291Personalized Management of Meningiomas
Meningiomas are the most common primary brain tumors and affect ~170,000
patients in the US. They are usually benign but can turn malignant in about 10 % of
cases. Even benign tumors require surgery if they affect the surrounding brain tissue
and disrupt neurological functions. Genomic analysis has shown that the entire
genetic landscape of meningiomas can be explained by abnormalities in just 5
genes. Nearly half of atypical meningiomas were neurofi bromin 2 (NF2)-mutant, an
already known mutation responsible for genomic instability as well as association
with malignancy and localizing to the cerebral and cerebellar hemispheres. The
other four gene mutations now discovered are (Clark et al. 2013 ):
- Mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, were found in nearly
one-fourth of all tumors. Meningiomas with these mutations are found in the
skull base and are unlikely to become malignant. - Recurrent mutation in KLF4, a transcription factor known for its role in inducing
pluripotency. It can induce stem cell formation, even in cells that have fully dif-
ferentiated into a specifi c tissue type. - AKT1(E17K), a mutation known to activate the PI3K pathway, and is linked to
malignancy. - SMO mutations, which activate Hedgehog signaling, were identifi ed in ~5 % of
non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically
distinctive-nearly always benign, with chromosomal stability, and originating
from the skull base. SMO mutations had previously been found in basal cell
carcinoma and are the target of an already approved drug for that form of skin
cancer. It is feasible to use targeted chemotherapy on patients with non-NF2
mutations, especially those with recurrent or invasive meningiomas and those
who are surgically at high risk. Individualized chemotherapies could also spare
patients irradiation treatment, a risk factor for progression of these generally
benign tumors.
Collectively, these fi ndings identify distinct meningioma subtypes, suggesting
novel avenues for targeted therapeutics. Tumors mutated with each of these genes
tend to be located in different areas of the brain, which can indicate how likely they
are to become malignant. Knowledge of the genomic profi le of the tumors and their
location in the brain make it possible for the fi rst time to develop personalized medi-
cal therapies for meningiomas, which currently are managed only surgically.
Future Prospects of Personalized Therapy of Malignant Gliomas
There has already been considerable progress in our understanding of what drives
neoplastic growth in glial tumors. Further molecular characterization of these
tumors in the future will accelerate biomarker discovery and facilitate the creation
of new diagnostic categories for gliomas. Only isocitrate dehydrogenase mutation
status (prognostic) and O6-methlyguanine methyl transferase methylation status
Personalized Management of Cancers of Various Organs