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Recently, novel somatic mutations in the promoter region of TERT have been identified in malignant melanomas. Subsequently two mutually exclusive cytidine-to-thymidine mutations, C228T and C250T, were also found in 55% of adult gliomas [31]. Such molecular alterations are present in all types of tumors with particular high incidence among OD/AOD harboring combined IDH1/IDH2 mutations and 1p/19q co-deletion (98% of cases) and in IDH wild-type GBM (83–92% of cases), but they are relatively rare in DA (5–19% of cases, nearly exclusively carrying 1p/19q co-deletion, i.e., “molecularly” OD) and AA (2–25% of cases) [12, 13, 31, 32, 36]. It is the most frequent molecular abnormality of pGBM, which is more common in older patients [36].

Activating mutation of TERT promoter results in a 2- to 4-fold increase of its transcriptional activity and mRNA expression, which in turn correlates with telomerase upregulation, thus directly relates to the ability of neoplastic cells to proliferate indefinitely [31, 36]. However, this genetic abnormality may play different roles in the tumorigenesis of OD/AOD and GBM [31]. It is generally identified by Sanger sequencing and pyrosequencing [9, 31, 36].

TERT promoter mutations are mutually exclusive with ATRX loss [12, 31, 32]. Thus their co-existence with 1p/19q co-deletion may be considered the molecular signature of oligodendroglial tumors [13], but the mechanism behind the strong association of these genetic events, as well as the chronological order between them, is currently unclear [31]. In IDH wild-type GBM TERT promoter mutations are frequently associated with HD of CDKN2A, EGFR amplification, and LOH of chromosome 10q, but are independent of alterations of TP53, CDK4 (cyclin-dependent kinase 4; located at 12q14), MDM2, and MGMT promoter methylation [31, 36]. TERT promoter mutation is likely to precede EGFR amplification (since almost all tumors harboring EGFR amplification also have TERT promotion mutation while many TERT promoter mutations occur without EGFR amplification), but the chronological order relative to alteration of CDKN2A is unknown [31].

In mixed cohorts of WHO grade II and III gliomas the presence of TERT promoter mutation did not impact prognosis, but was associated with less favorable outcome in the subgroup of 1p/19q non-codeleted neoplasms [9]. In contrast, in pGBM TERT promoter mutation was defined as an independent factor negatively influencing both PFS and overall survival, which might even eliminate the positive prognostic impact of IDH1/IDH2 mutations [36]. However, the effect may be somewhat opposite in the subgroup of tumors carrying EGFR amplification [36].