الفهرس يوجد فقط 14 صفحة متاحة للعرض العام
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المستخلص
Telomere dynamics are considered highly significant in
the development of cancer cells. Increased expression or
amplification of hTERT and hTERC genes was reported to
induce upregulation of telomerase enzyme and telomere
lengthening. Amplification of these genes are now believed to
play important role in confirmation of diagnosis and prognosis
of cancer cell line.
Increased expression of these genes is attributed to
alteration of their regulatory mechanisms. Both genes seems to
be parallel in most of their regulatory mechanisms. Yet some
cases, where both genes are not parallel to each other suggest
other regulatory factors of hTERC that needs further studies.
Concerning hematological malignancy, many studies
revealed amplification or increased expression of the hTERT
and hTERC genes, increased telomerase activity and telomere
length maintenance in pediatric acute lymphoblatic leukemia.
It was reported that these series of events are common
events in leukemogenesis. In the light of this, the current study
aimed to detection of hTERT and hTERC genes amplification in
pediatric acute lymphoblatic leukemia by FISH analysis and its
relation to standard prognostic factors and patient outcome.
The study was carried out on 25 pediatric newly
diagnosed ALL patients, attended Ain Shams university
hospitals. Their ages ranged from 0.9 to 9 years old with a mean
value of 4.78±2.1. They were 13 males and 12 females with
male to female ratio of 1.1: 1.
Summary
203
Detection of amplification of hTERT and hTERC by
FISH technique using dual colour LSI probes (5 P 15.33 / 5 q
31) for hTERT gene and (3q26 / alphasatallite) for hTERC gene
in pediatric patients with acute lymphoblastic leukemia at
diagnosis and at first hematological remission.
Follow up was done for 6-24 months following the
diagnosis and induction therapy as regard first hematological
remission after initial induction dose at day 28 to 35, complete
remission or hematological, CNS or testicular relapse in males.
hTERT and hTERC genes amplification was detected in all
bone marrow samples by FISH analysis and revealed
amplification in 100% and 92% of examined cases, at diagnosis
respectively. At first hematological remission hTERT and hTERC
genes revealed amplification in 72% and 64% of examined cases,
respectively. Number of copies of hTERT and hTERC genes was
also concerned in this study. At diagnosis, wide range of hTERT
copy number, ranging from 2 to 22 copies per examined
interphase cell was detected. hTERC gene copy number, on the
other hand, ranged from 2 to 15 copies with relative decrease in
copy number at first hematological remission. In contrast, normal
subjects revealed 2 copies per interphase cell.
Regarding relation to prognostic factors, hTERT revealed
positive correlation to LDH at diagnosis and at first hematological
remission while hTERC revealed positive correlation to LDH at
diagnosis only. Besides, a positive correlation between blast
percent at first hematological remission and hTERT and hTERC
genes percentage of amplification. This was evident both at
diagnosis and on day 28-38 of induction therapy.
Summary
204
Also significant increase in percentages of amplification
of hTERT and hTERC genes was evidenced in patient groups
with extramedullary infiltration.
By follow up of studied case, hTERT and hTERC genes
percentages of amplification showed higher levels in patients
with inferior outcome. So these genes play important role not
only in confirmation of diagnosis but also in prognosis of
studied cases. It was proved in this study that hTERT gene is the
best gene in prediction of relapse as regard its percentage of
amplification at first hematological remission; at day 28 to 35 of
induction therapy. A cutoff value of 6.5% of amplification of
hTERT gene was found to be reliable in prediction of relapse
with sensitivity of 100%, specificity of 71%, PPV of 64%, NPV
of 100% and diagnostic accuracy of 81%.
At the level of copy number, cases with hTERT and
hTERC genes copy number of 10 or more were found to be of bad
prognosis. This was reported in many studies to be due to
increased telomerase activity by 30 to 50%. Besides, patients with
10 or more copy number revealed shorter OS and RFS times.
The current study findings go with the fact reported by
many studies that telomerase genes amplification is a diagnostic
and prognostic tool in pediatric ALL.