Alternative lengthening of telomeres, ATRX loss and H3‐K27M mutations in histologically defined pilocytic astrocytoma with anaplasia

Rodríguez, Fausto J.; Brosnan-Cashman, Jacqueline A.; Allen, Sariah J.; Vizcaíno, M. Adelita; Giannini, Caterina; Camelo-Piragua, Sandra; Webb, Milad; Matsushita, Marcus; Wadhwani, Nitin R.; Tabbarah, Abeer; Hamideh, Dima; Jiang, Liqun; Chen, Liam; Arvanitis, Leonidas; Alnajar, Hussein; Barber, John R.; Rodríguez-Velasco, Alicia; Orr, Brent A.; Heaphy, Christopher M.

doi:10.1111/bpa.12646

Cited by 55 publications

(41 citation statements)

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“…There were no differences as to TERTp or ATRX status between the K27M-mutant pHGG that activated ALT and those that did not, suggesting that other concomitant mutations or factors might contribute to activating ALT in such cases. As expected, cases with ATRX nuclear loss always trigger ALT, regardless of H3F3A status, confirming a strong association with ALT in pHGG [2,9,25,46]. Moreover, our results also demonstrate that H3F3A/ATRX/TERTp-wildtype pHGG never activate mechanisms for telomere elongation (this was seen in none of our 20 cases).…”

Section: Discussionsupporting

confidence: 85%

Alternative lengthening of telomeres in molecular subgroups of paediatric high-grade glioma

et al. 2020

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Purpose The maintenance of telomere length prevents cancer cell senescence and occurs via two mutually exclusive mechanisms: (a) reactivation of telomerase expression and (b) activation of alternative lengthening of telomeres (ALT). ALT is frequently related to alterations on ATRX, a chromatin-remodelling protein. Recent data have identified different molecular subgroups of paediatric high-grade glioma (pHGG) with mutations of H3F3A, TERTp and ATRX; however, differences in telomere length among these molecular subgroups were not thoroughly examined. Methods We investigated which genetic alterations trigger the ALT mechanism in 52 IDH-wildtype, 1p/19q-wildtype pHGG. Samples were analysed for telomere length using Tel-FISH. ATRX nuclear loss of expression was assessed by IHC, H3F3A and TERTp mutations by DNA sequencing, and TERTp methylation by MS-PCR. Results Mutant H3.3 was found in 21 cases (40.3%): 19.2% with K27M mutation and 21.1% with G34R mutation. All H3.3G34R-mutated cases showed the ALT phenotype (100%); on the opposite, only 40% of the H3.3K27M-mutated showed ALT activation. ATRX nuclear loss was seen in 16 cases (30.7%), associated sometimes with the G34R mutation, and never with the K27M mutation. ATRX nuclear loss was always related to telomere elongation. TERTp C250T mutations were rare (5.4%) and were not associated with high intensity Tel-FISH signals, as TERTp hyper-methylation detected in 21% of the cases. H3.3/ATRX/TERTp-wildtype pHGG revealed all basal levels of telomere length. Conclusion Our results show a strong association between H3.3 mutations and ALT, and highlight the different telomeric profiles in histone-defined subgroups: H3.3-G34R mutants always trigger ALT to maintain telomere length, irrespective of ATRX status, whereas only some H3.3-K27M tumours activate ALT. These findings suggest that acquiring the gly34 mutation on H3.3 might suffice to trigger the ALT mechanism.

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Section: Discussionsupporting

confidence: 85%

Alternative lengthening of telomeres in molecular subgroups of paediatric high-grade glioma

et al. 2020

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“…BRAF duplications/fusions were present in 8/26 cases tested, with no BRAF p.V600E mutations identified. Interestingly, H3-K27M was present in 5 of 32 (16%) cases along with ATRX loss and ALT suggesting that A-PAs are heterogeneous neoplasms harboring genetic alterations usually associated with both PA and diffuse gliomas [9]. Loss of ATRX expression in A-PA has been reported by others [10].…”

Section: Pilocytic Astrocytoma With Anaplasia No Who Gradementioning

confidence: 65%

“…Another study focusing on histologically defined pilocytic astrocytoma with anaplasia documented the presence of ATRX and H3-K27M alterations, as well as alternative lengthening of telomeres (ALT), in 57 A-PA resections from 36 patients [9] (Figure 1 C-F). ALT was present in 25 cases and 9 of 11 benign PA precursors.…”

Section: Pilocytic Astrocytoma With Anaplasia No Who Gradementioning

confidence: 99%

Pathologic and molecular aspects of anaplasia in circumscribed gliomas and glioneuronal tumors

