Detekcija i karakterizacija genomske nestabilnosti tumora mozga glijalnog porekla
Detection and characterization of genomic instability in patients with malignant glioma
Authors:
Milinković, VedranaContributors
Tanić, NikolaMatić, Gordana
Banković, Jasna
Rakić, Miodrag
Ruždijić, Sabera
Document Type:
Doctoral thesis (Published version)
Metadata
Show full item recordAbstract:
Glioblastoma is the most frequent and the most malignant human brain tumor. Despite a similar
histological appearance, primary and secondary glioblastomas are distinct tumor entities with
different genetic alterations but none being specific enough to distinguish them. Despite better
insight in its complex genetic nature, glioblastoma is still incurable disease, with extremely
short median survival. The purpose of this study was to detect specific genetic changes, as well
as to quantify overall level of genomic instability in samples of malignant glioma patients.
Besides, we analyzed genetic alterations of key tumor suppressors (p53, PTEN and p16) and
EGFR oncogene, commonly aberrant in glioma samples. Alterations of two or more genes were
present in majority of analyzed samples indicating importance of multiple changes for
gliomagenesis.
AP-PCR DNA profiling revealed two types of genetic differences between tumor and normal
tissue: qualitative changes which represent accumulation of changes in DNA sequence and are
the manifestation of microsatellite and point mutation instability (MIN-PIN) and quantitative
changes which represent amplifications or deletions of existing chromosomal material and are
the manifestation of chromosomal instability (CIN). Both types of alterations were present in
all analyzed samples contributing almost equally to the total level of genomic instability, and
showing no differences between histological subtypes. Further investigation of alterations in
DNA profiles revealed specific changes in the following 11 genes that were not previously
associated with glioma pathogenesis: LHFPL3, SGCG, HTR4, ITGB1, CPS1, PROS1, GP2,
KCNG2, PDE4D, KIR3DL3, and INPP5A. Most of identified genes have significant role in
signal transduction or cell adhesion, which are important processes for cancer development and
progression.
The frequencies of observed alterations were correlated with clinicopathologic parameters, the
level of genomic instability and patient survival, as well as with presence of alterations in p53,
PTEN, p16 and EGFR genes. Some of the identified genes showed significant association with
p53 and p16 tumor suppressors, as well as with EGFR, but there was no significant correlation
between loss of PTEN and any of identified genes.
In conclusion, our results confirmed complexity of glioma genetic nature, emphasizing high
level of genomic instability as hallmark of this tumor type. Identified novel genes could be used
as potential biomarkers for diagnosis of primary and secondary glioblastoma, as well as
predictors of patients’ outcome.
Keywords:
Cancer; Glioma; Anaplastic astrocytoma; Glioblastoma; Genomic instabilty; p53; PTEN; p16; EGFR; BiomarkersSource:
University of Belgrade, Faculty of Biology, 2013, 1-140Funding / projects:
- Advanced technologies for monitoring and environmental protection from chemical pollutants and radiation burden (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-43009)
- Identification of predictive molecular markers for cancer progression, response to therapy and disease outcome (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41031)
URI
http://eteze.bg.ac.rs/application/showtheses?thesesId=1087https://fedorabg.bg.ac.rs/fedora/get/o:7792/bdef:Content/download
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http://nardus.mpn.gov.rs/123456789/2160
https://radar.ibiss.bg.ac.rs/handle/123456789/2396