MOLECULAR ADVANCEMENT IN MENINGIOMA

1. PRESENTER-VIKAS KUMAR DWIVEDI
NEUROSURGERY
SGPGI LUCKNOW
MOLECULAR ADVANCEMENT IN
MENINGIOMA

2. INTRODUCTION
 2-10 cases per 100,000 individuals.
 20% of all primary intracranial neoplasms
 Women affected twice as often as men.
 Incidence increases with age.
 With the most common locations being the
convexity, olfactory groove, tuberculum sellae,
parasagittal, falcine, sphenoid wing, petroclival,
posterior fossa, or spinal

3. RISK FACTORS
 First degree relative.
 NF2 gene – Chromosome 22q12.2
Lower expression in meningioma and loss of Merlin
protein lead to development of benign meningioma.

4. • Exposure to ionizing radiation
Cranial radiation associated with increased risk of
meningioma and other central nervous system
tumors in survivors of childhood cancer.
Computed tomography scans during childhood or
adolescence associated with increased risk of brain
cancer

5. SYNDROMES
1. Hereditary syndromes associated with
meningioma include Li-Fraumeni syndrome –
AD, Sarcoma, breast, leukaemia and adrenal
gland (SBLA) syndrome.
2. Turcot – DNA repair, HNPCC + Brain tumour.
3. Gardener – 5q21
4. Von Hippel-Lindau – 3p25, AD, VHL suppresor
gene
5. Cowden – PTEN tumour suppresor.
6. Gorlin – 9q22 tumour suppressor
7. Multiple endocrine neoplasia type I – pituitary,
parathyroid, and pancreas.

7. HISTOLOGICAL GRADING
WHO grading 2007
1. WHO- 1 meningioma : 80-90%
 Varying rates of progression to higher grade
 7%-20% recurrence rate
 Pathologic features include -Pleomorphic, Occasional
mitotic figures
 Histologic types include - Meningothelial,
Psammomatous, Secretory, Fibroblastic,
Angiomatous, Lymphoplasmacyte rich, Transitional,
Microcytic, Metaplastic

8. 2-WHO 2 atypical meningioma (atypical, clear cell,
chordoid)
• 5-15 %
• 30%-40% recurrence rate
• Pathologic features include any of 4 mitotic figures per 10
high-power fields (a) increased cellularity, (b) small cells
with high N:C ratio, (c) prominent nucleoli, (d) sheet-like
growth, (e) necrosis & brain invasion

9. 3-WHO 3 malignant meningioma (rhabdoid,
anaplastic, papillary) :
 1-3 %
 50%-80% recurrence rate
 pathologic features - 20 mitotic figures per 10
high-power fields or frank anaplastic features

11. PROLIFERATIVE ACTIVITY
 The degree of mitotic activity is an indicator of the
proliferative potential of the tumor.
Immunohistochemical staining of MIB-1/Ki-67 is
often used to estimate the proliferative potential of
the tumor.

12. Genomic Alterations in Meningiomas
A-Copy number alteration
 Loss of chromosome 22 is most common in meningiomagenesis
 The incidence of 22q increases with WHO grade with a 50%
prevalence in WHO grade I tumors and 75–85% prevalence in
WHO grades II and III tumors.
 Deletion of chromosome 1p is the second most common CAN
associated with higher grade tumour.

14.  Others chromosomes 1p, 6q, 10, 14q, and 18q, as
well as gain of chromosomes 1q, 9q, 12q, 15q,
17q, and 20q
 Copy number gains especially polysomy 5 are also
characteristic of angiomatous meningiomas a grade I
subtype.

16. B-Gene Mutation Signature
Devided into two types
A- NF2 type
B-Non NF type

18. NF2 Type
 Focal NF2 mutations are found in 30–50% of sporadic
meningiomas and identified in meningiomas of all 3
histopathological grades.
 NF2 regulate multiple pathways like PI3K/mTORC1/Akt,
cause truncation of the protein due to frameshift, nonsense,
or splice-site mutations producing a nonfunctional protein
product neurofibromin (merlin ).

19.  Have higher proliferative and larger tumour size
 Loss of NF2 also associated with overexpression of focal
adhesion kinase (FAK), resulting in increased cellular
migration and invasion.
 This association with overexpression of FAK may cause
these tumors sensitive to FAK inhibitors, which is currently
under investigation in a clinical trial (NCT02523014)

20. Non NF
 TRAF7 –most common and located on 16p13
 AKT1 mutations occur in 10% of sporadic meningiomas.
 TRAF7,AKT1, and KLF4 mutations are almost exclusively
observed in WHO grade I meningiomas
 Secretory meningiomas associated with TRAF7 and
KLF4K409Q mutations.
 Meningiomas with AKT1E17K mutation have meningothelial
and transitional histopathological morphology.