2019

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Many breakthroughs have been made in the past decade regarding our knowledge of the biological basis of the diffuse gliomas, the most common primary central nervous system (CNS) tumors. These tumors as a group are aggressive, associated with high mortality and have a predilection for adults. However, a subset of CNS glial and glioneuronal tumors are characterized by a more circumscribed pattern of growth and occur more commonly in children and young adults. They tend to be indolent, but our understanding of anaplastic changes in these tumors continues to improve as diagnostic classifications evolve in the era of molecular pathology and more integrated and easily-accessible clinical databases. The presence of anaplasia in pleomorphic xanthoastrocytomas and gangliogliomas is assigned a WHO grade III under the current classification, while the significance of anaplasia in pilocytic astrocytomas remains controversial. However, recent data highlight the association of the latter with aggressive clinical behavior, as well as the presence of molecular genetic features of both pilocytic and diffuse gliomas, with the recognition that the precise terminology remains to be defined. We review current concepts and advances regarding histopathology and molecular understanding of pilocytic astrocytomas, pleomorphic xanthoastrocytomas and gangliogliomas, with a focus on their anaplastic counterparts.

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“…When focusing on the rare pediatric cases of PAAF (summarized in Table 2), the histomolecular characteristics of our single MC-AAP (patient 27) were in fact not substantially different from the literature, although available detailed histomolecular data were less extensive than for adult MC-AAP [17,21,[26][27][28]. Interestingly, PAAF and/or MC-AAP in children do not share the main characteristics described in their adult counterparts.…”

Section: Discussionmentioning

confidence: 80%

“…The newfound interest in this histomolecular entity raises the question of its relevance in a pediatric setting. Indeed, of the all PAAF cases described in the literature, only 22 cases were pediatric, with or without MAPK alteration [17,20,21,24,27,28] including 6 with DNA methylation profiling [26]. Our study consists of a retrospective analysis of 31 pediatric (< 18 years) PAAF cases defined according to strict histomolecular criteria.…”

Section: Introductionmentioning

confidence: 99%

The histomolecular criteria established for adult anaplastic pilocytic astrocytoma are not applicable to the pediatric population

et al. 2019

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Pilocytic astrocytoma (PA) is the most common pediatric glioma, arising from a single driver MAPK pathway alteration. Classified as a grade I tumor according to the 2016 WHO classification, prognosis is excellent with a 10-year survival rate > 95% after surgery. However, rare cases present with anaplastic features, including an unexpected high mitotic/proliferative index, thus posing a diagnostic and therapeutic challenge. Based on small histomolecular series and case reports, such tumors arising at the time of diagnosis or recurrence have been designated by many names including pilocytic astrocytoma with anaplastic features (PAAF). Recent DNA methylation-profiling studies performed mainly on adult cases have revealed that PAAF exhibit a specific methylation signature, thus constituting a distinct methylation class from typical PA [methylation class anaplastic astrocytoma with piloid features-(MC-AAP)]. However, the diagnostic and prognostic significance of MC-AAP remains to be determined in children. We performed an integrative work on the largest pediatric cohort of PAAF, defined according to strict criteria: morphology compatible with the diagnosis of PA, with or without necrosis, ≥ 4 mitoses for 2.3 mm 2 , and MAPK pathway alteration. We subjected 31 tumors to clinical, imaging, morphological and molecular analyses, including DNA methylation profiling. We identified only one tumor belonging to the MC-AAP (3%), the others exhibiting a methylation profile typical for PA (77%), IDH-wild-type glioblastoma (7%), and diffuse leptomeningeal glioneuronal tumor (3%), while three cases (10%) did not match to a known DNA methylation class. No significant outcome differences were observed between PAAF with necrosis versus no necrosis (p = 0.07), or with 4-6 mitoses versus 7 or more mitoses (p = 0.857). Our findings argue that the diagnostic histomolecular criteria established for anaplasia in adult PA are not of diagnostic or prognostic value in a pediatric setting. Further extensive and comprehensive integrative studies are necessary to accurately define this exceptional entity in children.

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Alternative lengthening of telomeres, ATRX loss and H3‐K27M mutations in histologically defined pilocytic astrocytoma with anaplasia

Cited by 55 publications

References 50 publications

Alternative lengthening of telomeres in molecular subgroups of paediatric high-grade glioma

Alternative lengthening of telomeres in molecular subgroups of paediatric high-grade glioma

Pathologic and molecular aspects of anaplasia in circumscribed gliomas and glioneuronal tumors

The histomolecular criteria established for adult anaplastic pilocytic astrocytoma are not applicable to the pediatric population

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