281Genetics and Genomics of Brain Cancer
Genetic alterations in GBM have been studied extensively using molecular diagnos-
tic technologies. Gene expression profi ling reveals extensive differences in gene
expression among GBMs, particularly in genes involved in angiogenesis, immune
cell infi ltration, and extracellular matrix remodeling. One gene, FABP7, is associ-
ated with survival and is a prognostic marker of both biologic and clinical signifi -
cance. Several types of deletions of chromosome 1 have been identifi ed but only the
complete loss of the short arm of chromosome 1 combined with complete loss of the
long arm of chromosome 19 signifi es a good prognosis. Partial loss of the short arm
of chromosome 1, on the other hand, characterized more aggressive tumors. These
fi ndings are recorded by using high-density array-comparative genomic hybridiza-
tion (CGH) analysis. By using these tools, physicians can revamp and refi ne tumor
classifi cation to enable more individualized treatment. Expression profi ling com-
bined with mutation analysis has an important role in the development of rational
therapies for GBM.
Genetic differences may also have indirect effects on drug response that are
unrelated to drug metabolism or transport, such as methylation of the methylgua-
nine methyltransferase (MGMT) gene promoter, which alters the response of GBM
to treatment with carmustine. The mechanism of this effect is related to a decrease
in the effi ciency of repair of alkylated DNA in patients with methylated MGMT.
Activation of the transcription factor STAT3 is considered to potently promote
oncogenesis in a variety of tumors including GBM leading to intense efforts to
develop STAT3 inhibitors for treatment. However, the function of STAT3 in GBM
pathogenesis has remained unknown. STAT3 is a key gene that turns neural stem
cells into astrocytes during normal development. STAT3 has been reported to play
a pro-oncogenic or tumor-suppressive role depending on the mutational profi le of
the tumor (de la Iglesia et al. 2008 ). Defi ciency of the tumor suppressor PTEN trig-
gers a cascade that inhibits STAT3 signaling in murine astrocytes and human
GBM. Specifi cally, there is a direct link between the PTEN–Akt–FOXO axis and
the leukemia inhibitory factor receptor β (LIFRβ)–STAT3 signaling pathway.
Accordingly, PTEN knockdown induces effi cient malignant transformation of
astrocytes upon knockout of the STAT3 gene. Remarkably, in contrast to the tumor-
suppressive function of STAT3 in the PTEN pathway, STAT3 forms a complex with
the oncoprotein epidermal growth factor receptor type III variant (EGFRvIII) in the
nucleus and thereby mediates EGFRvIII-induced glial transformation. In short,
when EGFR is mutated, STAT3 is an oncogene; with a PTEN mutation, STAT3 is
a tumor suppressor. These fi ndings indicate that STAT3 plays opposing roles in
glial transformation depending on the genetic background of the tumor, providing
the rationale for personalized treatment of GBM. STAT3 has also been implicated
in prostate and breast cancers, so these results may translate to other types of
tumors as well.
Mutations of EGFR are found in over 50 % of GBMs. Concomitant activation
of wild-type and/or mutant (vIII) EGFR and ablation of Ink4A/Arf and PTEN
tumor suppressor gene function in the adult mouse CNS induces rapid onset of an
Personalized Management of Cancers of Various Organs