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
Malak AbedalthagafiJoanna J. PhillipsGrace KimSabine MuellerDaphne A Haas-KogenRoxanne MarshallSidney CroulMariarita SantiJing ChengShengmei ZhouLisa SullivanMaria Martinez‐LageAlexander R. JudkinsArie Perry
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The WHO 2016 classification of diffuse gliomas combines histological and molecular parameters for diagnosis. However, in view of cost constraints for molecular testing, an economical working formula is essential to reach a meaningful diagnosis in a resource-limited setting. The aim of this study was to establish a practical algorithmic approach using histology and immunohistochemistry (IHC) in the classification of diffuse gliomas in such a set-up.Diffuse gliomas of WHO grade II and III diagnosed in our institute in the year 2016 were analysed for histological and IHC features, using the markers isocitrate dehydrogenase 1 (IDH1R132H) and α thalassemia/mental retardation syndrome X-linked gene (ATRX). Fluorescence in situ hybridisation (FISH) for 1p/19q co-deletion was performed when requested.449 diffuse gliomas (grades II/III) were included in the study. Integrating histology and IHC features, as per the WHO 2016 guidelines, we derived the following groups: Astrocytoma, IDH-mutant (A,IDH-mt, 37.2%); astrocytoma, not otherwise specified (A,NOS, 12.7%); oligoastrocytoma, NOS (OA,NOS, 4.5%); and oligodendroglioma, NOS (ODG,NOS, 45.6%). FISH was performed in a subset of ODG,NOS, OA,NOS and A,NOS gliomas. This revealed 1p/19q co-deletion in all cases of ODG,NOS, 15.8% of OA,NOS and 37.5% of A,NOS. Sequencing for rare IDH 1/2 mutations was not carried out in this study.In a resource-limited set-up, histology with IHC (IDH1(R132H) and ATRX) form the baseline to reasonably derive four histomolecular subgroups of diffuse glioma. Of these, we recommend, OA,NOS and IDH1(R132H)-non-mt ODG,NOS to be our priority for performing 1p/19q co-deletion studies in comparison to IDH-mt ODG,NOS, and it would not be mandatory for astrocytoma. Sequencing for rare IDH mutations is advised for A,NOS and OA,NOS groups, but not for the IDH1(R132H)-non-mutant diffuse gliomas with 1p/19q co-deletion.
Histology
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? Objective To disscuss the expression of C met and P 53 protein in human brain astrocytoma and it's relationship with the occurance,develepment and prognosis of tumors.Methods Immunohistochemical staining technique was undertaken to detect antibody of C met and P 53 protein in ninty cases of astrocytoma.Results There were expressions of C met and P 53 in all astrocytomes even in much higher grade ones.Conclusions There's pertinence between the expression of C met and P 53 protein and occurance development in astrocytoma.The immunohistochemical expression of C met and P 53 contributes to the understanding of the functions of C met and P 53 in tumor tissues. 〔
Anaplastic astrocytoma
P53 protein
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Astrocytoma and oligodendroglioma are histologically and genetically well-defined entities. The majority of astrocytomas harbor concurrent TP53 and ATRX mutations while most oligodendrogliomas carry the 1p/19q co-deletion. Both entities share high frequencies of IDH mutations. In contrast, oligoastrocytomas (OA) appear less clearly defined and, therefore, there is an ongoing debate whether these tumors indeed constitute an entity or whether they represent a mixed bag containing both, astrocytomas and oligodendrogliomas. We investigated 43 OA diagnosed in different institutions employing histology, immunohistochemistry and in-situ hybridization addressing the molecular genetic markers IDH1R132H, TP53, ATRX and 1p/19q loss. In all but one OA the combination of nuclear p53 accumulation and ATRX loss was mutually exclusive with 1p/19q co-deletion. In 31/43 OA only alterations typical for oligodendroglioma were observed while in 11/43 OA only indicators typical for astrocytomas were detected. A single case exhibited both, nuclear expression of p53, ATRX loss, IDH1 mutation and 1p/19q loss. However, this was the only patient undergoing radiotherapy prior to surgery, possibly resulting in acquisition of this uncommon combination. In fact, evaluation of the initial lesion demonstrated retained ATRX expression and no p53 upregulation. In OA with oligodendroglioma typical alterations, the portions corresponding to astrocytic part were determined as reactive (harbouring none of the alterations), while in OA with astrocytoma typical alterations the portions corresponding to oligodendroglial differentiation were neoplastic (harbouring identical alterations as the histologically astrocytic part). These data provide strong evidence against the existence of an independent OA entity. (under revision for Acta Neuopathologica)
ATRX
Oligodendroglial Tumor
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Objective
To investigate the role of ATRX and P53 gene mutations in the classification of diffuse glioma in Chinese.
