Dissertation committee:
Αλεπόρου-Μαρίνου Βασιλική Αναπλ. Καθηγήτρια (Επιβλέπουσα), Κόλλια Παναγούλα Αναπλ. Καθηγήτρια, Μανωλά Καλλιόπη Ερευνήτρια Α΄ <<Ε.Κ.Ε.Φ.Ε. Δημόκριτος>>
Summary:
Acute Myelogenous Leukemia (AML) comprise a heterogeneous disease. The etiology
of AML development is currently unknown; however, the interaction between
environmental exposure and genetic individual’s background has been postulated
to be a possible cause for the development of AML. Τhe aim of this thesis was
to investigate the role of genetic polymorphisms of the detoxification genes
CYP2B6 (G516T, C777A, A785G), GSTP1 (A313G) and DNA repair genes RAD51 (G135C),
XPD23 (A23927C) and LIG4 (C26T) in the development of AML. We also investigated
the methylation status of the promoter of GSTP1 gene in the development of AML.
The study was performed in 619 AML patients and 430 unrelated healthy donors.
Research methodology included cytogenetic analysis of bone marrow samples,
genotyping analysis of the above mentioned polymorphisms and methylation
analysis of the promoter of the GSTP1 gene. The results of this study revealed
an increased frequencies of the variant genotypes of G516T and A785G
polymorphisms of CYP2B6 gene as well as A313G GSTP1 and C26T LIG4 polymorphism
in AML patients compared to controls indicating the possible role of the above
polymorphisms in AML susceptibility. In contrast, the polymorphism C777A of
CYP2B6 gene and the polymorphisms G135C, A23927C of the repair genes RAD51 and
XPD23 respectively, revealed similar frequency distribution between patients
and controls, suggesting that probably the presence of these polymorphisms did
not increase the risk of AML. Identification of the CYP2B6 haplotypes was also
performed. Patients carriers the haplotype TAG (combination of three mutants
alleles) have 3-fold increased risk of AML development compared to controls.
The association between genotypes of the above genes and cytogenetic results of
patients showed statistical differences indicating the significant role of
polymorphisms in the formation of specific AML chromosomal aberrations.
Furthermore, the promoter of GSTP1 gene was found to be methylated in patients
with s-AML. Therefore, the results of this thesis contribute to the
understanding of the role of polymorphisms of detoxification and repair genes
in susceptibility to AML and the development of specific cytogenetic
alterations.
Keywords:
Acute myeloid leukemia, Cytogenetics, Polymorphisms, Methylation, Chromosomal abberations