or BCR-ABL fusions were
determined as 4%, 2.8%, and 1.9% in CMPD?, ET, and PV subgroups
and excluded. In a total of 337 analysis the frequency of structuralnumerical
abnormalities were determined (CMPD:30.9%-20.3 n=123;
ET:13.8%-6.4% n=94; PV: 5.6%-9.3% n=54; CMML: 19.4%-45% n=40;
IMF: 10.0%-15.0% n=20; HES: 16.7%-16.7% n=6). Structural and numerical
gathered the leading chromosomal aberations were 17, 22, 11
for CMPD, 7, 17, 8 for ET, and 21, 8, 7 for PV.
P0530. Genetic aberrations appeared during the disease course
may be associated with clinical progression in CLL patients
E. Arranz 1 , O. González 1 , S. Ramiro 1 , M. Renedo 1 , C. Blas 1 , A. Pastor 1 , C.
Fernandez-R. 1 , A. Alonso 2 , E. Martí 2 , M. Pérez 2 , J. Fernández-Rañada 2 ;
1 Gemolab, Madrid, Spain, 2 Ruber Hospital, Madrid, Spain.
Chronic lymphocytic leukemia (CLL) is the most common type of
leukaemia in adults. Clonal aberrations are found in about 50% of
cases by chromosome analysis and in about 80% of CLL cases by
fluorescence in situ hybridization (FISH). Progression of disease is observed
in some cases, but genetic factors involved are not completely
known.
The aim of this study was to analyze the impact of genetic alterations
that appear during disease evolution in clinical progression in CLL patients.
Clinical parameters evaluated were: progression in stage, median
survival time and need for treatment.
FISH using LSI D13S319/13q34/CEP 12 and LSI p53/ LSI ATM multicolor
probe sets (Vysis) was performed on bone marrow or peripheral
blood samples from 21 CLL patients at various time points during the
disease course [median follow up: 5 years (2-14)].
Genetic aberrations occurred during disease development were observed
in 5/21(24%) patients. Genetic alterations detected included:
del (13q14) monoallelic (n=1), del (13q14) biallelic (n=1), del (13q14)
monoallelic and biallelic (n=1), del (11q 22.3) (ATM gene) (n=2).
The median overall survival (OS) and need for treatment were not
significantly different between patients with and without appearance
of genetic aberrations during the disease course. The only difference
between the 2 groups was a greater progression in stage in the former
group (80% vs. 44%). It is remarkable that progression occurred
despite the appearance of non high-risk genetic abnormalities (13q14
deletion).Although more cases are needed to confirm these results,
our data suggest that genetic aberrations appeared during evolution of
disease may be associated with clinical progression in CLL patients.
P0531. Genome copy number variations unique to CML
A. Chanalaris 1 , D. Brazma 1 , C. Grace 1 , J. Melo 2 , J. F. Apperley 2 , T. L. Hollyoake
3 , E. Nacheva 1 ;
1 Royal Free & UC Medical School, London, United Kingdom, 2 Imperial College
and Hammersmith Hospital, London, United Kingdom, 3 Glasgow Royal Infirmary,
University of Glasgow, Glasgow, United Kingdom.
Copy number variations (CNVs) are now a recognised feature of the
human genome with unknown phenotypic consequences. Chronic myeloid
leukaemia (CML) is a haematopoietic stem cell disorder defined
by expression of the BCR-ABL fusion gene, a constitutively activated
tyrosine kinase. We studied 49 CML samples at various stages of the
disease by arrayCGH using a 1 Mbase BAC chip (SGI2600, Perkin
Elmer). The aCGH profiles revealed a large number of single BAC
imbalances where fluorescence ratios exceeded a ± 3 SD threshold.
We limited our analysis to imbalances found in at least three samples.
A total of 194 BACs met this criterion and were compared with the
CNVs recently published (Redon 1 at al., Nature Genetics, 2006 and
Database of Genomic Variations at http://projects.tcag.ca/variation).
Many of the loci identified corresponded to the published data. However,
among the 99 loci unique to our study, the two most frequent were
BAC clones RP11-452O22 (35%) and RP11-89C6 (26%). Confirmed
by Q-PCR, these imbalances are not reported elsewhere. CML occurs
in about 1 per 100,000 of the general population, so it is unlikely that
any constitutional CNVs offering a predisposition to CML would occur
in the 270 individuals studied by Redon et al. Our results suggest that
these newly identified unique CNVs, either constitutional or disease
associated, are specific to CML and offer new insights into the biology
of this malignancy.