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| COMMENTARY |
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| Year : 2021 | Volume
: 69
| Issue : 1 | Page : 135-136 |
TERT Promoter Mutations Correlate with IDHs, MGMT and EGFR in Glioblastoma Multiforme
Manendra Singh Tomar, Ashutosh Shrivastava
Center for Advance Research, Faculty of Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India
| Date of Submission | 29-Aug-2020 |
| Date of Decision | 27-Sep-2020 |
| Date of Acceptance | 30-Oct-2020 |
| Date of Web Publication | 24-Feb-2021 |
Correspondence Address:
Ashutosh Shrivastava
Center for Advance Research, Faculty of Medicine, King George's Medical University, Lucknow - 226 003, Uttar Pradesh
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0028-3886.310071
How to cite this article:
Tomar MS, Shrivastava A. TERT Promoter Mutations Correlate with IDHs, MGMT and EGFR in Glioblastoma Multiforme. Neurol India 2021;69:135-6 |
There is a need of accurate molecular markers that could improve understanding about the nature and grades of glioma. In this issue, Epari et al. examined the correlation of Telomerase reverse transcriptase (TERT) promoter mutations in glioblastoma multiforme (GBM) with molecular markers including p53 expression, ATRX protein expression, Isocitrate dehydrogenases (IDHs) mutations, Epidermal growth factor receptor (EGFR) gene amplification and O[6]-Methylguanine-DNA methyltransferase (MGMT) methylation.[1] The investigators included total 155 samples of adult GBMs and illustrated that TERT promoter mutations are mutually exclusive with ATRX loss and IDHs mutations and commonly linked with amplified EGFR. Killela et al. analyzed 1230 samples from various cancers and noted that TERT promoter mutations are predominantly linked to GBM.[2] The high frequency at which TERT promoter mutations are found in GBM led to the idea that this could be of prognostic significance and a potential biomarker.
The diffused glioma has traditionally been characterized using histopathology of tumor sections. The advent of new molecular diagnostic markers was incorporated subsequently resulting in the updated WHO 2016 classification of glioma.[3] Incorporation of clinical histopathology with high end laboratory-based molecular markers basically integrated phenotypic and genomic information. Diffuse oligodendroglial and astrocytic tumors are now differentiated by the detection of IDHs mutations, 1p/19q co-deletions and MGMT promoter methylation.[4] These molecular markers have proven prognostic value and are routinely performed in diagnostic laboratories aiding to precision medicine of GBM. However, there is a need to further stratify this classification within the Glioma grade. A wider molecular analysis of GBM expression profiling of various oncogenic transformations such as EGFR amplification, MGMT promoter methylation, IDHs and ATRX mutation was still needed.[5],[6]
IDHwt/TERT promoter mutation is related to poor long-term survival of GBM patients. IDH mutations are frequently noticed in grade II and grade III glioma but are rare in stage IV glioma or GBM.[7] Patients with both IDHs and TERT promoter mutation have better prognosis then patients who have TERT promoter mutated/IDH-wildtype glioma.[6] About half of the primary GBM (IDHwt) are known to have amplified EGFR. Labussiere et al. studied patients with both EGFR and TERT promoter wild types have better survival compared to EGFR overexpressing GBM, while EGFR amplification with TERT promoter mutations have improved survival.[8] GBM Patients with triple-negative mutations of EGFR, TERT promoter and IDHs have better prognosis. EGFR in combination with TERT promoter shows the prognostic impact in grade II glioma, however not in GBM.[8] GBM with TERT promoter mutation has unmethylated MGMT.[6] Methylated MGMT promoter is a distinct hallmark of tumor sensitivity to Temozolomide, a prominent GBM drug.[6] It is important to note that correlation analysis of MGMT methylation and TERT promoter mutation shows the prognostic impact in grade II or III glioma but not in grade IV glioma.[6]
A retrospective review of ATRX or ALT status revealed that TERT promoter and ATRX mutations are mutually exclusive.[9] Whole-genome sequencing data of 1122 diffused glioma samples and outlined data revealed that ATRX loss but not TERT promoter mutations were related to telomere maintenance.[9] This loss of ATRX activates alternative lengthening of telomere (ALT). Napier et al. demonstrated the addition of ATRX repressed ALT phenotype suggesting that ATRX loss associated with ALT phenotype.[10] But it remains unclear that ATRX loss alone is capable to induce ALT phenotype. Therefore, more studies needed to find the mechanism through which ATRX induce ALT induction.
The correlation studies of TERT mutations with other targeted prognostic markers would help in stratifying the classification of GBMs. It will be remarkably interesting if those patients could be followed up prospectively using TERT promoter mutation, IDHs status and MGMT methylation and this will provide useful information of prognostic significance of this panel for targeted GBM cohort. The full story behind the Impact of TERT promoter mutations in correlation with other molecular markers is not fully known yet. More such studies are needed to clarify their impact on prognosis as well as its role in tumor metastasis alone and in combination with other cancer-causing mutations.
| » References | |  |
| 1. | Barange M, Epari S, Gurav M, Shetty O, Sahay A, Shetty P, et al. TERT Promoter Mutation in adult Glioblastomas: It's Correlation with Other Relevant Molecular Markers. Neurol India 2021;69:171-79.  |
| 2. | Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA, et al.TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci U S A 2013;110:6021-6. |
| 3. | Brito C, Azevedo A, Esteves S, Marques AR, Martins C, Costa I, et al.Clinical insights gained by refining the 2016 WHO classification of diffuse gliomas with: EGFR amplification, TERT mutations, PTEN deletion and MGMT methylation. BMC Cancer 2019;19:968. |
| 4. | Aquilanti E, Miller J, Santagata S, Cahill DP, Brastianos PK.Updates in prognostic markers for gliomas. Neuro Oncol 2018;20(suppl_7):vii17-26. |
| 5. | Ohba S, Kuwahara K, Yamada S, Abe M, Hirose Y.Correlation between IDH, ATRX, and TERT promoter mutations in glioma. Brain Tumor Pathol 2020;37:33-40. |
| 6. | Kim HS, Kwon MJ, Song JH, Kim ES, Kim HY, Min KW.Clinical implications of TERT promoter mutation on IDH mutation and MGMT promoter methylation in diffuse gliomas. Pathol Res Pract 2018;214:881-8. |
| 7. | Eckel-Passow JE, Lachance DH, Molinaro AM, Walsh KM, Decker PA, Sicotte H, et al.Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med 2015;372:2499-508. |
| 8. | Labussière M, Boisselier B, Mokhtari K, Di Stefano AL, Rahimian A, Rossetto M, et al.Combined analysis of TERT, EGFR, and IDH status defines distinct prognostic glioblastoma classes. Neurology 2014;83:1200-6. |
| 9. | Ceccarelli M, Barthel FP, Malta TM, Sabedot TS, Salama SR, Murray BA, et al.Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 2016;164:550-63. |
| 10. | Napier CE, Huschtscha LI, Harvey A, Bower K, Noble JR, Hendrickson EA, et al.ATRX represses alternative lengthening of telomeres. Oncotarget 2015;6:16543-58. |
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