Identification of patient-derived glioblastoma stem cell (GSC) lines with the alternative lengthening of telomeres phenotype | Acta Neuropathologica Communications | Full Text

Identification of patient-derived glioblastoma stem cell (GSC) lines with the alternative lengthening of telomeres phenotype | Acta Neuropathologica Communications | Full Text

Acta Neuropathologica Communications

Identification of patient-derived glioblastoma stem cell (GSC) lines with the alternative lengthening of telomeres phenotype

• Ahsan Farooqi,
• Jie Yang,
• Vladislav Sharin,
• Ravesanker Ezhilarasan,
• Carla Danussi,
• Christian Alvarez,
• Sharvari Dharmaiah,
• David Irvin,
• Jason Huse and
• Erik P. SulmanEmail authorView ORCID ID profile

Acta Neuropathologica Communications20197:76

https://doi.org/10.1186/s40478-019-0732-4

©  The Author(s). 2019

• Received: 13 March 2019
• Accepted: 3 May 2019
• Published: 16 May 2019

Glioblastoma multiforme (GBM) is an aggressive brain tumor with a poor overall prognosis. Current standard of care involves surgical resection followed by adjuvant treatment with radiation (RT), temozolomide, and tumor treating fields (TTF) [13]. Despite this aggressive treatment modality, median overall survival is approximately 15 months. Telomeres are terminal DNA elements found at eukaryotic chromosomal ends consisting of hexagonal repeats of (TTAGGG)nwhich are essential for maintaining genomic stability [1]. To maintain telomere length and circumvent the end-replication problem, most cancer cells express telomerase [8]. Telomerase is composed of two subunits: a catalytic component with reverse-transcriptase activity encoded by the gene TERT, and an 11 base-pair RNA template encoded by the gene TERC [11]. Mutations in the promoter region for TERT occur in approximately 60–80% of GBM, leading to increased telomerase activity and enabling replicative immortality [10]. A defining feature of anaplastic astrocytomas and a small fraction of secondary GBM, is activation of a telomerase-independent alternative lengthening of telomeres (ALT) mechanism, driven by homologous recombination (HR) machinery [7]. ALT tumors can readily be detected by assaying for the presence of extrachromosomal telomeric DNA C-Circles (CCs) via qPCR or ALT-associated telomere foci by FISH on pathological specimens [6]. ALT+ high grade glioma (HGG) are enriched in tumors with loss of function mutations in ATRX (alpha-thalassemia/mental retardation X-linked) and less commonly, SMARCAL1. When these chromatin remodeling genes are inactivated, the resultant replication stress and aberrant HR at telomeres is hypothesized to lead to ALT [2]. Mutations in both ATRX and SMARCAL1 are mutually exclusive with TERT promoter mutations suggesting functional redundancy between these two mechanistic pathways [3, 4].