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| EDITORIAL |
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| Year : 2015 | Volume
: 63
| Issue : 4 | Page : 491-492 |
Meningiomas decoded: Looking beyond microsurgery
Suresh Nair, BJ Sudhir
Department of Neurosurgery, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India
| Date of Web Publication | 4-Aug-2015 |
Correspondence Address:
Suresh Nair
Department of Neurosurgery, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0028-3886.161985
How to cite this article:
Nair S, Sudhir B J. Meningiomas decoded: Looking beyond microsurgery. Neurol India 2015;63:491-2 |
Despite significant advancements in neurosurgical techniques and knowledge of pathogenesis of meningiomas, the treatment of meningiomas continues to stagnate with surgery, radiotherapy, and radiosurgery. These modalities have a potentially curative role in the majority of meningiomas, whereas a small subset of atypical and anaplastic meningiomas unleash an aggressive saga of refractoriness to treatment and recurrences. With chemotherapy and hormonal therapy regimes failing to brew hope in treating atypical and anaplastic meningiomas, the focus has shifted to potential molecular targets for treatment. Future therapies could be tailor-made to the genetic signature of meningiomas. Research-based permutations and combinations, assumptions, and deductions have etched the genetic map of atypical and anaplastic meningiomas.
A plethora of genetic loci have been investigated in the research on atypical and anaplastic meningiomas. Up to 78% of sporadic meningiomas and all NF2-associated meningiomas have allelic losses at 22q12.2. [1] Merlin, the NF2 gene-encoded protein, is a tumor suppressor and plays a crucial role in regulating cell growth and proliferation. Investigations into the Merlin protein led to exploration of the role of other proteins of similar homology and function in the protein 4.1 band, in meningiomas. [1] Protein 4.1B encoded by the 18p11.3 locus gene, the EPB41 L3 or DAL1 is a regulator of cell proliferation and apoptosis. Protein 4.1B is considered to be a tumor suppressor and has been implicated in meningioma pathogenesis. However, the role of protein 4.1B/DAL1 in the genesis of meningiomas is yet to be resolved. Loss of expression of tumor suppressor in lung cancer-1, a factor that binds with protein 4.1B, has been found in high-grade meningiomas and portends a dismal prognosis. [2]
While aberrations in 22q and protein 4.1 family are responsible for the genesis of meningiomas, the driving factor behind progression of meningiomas to higher grades is obscure, but accumulation of chromosomal losses and gains has been suspected to offer a growth advantage. [3] Losses on 1p, 10q, 14q, 6q, and 18q, and gains on 1q, 9q, 12q, 15q, 17q, and 20q have been identified in atypical and anaplastic meningiomas, respectively. Choy et al. also report that more frequent losses of 6q, 10q, 14q, and 9p and amplification on 17q23 have been noted in anaplastic meningiomas. [1] Loss of chromosome 1p, the second most common chromosomal aberration identified in meningiomas, is more frequent in high-grade meningiomas. Candidate gene targets including CDKN2C, RAD54 L, EPB41, GADD45A, and ALPL have been extensively investigated, but a cause-effect relationship has failed to emerge. [1] Liu et al. reported that rather than loss of specific genetic loci on 1p, epigenetic silencing via abnormal hypermethylation of TP73 at 1p26.32 could be the catalyst for progression of meningiomas. [4] Candidate genes on chromosome 14 include the N-Myc downstream-regulated gene 2 (NDRG2) and maternally expressed gene 3 (MEG3). [5],[6] NDRG2 is a potential biomarker for aggressiveness of meningiomas; hypermethylation of the promoter locus has been identified to downregulate the expression of this tumor suppressor gene. Aggressive meningiomas have been found to have a loss of expression of MEG3, allelic loss, or promoter hypermethylation. Co-deletion of 1p and 14q is frequent in anaplastic meningiomas and is known to be associated with a poor prognosis. Kumar et al. reported 30% incidence of 1p/14q co-deletion in grade III convexity meningiomas and 20% of sub-totally resected petroclival meningiomas. [7]
Mutation of the human telomerase reverses transcriptase reactivates telomerase activity and sustains cell division and is found in up to 92% of atypical and 100% of anaplastic meningiomas. [1],[2],[8] New mutations such as the TRAF7, AKT1, KLF4, and SMO continue to be discovered in atypical and anaplastic meningiomas, as more research groups focus their attention on the genetics of meningiomas. [2] The role of these genes in tumor progression to higher grades is yet to be fully ascertained. These chromosomal aberrations induce tumor progression to higher grades through signaling pathways. Thus, a deep understanding of the signaling pathways and how the mutations work their way to tumor progression is the key to the development of novel gene therapeutic agents against high-grade meningiomas.
Sadashiva et al. have released a key paper in the realm of meningioma genetics in an Indian cohort. They have studied allelic loss of four crucial gene loci using fluorescence in situ hybridization technique. The NF2 gene as the initiator of tumorigenesis and accumulation of mutations leading to progression of meningiomas to higher grades has been clearly demonstrated. On the basis of their study, the authors have revisited the 1p/14q co-deletion status and have found a statistically significant correlation between a high mitotic index and an aggressive behavior. It is interesting to understand that the authors have not found any association between survival and deletion status. We are curious to query whether the extent of resection/Simpson grade of excision of the tumors had a role in survival in the shadow of meningioma genetics. Perhaps, the authors would advance their research with a larger cohort and include this key parameter in analysis and unlock the genetics-survival question. It is encouraging to see pioneering steps taken by Indian research groups to unfold the genetic mystery of meningiomas. It is time to look beyond the microscope, explore beyond the boundaries, and treat beyond the realms of our current understanding of aggressive meningiomas.
| » References | |  |
| 1. | Choy W, Kim W, Nagasawa D, Stramotas S, Yew A, Gopen Q, et al. The molecular genetics and tumor pathogenesis of meningiomas and the future directions of meningioma treatments. Neurosurg Focus 2011;30:E6.  |
| 2. | Shibuya M. Pathology and molecular genetics of meningioma: Recent advances. Neurol Med Chir (Tokyo) 2015;55:14-27. [ PUBMED] |
| 3. | Asirvatham JR, Pai R, Chacko G, Nehru AG, John J, Chacko AG, et al. Molecular characteristics of meningiomas in a cohort of Indian patients: Loss of heterozygosity analysis of chromosomes 22, 17, 14 and 10. Neurol India 2013;61:138-43. [ PUBMED]  |
| 4. | Liu Y, Pang JC, Dong S, Mao B, Poon WS, Ng HK. Aberrant CpG island hypermethylation profile is associated with atypical and anaplastic meningiomas. Hum Pathol 2005;36:416-25. |
| 5. | Lusis E, Gutmann DH. Meningioma: An update. Curr Opin Neurol 2004;17:687-92. |
| 6. | Zhang X, Gejman R, Mahta A, Zhong Y, Rice KA, Zhou Y, et al. Maternally expressed gene 3, an imprinted noncoding RNA gene, is associated with meningioma pathogenesis and progression. Cancer Res 2010;70:2350-8. |
| 7. | Kumar S, Kakkar A, Suri V, Kumar A, Bhagat U, Sharma MC, et al. Evaluation of 1p and 14q status, MIB-1 labeling index and progesterone receptor immunoexpression in meningiomas: Adjuncts to histopathological grading and predictors of aggressive behavior. Neurol India 2014;62:376-82. [ PUBMED] |
| 8. | Goutagny S, Nault JC, Mallet M, Henin D, Rossi JZ, Kalamarides M. High incidence of activating TERT promoter mutations in meningiomas undergoing malignant progression. Brain Pathol 2014;24:184-9. |
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