Читать книгу Intracranial Gliomas Part II - Adjuvant Therapy - Группа авторов - Страница 34

Malignant progression of LGG in adults varied in different series with a wide range from 11 to 74% [48, 73–75]. Astrocytic neoplasms carry greater risk of this unfavorable event [73, 74]. Analysis of the North Central Cancer Treatment Group (NCCTG) database revealed that at the time of recurrence 45% of OD, 70% of oligoastrocytomas, and 74% of DA are transformed into higher grade tumors (p = 0.031) [74]. In contrast, malignant progression of pediatric LGG was noted in only 2.9% of cases, while in comparison with adults such changes were relatively more frequent in PA, PXA, and gangliogliomas [39].

Genomic analysis of secondary HGG both in adults and children revealed common alterations of the p53 pathway [39]. In 1994 Lang et al. [49] suggested that inactivation of TP53 is an early event in astrocytoma progression, and that low-grade tumors with this molecular abnormality have a greater probability for acquiring further genetic aberrations leading to their malignant transformation. It has also been reported that LGG carrying IDH1/IDH2 mutations, especially those with additional MGMT promoter methylation and TP53 mutation, have a 3–5 times greater hazard and shorter period to development of malignant transformation [8, 48]. However, it may reflect an association of IDH1/IDH2 mutations with prolonged survival of patients, thus allowing them more time at risk for tumor progression. Of interest, in cases of malignant transformation of LGG with IDH1/IDH2 mutation, secondary HGG are diagnosed 3.5 times more often as WHO grade III than as WHO grade IV (in IDH wild-type tumors this ratio is 1.2) and are associated with relatively longer survival of patients, which may reflect a more benign clinical course even at the time of progression [48]. Thus, such early founding molecular event as IDH1/IDH2 mutation does not seem to drive malignant transformation [13, 48].

While inactivation of p53 plays an important role in malignant progression of low-grade astrocytomas, it is certainly not the sole determining factor. There are multiple pathways for development of HGG [49]. Loss of other tumor suppressor genes, such as PTEN and RB1, and amplification of MDM2 may each contribute to progression of wild-type TP53 neoplasms [51]. Alterations of the p16/CDK4/pRb signaling pathway are particularly common in secondary HGG, thus development of these tumors might be strongly related to the inactivation of CDKN2A[39]. Amplifications of PDGFRA and the proto-oncogene MET(mesenchymal-epithelial transition factor; located at 7q31) also play an important role. The former may be specifically important for transformation of IDH1/IDH2-mutant AA into GBM [35]. On the other hand, progression of OD into AOD may be associated with mutations of PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha; located at 3q26.32) and PIK3R1 (phosphoinositide-3-kinase, regulatory subunit 1; located at 5q13.1) [13].

A high proportion of pediatric LGG that later undergo malignant transformation, display strong immunopositivity to p53 and deletions of CDKN2A[39]. These molecular alterations are extremely uncommon in tumors that do not progress to high-grade, and suggest early ablation of the cell cycle control. Moreover, 80% of neoplasms in matched samples demonstrate increases of p53 immunopositivity during progression from LGG to HGG. In children malignant progression of gliomas is more common in the presence of BRAF^V600E mutations. However, this predisposition may be related to greater time at risk, since such tumors have a significantly longer latency period to malignant transformation and are associated with better 5-year survival rates in comparison to neoplasms with wild-type BRAF.

Of note, some genetic abnormalities revealed at the time of malignant progression may be unrelated to the natural development of the tumor, but may be induced by the previous therapy.