Frequent alternative lengthening of telomeres and ATRX loss in adult NF1-associated diffuse and high-grade astrocytomas

Rodríguez, Fausto J.; Vizcaíno, M. Adelita; Blakeley, Jaishri O.; Heaphy, Christopher M.

doi:10.1007/s00401-016-1619-0

Cited by 23 publications

(26 citation statements)

References 7 publications

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“…The potential importance of telomere maintenance in PXA is further supported by the identification of a loss of function mutation in ATRX in a tumor without TERT alterations. Previously, two cases with ATRX deletion and one case with activation of the alternative lengthening of telomeres pathway in combination with ATRX protein mislocalization have been reported in anaplastic PXA . Additional studies are needed to investigate the prognostic role for TERT and ATRX alterations in PXA and their potential role in anaplastic progression.…”

Section: Discussionmentioning

confidence: 99%

The genetic landscape of anaplastic pleomorphic xanthoastrocytoma

et al. 2018

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Pleomorphic xanthoastrocytoma (PXA) is an astrocytic neoplasm that is typically well circumscribed and can have a relatively favorable prognosis. Tumor progression to anaplastic PXA (WHO grade III), however, is associated with a more aggressive biologic behavior and worse prognosis. The factors that drive anaplastic progression are largely unknown. We performed comprehensive genomic profiling on a set of twenty-three PXAs from 19 patients, including 15 with anaplastic PXA. Four patients had tumor tissue from multiple recurrences, including two with anaplastic progression. We find that PXAs are genetically defined by the combination of CDKN2A biallelic inactivation and RAF alterations that were present in all 19 cases, most commonly as CDKN2A homozygous deletion and BRAF p.V600E mutation but also occasionally BRAF or RAF1 fusions or other rearrangements. The third most commonly altered gene in anaplastic PXA was TERT, with 47% (7/15) harboring TERT alterations, either gene amplification (n=2) or promoter hotspot mutation (n=5). In tumor pairs analyzed before and after anaplastic progression, two had increased copy number alterations and one had TERT promoter mutation at recurrence. Less commonly altered genes included TP53, BCOR, BCORL1, ARID1A, ATRX, PTEN, and BCL6. All PXA in this cohort were IDH and histone H3 Accepted ArticleThis article is protected by copyright. All rights reserved.wildtype, and did not contain alterations in EGFR. Genetic profiling performed on six regions from the same tumor identified intratumoral genomic heterogeneity, likely reflecting clonal evolution during tumor progression. Overall, anaplastic PXA is characterized by the combination of CDKN2A biallelic inactivation and oncogenic RAF kinase signaling as well as a relatively small number of additional genetic alterations, with the most common being TERT amplification or promoter mutation. These data define a distinct molecular profile for PXA and suggest additional genetic alterations, including TERT, may be associated with anaplastic progression.

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Section: Discussionmentioning

confidence: 99%

The genetic landscape of anaplastic pleomorphic xanthoastrocytoma

et al. 2018

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“…Upon anaplastic transformation, only three cases showed additional genetic alterations well‐characterized in other CNS tumors, including the case described above with SMARCB1 loss and two recurrent tumors with focal deletion of ATRX . To our knowledge, activation of the alternative lengthening of telomeres pathway has been reported in a single A‐PXA without loss of ATRX expression and deletion (vs. mutation) is an uncommon mechanism of ATRX inactivation.…”

Section: Discussionmentioning

confidence: 99%

Recurrent copy number alterations in low‐grade and anaplastic pleomorphic xanthoastrocytoma with and without BRAF V600E mutation

