Transcriptional Characterization of Glioma Neural Stem Cells Diva ...

1.3 Primary and Secondary Glioblastomas Introduction
but mutations in this gene are known to cause a familial form of Parkinson’s
disease known as autosomal recessive juvenile Parkinson disease [229]. The
most significant loss-of-heterozygosity (LOH 15 ) event identified in the TCGA
dataset was observed on the long arm of chromosome 17 where the TP53 gene
resides [326].
Cytosine-phosphate-Guanine (CpG 16 ) islands are regions of DNA in which a
cytosine is linked to a guanine via a phopsphodiester bond to form the dinu-
cleotide CpG that is repeated many times along a linear sequence. In formal
definitions, a CpG island must occupy more than 50% of a 200bp sequence
and have an expected/observed CpG ratio of 0.6 [102,159]. Methylation of the
5’ carbon of cytosine is a form of epigenetic modification that affects regula-
tion of gene expression via non-sequence based interactions. Such methylated
cytosines are present in the coding regions of mammalian genes and, over evo-
lutionary time, spontaneously deaminate to become thymines [102,287]. In
mammals, 70% to 80% of CpG cytosines are methylated [208]. Oppositely,
CpG islands in promoters tend to be unmethylated when genes are expressed,
suggesting that methylation is an inhibiting event for gene expression [142,214].
Methylation of CpG sites within promoters has been observed as a mechanism
of tumour suppressor gene silencing in a number of human cancers. In contrast,
the hypomethylation of CpG sites has been associated with the over-expression
of oncogenes within cancer cells [214].
Evaluation of promoter methylation was conducted in the TCGA project across
91 glioblastoma samples. A pattern emerged between the methylation of the
O-6-methylguanine-DNA methyltransferase (MGMT) promoter and the sub-
stitution spectrum of treated samples. MGMT is a DNA repair enzyme that
repairs damaged alkylated guanine residues and its promoter methylation sta-
tus has already been associated to sensitivity to the temozolomide alkylating
agent, which is the current standard of care for glioblastoma patients [79,204].
Amongst the 13 samples treated with alkylating agent that did not show
MGMT methylation, the validated somatic mutations from GC to AT, caused
by the spontaneous deamination of methylated cytosines to thymines, occurred
in comparable amounts between CpG and non-CpG dinucleotides. However,
in the six treated samples with MGMT methylation, the GC to AT transitions
15 The loss of normal function of one allele of a gene in which the other allele was already
inactivated. In the context of oncogenesis it refers to when the remaining functional allele
in a somatic cell of the offspring becomes inactivated by mutation.
16 The "CpG" notation is used to distinguish CG base-pairing of cytosine and guanine.
15