The alternative lengthening of telomere phenotype is significantly associated with loss of ATRX expression in high-grade pediatric and adult astrocytomas: a multi-institutional study of 214 astrocytomas

Abstract

Loss-of-function of alpha thalassemia/mental retardation syndrome X-linked (ATRX) protein leads to a phenotype called alternative lengthening of telomeres (ALT) in some tumors. High-grade astrocytomas comprise a heterogeneous group of central nervous system tumors. We examined a large cohort of adult (91) and pediatric (n=88) high-grade astrocytomas as well as lower grade forms (n=35) for immunohistochemical loss of ATRX protein expression and the presence of ALT using telomere-specific fluorescence in situ hybridization, with further correlation to other known genetic alterations. We found that in pediatric high-grade astrocytomas, 29.6% of tumors were positive for ALT and 24.5% were immunonegative for the ATRX protein, these two alterations being highly associated with one another (P<0.0001). In adult high-grade astrocytomas, 26.4% of tumors were similarly positive for ALT, including 80% of ATRX protein immunonegative cases (P<0.0001). Similar frequencies were found in 11 adult low-grade astrocytomas, whereas all 24 pilocytic astrocytomas were negative for ALT. We did not find any significant correlations between isocitrate dehydrogenase status and either ALT positivity or ATRX protein expression in our adult high-grade astrocytomas. In both cohorts, however, the ALT positive high-grade astrocytomas showed more frequent amplification of the platelet-derived growth factor receptor alpha gene (PDGFRA; 45% and 50%, respectively) than the ALT negative counterparts (18% and 26%; P=0.03 for each). In summary, our data show that the ALT and ATRX protein alterations are common in both pediatric and adult high-grade astrocytomas, often with associated PDGFRA gene amplification.

Figure 1

Representative ALT-positive pancreatic neuroendocrine tumors control. (a) Telomere-specific FISH of this tumor shows the ALT-positive phenotype (large, ultrabright telomere FISH signals (red)). (b) Immunolabeling of pancreatic neuroendocrine tumors shows intact nuclear ATRX protein in neoplastic cells. (c) Immunolabeling of the same pancreatic neuroendocrine tumors in panel a shows loss of nuclear ATRX protein in neoplastic cells.

Figure 2

Representative ALT-positive, ATRX-immunonegative glioblastomas. (a) Example of an ALT-positive glioblastoma (large, ultrabright telomere FISH signals (red)). (b) Immunolabeling of the same glioblastoma in panel a shows loss of nuclear ATRX protein in neoplastic cells. (c) Example of an ALT-negative glioblastoma. (d) Immunolabeling of the same glioblastoma in panel c shows intact nuclear ATRX protein in neoplastic cells.