Κατεύθυνση Εφαρμογές της Βιολογίας στην Ιατρική
Library of the School of Science

2018-11-15

2018

Chatzidrosou Vasiliki-Drosia

Β. Αλεπόρου, Καθηγήτρια Τομέα Γενετικής & Βιοτεχνολογίας, Τμήμα Βιολογίας Πανεπιστημίου Αθηνών (Επιβλέπουσα)
Π. Κόλλια, Αναπληρώτρια Καθηγήτρια Τομέα Γενετικής & Βιοτεχνολογίας, Τμήμα Βιολογίας Πανεπιστημίου Αθηνών
Κ. Μανωλά, Βιολόγος-Κυτταρογενετίστρια, Διευθύντρια Ερευνών, Ε.Κ.Ε.Φ.Ε.«ΔΗΜΟΚΡΙΤΟΣ» (Επιστ. Υπεύθυνη)

Μοριακή και κυτταρογενετική διερεύνηση Οξείας Μυελογενούς Λευχαιμίας (ΟΜΛ)

English
Greek

Molecular and cytogenetic investigation of Acute Myeloid Leukemia (AML)

INTRODUCTION
Acute Myeloid Leukemia (AML) is a heterogenous clonal disorder of the immature
bone marrow hematopoietic cells, which have lost their ability to regulate their selfrenewal
and differentiation to mature blood cells. Genetic and epigenetic
factors appear to contribute to the onset of the disease, while the interaction between
exposure to genotoxic agents and genetic predisposition has been implicated as a
possible cause of AML. Indeed, it has been suggested that genes encoding enzymes
that metabolize genotoxic substances when they do not function properly or even
genetic polymorphisms that affect the activity of the enzymes produced may be
involved in the AML onset. Human serum Paraoxonases (PON1, PON2, PON3) are a
family of enzymes that play an executive role in the antioxidant defense protecting cells
from gonotoxic factors like organophosphates and ROS that mediate carcinogenesis
by causing metabolic malfunction and DNA damage. The presence of the Gln192Arg
polymorphism (rs662) at PON1 coding region results in gloutamine to arginine
substitution at the position 192 (R>Q) of encoded protein product. The polymorphism
Q192R (rs662) refers to the different catalytic activity of the enzyme towards some
organophosphorous substances. Thus homozygous individuals for the normal allele
(QQ) have high enzymatic activity, heterozygous (QR) reduced and homozygous
individuals for the mutant allele (RR) have low enzymatic activity.
PURPOSE OF THE STUDY
The aim of this study was to investigate the possible role of the genetic polymorphism
Q192R of the PON1 gene at the predisposition of Acute Myeloid Leukemia (AML) and
its specific chromosomal aberrations.
MATERIALS AND METHODS
The methodology followed involves the molecular analysis for the Q192R polymorphism
of the PON1 gene at a group of patients with AML (study group) and a group of healthy
controls, as well as the cytogenetic analysis of the patients. The study included 85
patients with AML, 39 men and 46 women, 56 years old average aged (17-89 years),
and 104 healthy controls of similar age and sex. The study group was analysed for the
detection of chromosomal aberrations with karyotyping. Genotypic analysis was
performed to isolate total genomic DNA from the bone marrow samples of the patients
and the peripheral blood samples of the healthy donors, and then analysed by
Restricted Fragment Length Polymorphism (RFLP) for the detection of the Q192R
polymorphism. Finally, the genotypic findings were correlated with the demographic
characteristics of patients (age group, sex) and the cytogenetic findings. PON1
genotypic and allele frequencies distributions between AML patients and healthy
controls were compared by chi-square test. A p-value <0.05 was considered
significant. Odds ratios (ORs) were given with 95% confidence interval (CI).
RESULTS
Cytogenetic analysis was successful at 83/85 of the patients (98%). 36% of the
patients had normal karyotype while in the 64% of them clonal cytogenetic aberrations
were observed. The results were trisomy 8 (+8) at 12%, t (15; 17) (q24.1; q21.1); PMLRARA
and -7 / del (7q) at 7.2% and complex karyotype at the 8.4% of the patients.
The Q192R polymorphism genotyping was successful at all of the samples. At the
control group, the genotype frequencies of PON1 were 63.46% (Q/Q) homozygotes
for the normal allele Q, 31.73% (Q/R) eterozygotes and 4.81% homozygotes for the
mutant allele R (R/R). Respectively, the distribution of genotypes in the group of
patients was 65.9% (Q/Q), 29.4% (Q/R) and 4.6% (R/R). In the control group the
frequency of the two alleles was 0.793 for the normal allele (Q) and 0.207 for the
mutant allele (R) while in the study group the frequency was 0.806 for the normal allele
(Q) and 0.194 for the mutant allele (R). The frequency of the mutant genotype in
patients did not show any statistically significant difference compared to the group of
the healthy controls (p = 0.939, x2 = 0.125, df = 2).
CONCLUSION
The results of this study do not highlight the contribution of PON1 gene polymorphism
Q192R to the AML predisposition. Also, the contribution of the Q192R polymorphism to
the occurrence of specific cytogenetic abberations appears to be negative too,
although this is probably due to the small number of patients included in each
cytogenetic group.Thus, the occurrence of the cytogenetic abnormality trisomy 8
appears to correlate with the above mentioned polymorphism. Further investigation is
recommended, at a larger patient group, for the possible correlation of the
polymorphism studied with AML predisposition.

Health Sciences

leukemia, AML, Acute Myedoid Leukemia, predisposition, PON1, Q192R, polymorphism, snp, cytogenetics, molecular genetics

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