Читать книгу Intracranial Gliomas Part II - Adjuvant Therapy - Группа авторов - Страница 26

Mutations of ATRXare frequently noted in WHO grade II and III astrocytomas (45–71% of cases), tumors with mixed oligoastrocytic morphology (27–68% of cases), and sGBM (57% of cases), but they are rarely encountered in pGBM and practically never seen in OD/AOD [7, 12, 14, 25]. Diffusely infiltrating gliomas of any WHO grade occurring in young adults are more likely to harbor this genetic abnormality [7, 25].

The encoding protein ATRX forms a complex with DAXX and mediates incorporation of histone H3.3 in the pericentromeric heterochromatin and the telomere [14]. Inactivating mutations or deletions of ATRX or DAXX are associated with the ALT (alternative lengthening of telomerase) phenotype of gliomas, thus may be involved in mechanisms of telomerase upregulation and maintenance of telomere length [7, 14, 25, 31]. ATRX status can be distinctively assessed with IHC, and loss of ATRX expression in the nuclei of all neoplastic cells with retained staining in the nuclei of endothelial cells, neurons, microglia, lymphocytes and reactive astrocytes (served as an internal positive control) is tightly associated with the presence of mutation [7, 12]. Moreover, ATRX immunonegativity may be occasionally revealed even in cases with negative sequencing, but it is still considered a marker of this molecular alteration [7]. Occasionally, ATRX staining may be limited to specific tissue areas, but it is not truly heterogeneous [12].

ATRX loss is tightly associated with IDH1/IDH2 mutations, and has been identified in 65–97% of IDH1/IDH2-mutant astrocytomas [12, 25]. Similarly, its concordance with TP53 mutations occurs in 70–94% of cases, whereas wild-type TP53tumors demonstrating ATRX loss are uncommon [7, 13, 32, 54]. There is no association between ATRX loss and MGMT promoter methylation [25]. Importantly, ATRX mutations are nearly mutually exclusive with 1p/19q co-deletion, thus their identification may be helpful in the typing of diffusely infiltrating gliomas and in supporting the diagnosis of astrocytic tumors [7, 12–14, 17, 25, 55]. Although the prognostic and predictive values of ATRX loss need further investigation, it has been suggested that AA with co-mutations of IDH1/IDH2 and ATRX may carry a relatively better prognosis [14, 25].