21.  TRAF7, AKT1, and KLF4 mutations more commonly
located in anterior and middle fossa skull base
meningiomas.
 Mutations in Smoothened (SMO) and suppressor of fused
homolog (SUFU) genes observed in WHO grade I
meningiomas and occur in the anterior midline skull base.
 Vismodegib, a competitive antagonist of the SMO receptor,
is currently ongoing (NCT02523014).

22.  POLR2A-mutant meningiomas are associated wirh WHO
grade I tumors that are most likely to be found in anterior
skull base (tuberculum sellae) tumors and tend to harbor a
meningothelial histopathological morphology.
 Loss-of-function in core subunit of the SWI/SNF complex,
SMARCE1 are a molecular signature of the clear-cell
subtype of meningiomas.

23.  Mutations in SWI/SNF complex genes are observed at
higher frequency in anaplastic meningiomas with grades I
and II meningiomas and hence are associated with poor
prognoses.
 BAP1 gene have been identified in a rare subset of
aggressive meningiomas with rhabdoid morphology.
 Vatalinib (PTK787/ZK22584) a tyrosine kinase
inhibitor of VEGFR1 to VEGFR3 was used in
meningiomas of all grades.

26.  In meningiomas, there has been recent recognition of the
role of mutations in the telomerase reverse transcriptase
(TERT) promoter.
 TERT promoter mutations –
Most common mutations in all human cancers
Potential biomarker for meningiomas with aggressive
behavior that exhibit higher rates of recurrence and shorter
time to progression.

27. EPIGENOMIC ALTERATIONS IN MENINGIOMA
 DNA Methylation
 Global DNA hypomethylation and focal DNA
hypermethylation are associated with tumorigenesis
 DNA methylation in meningiomas are tissue inhibitor of
metalloproteinase 3 (TIMP3), cyclin-dependent kinase
inhibitor 2A (CDKN2A), and tumor protein 73 (TP73).

28.  TIMP3- higher-grade meningiomas with a
frequency of 40–60% in grade III tumors and
shorter time to recurrence.

29. Micro-RNA
 miRNA-145 expression is markedly decreased in higher-
grade tumors
 Overexpress miRNA-109a and underexpress miRNA-29c-
3p and miR-219-5p are associated with higher recurrence
rates in meningiomas.

30. Transcriptomic Signatures in
Meningioma
 Microarray gene expression analysis
 Increased transglutaminase 2 (TGM2) expression has
been described in higher-grade meningioma.

31. PROTEOMIC SIGNATURES IN
MENINGIOMAS
 Used gel electrophoresis combined with mass
spectrometry
 Identified 15 proteins expressed between benign and
atypical tumors and 9 proteins expressed between
atypical and malignant tumors.

32.  In grade II and III meningiomas that progress after
surgery and standard radiation, checkpoint
blockade with nivolumab is under trial
(NCT02648997).

33. APPROACHES
 Surgery is the first line of therapy for symptomatic meningiomas.
 Extent of resection is the most significant factor in determining the
chance of recurrence.
 For Grade II patients undergoing gross total resection, the clinical
benefit of fractionated radiation therapy vs. observation is still unclear
(Clinical Trial NCT03180268).
 Gross total resection is not possible (independent of tumor grade) or
surgery is contraindicated, either SRS of FRT or systemic adjuvant
chemotherapy or both are used to improve outcomes.

35. REFERENCES
 Abedalthagafi M, Bi WL, Aizer AA, Merrill PH,
Brewster R, Agarwalla PK, et al. Oncogenic PI3K
mutations are as common as AKT1 and SMO
mutations in meningioma. Neuro Oncol (2016)
18(5):649–55. doi:10.1093/neuonc/nov316
 Bi WL, Abedalthagafi M, Horowitz P, Agarwalla PK,
Mei Y, Aizer AA, et al. Genomic landscape of
intracranial meningiomas. J Neurosurg (2016).
doi:10.3171/2015.6.JNS15591
 Rizvi NA, Hellmann MD, Snyder A, Kvistborg P,
Makarov V, Havel JJ, et al. Cancer immunology.
Mutational landscape determines sensitivity to PD-1
blockade in non-small cell lung
cancer. Science (2015) 348(6230):124–8.
doi:10.1126/science.aaa1348

36. THANK YOU