et al. 2017

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Pleomorphic xanthoastrocytoma (PXA) is a rare localized glioma characterized by frequent BRAF V600E mutation and CDKN2A/B deletion. We explored the association of copy-number variants (CNVs) with BRAF mutations, tumor grade, and patient survival in a cohort of 41 PXA patients using OncoScan chromosomal microarray. Primary resection specimens were available in 38 cases, including 24 PXA and 14 anaplastic PXA (A-PXA), 23 BRAF V600E mutant tumors (61%). CNVs were identified in all cases and most frequently involved chromosome 9 with homozygous CDKN2A/B deletion (n = 33, 87%), a higher proportion than previously detected by comparative genomic hybridization (50%-60%) (37). CDKN2A/B deletion was present in similar proportion of PXA (83%), A-PXA (93%), BRAF V600E (87%), and wild-type (87%) tumors. Whole chromosome gains/losses were frequent, including gains +7 (n = 15), +2 (n = 11), +5 (n = 10), +21 (n = 10), +20 (n = 9), +12 (n = 8), +15 (n = 8), and losses -22 (n = 11), -14 (n = 7), -13 (n = 5). Losses and copy-neutral loss of heterozygosity were significantly more common in A-PXA, involving chromosomes 22 (P = 0.009) and 14 (P = 0.03). Amplification of 8p and 12q was identified in a single tumor. Histologic grade was a robust predictor of overall survival (P = 0.003), while other copy-number changes, including CDKN2A/B deletion, did not show significant association with survival. Distinct histologic patterns of anaplasia included increased mitotic activity in an otherwise classic PXA or associated with small cell, fibrillary, or epithelioid morphology, with loss of SMARCB1 expression in one case. In 10 cases, matched specimens were compared, including A-PXA with areas of distinct low- and high-grade morphology (n = 2), matched primary/tumor recurrence (n = 7), or both (n = 1). Copy-number changes on recurrence/anaplastic transformation were complex and highly variable, from nearly identical profiles to numerous copy-number changes. Overall, we confirm CDKN2A/B deletion as key a feature of PXA not associated with tumor grade or BRAF mutation, but central to the underlying genetics of PXA.

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“…At variance, NBLs showing telomere elongation by this mechanism (50%) are characterized by unfavourable prognosis and resistance to chemotherapy [ 342 ]. Regarding ATRX status, high-grade astrocytomas have been reported with concomitant ALT phenotype and ATRX loss, in both adult and paediatric tumours [ 295 , 296 , 298 , 337 ]. Such findings point towards a central role of ATRX in ALT in CNS tumours [ 337 ].…”

Section: Telomere Maintenance Mechanismsmentioning

confidence: 99%

Telomere Maintenance Mechanisms in Cancer

Gaspar

Sá

Lopes

et al. 2018

Genes

135

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Tumour cells can adopt telomere maintenance mechanisms (TMMs) to avoid telomere shortening, an inevitable process due to successive cell divisions. In most tumour cells, telomere length (TL) is maintained by reactivation of telomerase, while a small part acquires immortality through the telomerase-independent alternative lengthening of telomeres (ALT) mechanism. In the last years, a great amount of data was generated, and different TMMs were reported and explained in detail, benefiting from genome-scale studies of major importance. In this review, we address seven different TMMs in tumour cells: mutations of the TERT promoter (TERTp), amplification of the genes TERT and TERC, polymorphic variants of the TERT gene and of its promoter, rearrangements of the TERT gene, epigenetic changes, ALT, and non-defined TMM (NDTMM). We gathered information from over fifty thousand patients reported in 288 papers in the last years. This wide data collection enabled us to portray, by organ/system and histotypes, the prevalence of TERTp mutations, TERT and TERC amplifications, and ALT in human tumours. Based on this information, we discuss the putative future clinical impact of the aforementioned mechanisms on the malignant transformation process in different setups, and provide insights for screening, prognosis, and patient management stratification.

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Frequent alternative lengthening of telomeres and ATRX loss in adult NF1-associated diffuse and high-grade astrocytomas

Cited by 23 publications

References 7 publications

The genetic landscape of anaplastic pleomorphic xanthoastrocytoma

The genetic landscape of anaplastic pleomorphic xanthoastrocytoma

Recurrent copy number alterations in low‐grade and anaplastic pleomorphic xanthoastrocytoma with and without BRAF V600E mutation

Telomere Maintenance Mechanisms in Cancer

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