title: 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.
authors.affiliation: 1] Division of Neuropathology, Department of Pathology, University of California, San Francisco, San Francisco, CA, USA [2] Division of Surgical Pathology, Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Malak
authors.initials: M
authors.lastname: Abedalthagafi
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Phillips
authors.forename: Grace E
authors.initials: GE
authors.lastname: Kim
authors.forename: Sabine
authors.initials: S
authors.lastname: Mueller
authors.forename: Daphne A
authors.initials: DA
authors.lastname: Haas-Kogen
authors.forename: Roxanne E
authors.initials: RE
authors.lastname: Marshall
authors.forename: Sidney E
authors.initials: SE
authors.lastname: Croul
authors.forename: Mariarita R
authors.initials: MR
authors.lastname: Santi
authors.forename: Jing
authors.initials: J
authors.lastname: Cheng
authors.forename: Shengmei
authors.initials: S
authors.lastname: Zhou
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Sullivan
authors.forename: Maria
authors.initials: M
authors.lastname: Martinez-Lage
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Judkins
authors.forename: Arie
authors.initials: A
authors.lastname: Perry
mesh_terms: D000328:Adult; D000367:Age Factors; D001254:Astrocytoma / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics*; D001932:Brain Neoplasms / Q000737:chemistry* / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D002648:Child; D004265:DNA Helicases / Q000032:analysis*; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007521:Isocitrate Dehydrogenase / Q000032:analysis / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008297:Male; D009154:Mutation; D060787:Neoplasm Grading; D009656:North America; D009687:Nuclear Proteins / Q000032:analysis*; D016016:Proportional Hazards Models; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D012307:Risk Factors; D016615:Telomere / Q000235:genetics*; D059505:Telomere Homeostasis; D013997:Time Factors; D016896:Treatment Outcome; D000075924:X-linked Nuclear Protein
chemical_list: D014408:Biomarkers, Tumor; D009687:Nuclear Proteins; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D020796:Receptor, Platelet-Derived Growth Factor alpha; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein