2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

GLIOBLASTOMA: BIOLOGY, GENETICS AND BEHAVIOR
gates at the leading edge of sprouting vessels. In its most
florid form, angiogenesis takes the shape of “glomeruloid
bodies”—a feature that is most characteristic of GBM, but is
also an independent marker of poor prognosis in other forms
of cancer. 19 Since necrosis and hypoxia are located in the
GBM’s core and near the contrast-enhancing rim, hypoxiainduced
angiogenesis occurs further peripherally, favoring neoplastic
growth outward. The permissive nature of the CNS
parenchymal matrix to diffuse infiltration by individual
glioma cells allows for this burst of peripheral expansion. 4
Genetic Testing
A large and growing number of genetic alterations have
been identified in the diffuse gliomas, some of which are
used for diagnostic and prognostic purposes in neurooncology.
The genetic alterations that coincide with progression
to GBM include amplification of EGFR, deletion of
CDKN2A, and mutation or deletion of PTEN. Other diagnostic
and prognostic tests used in neuro-oncology include
assessment of 1p/19q, MGMT promoter methylation, IDH1,
and p53. 1
p53 Pathway Alteration
Alterations in the p53 tumor suppressor pathway are
frequent in infiltrative astrocytomas. The p53 pathway can
be altered mechanisms including mutation of TP53 and
deletion of the opposite allele, MDM2 gene amplification,
and p14ARF gene deletion. Point mutations in the DNAbinding
region of TP53 are the most frequent source of
inactivation. The majority (50% to 60%) of lower-grade
(WHO grade 2) infiltrating astrocytomas show such TP53
mutations, suggesting it occurs early. GBMs that arise from
grade 2 and 3 astrocytomas, so-called secondary GBMs, have
similar frequencies of TP53 mutations. TP53 mutations are
less frequent (30%) in primary, or de novo, GBMs, yet the
p53 pathway is altered by other mechanisms in these
tumors. The prognostic significance of TP53 mutations and
p53 protein expression in astrocytomas has been debated.
Young age is a strong predictor of prolonged survival among
patients with astrocytomas, especially GBM. Since TP53
mutations occur more frequently in GBMs from young
patients, their significance must be separated from the
survival advantage of youth.
For glioma classification, TP53 mutations currently have
limited utility. Since p53 derived from mutant genes has a
longer cellular half-life than wild type, the protein accumulates
in the nucleus. Thus, positive nuclear immunohistochemical
staining for the p53 protein correlates, albeit
imperfectly, with the presence of TP53 mutations. Positive
p53 immunostaining can be occasionally helpful for distinguishing
astrocytic from oligodendroglial differentiation,
since the oligodendrogliomas rarely harbor TP53 mutations.
1p/19q
There is a strong association of allelic losses on chromosomes
1p and 19q and the oligodendroglioma phenotype, and
60% to 80% of oligodendroglial neoplasms demonstrate combined
1p and 19q losses. 1,6 Enthusiasm for defining genetic
subsets of oligodendrogliomas increased substantially with
the demonstration of prognostically distinct groups. 20
1p and 19q losses are less frequent in other forms of
gliomas. For example, Smith and colleagues investigated the
allelic losses of 1p and 19q in 115 diffuse gliomas. 21 Combined
loss of 1p and 19q were seen in 11% of astrocytomas,
31% of the mixed oligoastrocytomas, and 64% of oligodendrogliomas.
Thus, while most oligodendrogliomas showed
1p/19q loss, not all did. Moreover, a small percentage of
mixed gliomas and astrocytomas also showed similar deletions.
More recent studies have demonstrated less frequent
1p/19q losses in diffuse astrocytomas. 22
Similar studies have interrogated the prognostic significance
of combined loss of 1p and 19q in diverse types of
diffuse gliomas and found them to be predictive of prolonged
overall survival only for patients with oligodendrogliomas.
Combined 1p and 19q losses are not predictive of prolonged
survival in astrocytomas or oligoastrocytomas of any
grade. 22-23 However, diagnostic testing for 1p/19q is often
used in cases of diffuse gliomas that have ambiguous morphology,
since 1p/19q codeletion is highly associated with
oligodedroglioma.
EGFR
Amplifications of the EGFR gene occur in approximately
40% of GBMs and 10% of anaplastic astrocytomas. 1 Amplifications
are much less frequent in low-grade astrocytomas
and are considered a late genetic event in the progression of
tumors to GBM. Either wild-type or mutated forms of EGFR
can be amplified. The most common EGFR amplification is a
mutated form lacking exons 2–7, which results in a truncated
cell surface protein with constitutive tyrosine kinase
activity (EGFRvIII).
The significance of EGFR gene amplification or EGFR
protein overexpression as a prognostic marker in GBM has
been debated. Most comprehensive studies have concluded
that EGFR status is not prognostically significant in patients
with GBM. However, therapies have been developed
that are directed at the overexpressed EGFR in GBMs.
Therefore, it may become critical to establish the EGFR
status of GBM as a part of the pathologic diagnosis in order
to predict pharmacologic responses to EGFR inhibitors. For
example, Mellinghoff and colleagues demonstrated that
those GBMs that have the best therapeutic response to
EGFR inhibitors are characterized by the coexpression of
EGFRvIII and PTEN. 24
Losses on Chromosome 10/PTEN Mutation
Some of the most frequent genetic deletions in GBMs
involve chromosome 10 and occur as losses of the entire
chromosome or as losses of only the long or short arms. Most
interest focuses on 10q, since it is commonly implicated in
high-grade progression and is the location of PTEN. Located
at 10q23.3, PTEN is mutated in 20% to 40% of GBMs and
generally occurs in the setting of chromosome 10 allelic loss.
Both chromosome 10 losses and PTEN mutations are much
more frequent in diffuse forms of astrocytoma than oligodendrogliomas.
They are also relatively late events in the
progression to GBM, since both are much more frequent in
GBMs than in AAs or grade 2 astrocytomas.
The high frequency of chromosome 10 losses in GBMs
(� 80%) and the tight correlation of its loss with the GBM
phenotype might suggest that it would not be a useful
prognostic marker across tumor grades. Indeed, in studies of
high-grade astrocytomas (AAs and GBMs), loss of heterozygosity
(LOH) of chromosome 10 (either 10p or 10q) has been
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