Comprehensive assessment of ATRX mutation, protein expression, and alternative lengthening of telomeres (ALT) phenotype in grade II and III gliomas.

Authors

Aline Becker

Aline P. Becker

The Ohio State University, Columbus, OH

Aline P. Becker , Erica Hlavin Bell , Jessica Fleming , Joseph P McElroy , Denise Fabian , Sasha Beyer , Andrea L Salavaggione , Mindy K Graham , Christopher M Heaphy , Oliver Oehlke , Ori Staszewski , Marco Prinz , Anca Grosu , Arnab Chakravarti

Organizations

The Ohio State University, Columbus, OH, Johns Hopkins University School of Medicine, Baltimore, MD, Radiation Oncology Department, University of Freiburg, Freiburg, Germany, University of Freiburg, Freiburg, Germany, Department of Neuropathology, University of Freiburg, Freiburg, Germany, German Cancer Research Center (DKFZ), Heidelberg, Germany and German Cancer Consortium (DKTK) partner site Freiburg, Freiburg, Germany

Research Funding

Other Foundation

Background: ATRX mutations are key molecular markers for classification of gliomas. We aimed to evaluate ATRXmutations and protein expression and the ALT phenotype as potential biomarkers for grade II and III gliomas. Methods: Retrospective analysis of 156 adult gliomas, with long-term follow up. Gene sequencing (IDH1/2 and ATRX), Oncoscan array (1p19q co-deletion), FISH assays (1p19q co-deletion and ALT phenotype) and immunohistochemistry (IDH1 R132H and ATRX) were performed and the results were correlated with OS and PFS. Results: Twenty-six out of 94 samples (27.7%) had ATRX mutations, commonly related to IDH1/2 mutant-1p/19q intact tumors (22/26 cases – p < 0.0001), however, 3 (11.5%) mutant tumors had concurrent 1p/19q co-deletions. ATRX loss of expression occurred in 66/150 cases (44%), consistently related to ATRX mutations (p < 0.0001). Intriguingly, 4/25 ATRX mutant tumors (2 frameshift and 2 point mutations with low/medium functional impact) showed weak/heterogeneous expression, while 18/65 (27.7%) ATRX wild type tumors had loss of protein expression. ALT phenotype was detected in 50/150 cases (33.3%), strongly related to ATRX mutations (23/32 cases), loss of protein expression (45/50 cases), and to IDH1/2 mutant-1p/19q intact tumors (35/41 cases). Two ATRX mutant tumors were ALT negative, while nine ATRX wild type tumors with loss of expression had ALT phenotype. ATRXmutations, loss of protein expression, and ALT phenotype were strongly related to longer OS in grade III gliomas (p = 0.006, 0.023 and 0.003, respectively). Further subset analyses were not completed due to small sample sizes. Conclusions:ATRX mutations and loss of protein expression as well as ALT phenotype are potential prognostic factors for grade III gliomas. Importantly, this study highlights possible discrepancies (although infrequent) between ATRX sequencing, immunohistochemistry, and FISH (ALT). In addition, other mechanisms of ATRX gene silencing should be further investigated in grade II and III gliomas. FUNDING: R01CA108633, R01CA169368, RC2CA148190, U10CA180850-01 (NCI), Brain Tumor Funders Collaborative Grant, and The Ohio State University CCC (all to AC).

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Abstract Details

Meeting

2017 ASCO Annual Meeting

Session Type

Poster Session

Session Title

Central Nervous System Tumors

Track

Central Nervous System Tumors

Sub Track

Central Nervous System Tumors

Citation

J Clin Oncol 35, 2017 (suppl; abstr 2064)

DOI

10.1200/JCO.2017.35.15_suppl.2064

Abstract #

2064

Poster Bd #

306

Abstract Disclosures

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