Methods
A total of 89 cases of diffuse astrocytoma (IDH mutation) or diffuse astrocytoma (IDH wild type) and all levels of oligodendroglioma from 2016 to 2017 were collected, and detected the expression of ATRX protein and over expression of P53 protein by immunohistochemistry, and analyzed their expression in different types of diffuse gliomas.
Results
The ratio of ATRX loss expression in diffuse astrocytoma (IDH mutation) (17/24) was higher than that in oligodendrogliomas (3/16), P<0.01; the ratio of P53 over expression in diffuse astrocytoma (IDH mutation) (15/24) was higher than that in oligodendrogliomas (1/16), P<0.01; the ratio of ATRX loss expression in diffuse astrocytoma (IDH mutation) (71%, 17/24) was higher than that in diffuse astrocytoma (IDH wild) (41%, 20/49), P<0.05.
Conclusions
ATRX and P53 mutation is one of the molecular genetic characteristics of diffuse astrocytoma (IDH mutation), which may be contributed to diagnose diffuse astrocytoma.
Key words:
Diffuse glioma; Tumor suppressor protein P53; Alpha thalassemia/mental retardation syndrome-X
ATRX
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Astrocytoma and oligodendroglioma are histologically and genetically well-defined entities. The majority of astrocytomas harbor concurrent TP53 and ATRX mutations while most oligodendrogliomas carry the 1p/19q co-deletion. Both entities share high frequencies of IDH mutations. In contrast, oligoastrocytomas (OA) appear less clearly defined and, therefore, there is an ongoing debate whether these tumors indeed constitute an entity or whether they represent a mixed bag containing both, astrocytomas and oligodendrogliomas. We investigated 43 OAs diagnosed in different institutions employing histology, immunohistochemistry and in-situ hybridization addressing surrogates for the molecular genetic markers IDH1R132H mutation, TP53 mutation, ATRX mutation, and 1p/19q co-deletion. In all but one OA the combination of nuclear p53 accumulation and loss of ATRX expression was mutually exclusive of 1p/19q loss. In 31/43 OA only the alterations typical for oligodendroglioma were observed while in 11/43 OA only indicators for mutations associated with astrocytomas were detected. A single case exhibited both, nuclear expression of p53, loss of ATRX expression, IDH1 mutation and 1p/19q loss in all tumor cells. However, this was the only patient undergoing radiotherapy prior to surgery, possibly resulting in acquisition of this uncommon combination. In 30/31 OA with oligodendroglioma typical alterations the portions corresponding to a morphologically astrocytic part were identified to be reactive (i.e. no mutant IDH protein, no p53, ATRX, or 1p/19q aberrations). The remaining case with oligodendroglioma-typical aberrations presented with identical alterations also in the morphologically astrocytic portions. In all 11 OA with astrocytoma-typical alterations the oligodendroglial differentiated areas were neoplastic but harboured identical aberrations as the astrocytic portions. Thus, in this molecular genetic analysis in-situ, none of the 43 diffuse gliomas previously diagnosed as OA revealed separate co-existing cell populations with astrocytoma- and oligodendroglioma-characteristics in the same tumor, despite intra-tumoral heterogeneity in morphology. These data provide strong evidence against the existence of an independent OA entity.
ATRX
Oligodendroglial Tumor
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ATRX
Oligodendroglial Tumor
Histopathology
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ATRX
Oligodendroglial Tumor
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The appropriate regulation of telomere length homeostasis is crucial for the maintenance of genome integrity. The telomere-binding protein TZAP has been suggested to regulate telomere length by promoting t-circle and c-circle excisions through telomere trimming, yet the molecular mechanisms by which TZAP functions at telomeres are not understood. Using a system based on TZAP overexpression, we show that efficient TZAP recruitment to telomeres occurs in the context of open telomeric chromatin caused by loss of ATRX/DAXX independently of H3.3 deposition. Moreover, our data indicate that TZAP binding to telomeres induces telomere dysfunction and ALT-like activity, resulting in the generation of t-circles and c-circles in a Bloom-Topoisomerase IIIα-RMI1-RMI2 (BTR)-dependent manner.
Death-associated protein 6
ATRX
Telomere-binding protein
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Following the introduction of the molecular classification of gliomas by the WHO in 2016, molecularly-proven lineage conversion during glioma recurrence has never been reported. The reported two cases were initially diagnosed as oligodendroglioma with 1p/19q-codeletion and mutation of isocitrate dehydrogenase 1 (IDH1)-R132H. The recurrent tumors showed loss of alpha-thalassemia/mental retardation X-linked (ATRX) expression, strong P53 positivity, and 1p/19q-nondeletion. Next generation sequencing analysis performed on the first case confirmed the transition of molecular traits from oligodendroglioma to astrocytoma. An IDH mutation of R132H was preserved in the episodes of recurrence, but ATRX and TP53 mutations were newly acquired and TERT promoter mutation C228T was lost at the most recent recurrence. The issue in question for the presented cases is whether the original tumors were pure oligodendrogliomas that then transdifferentiated into astrocytomas, or whether the original tumor was an oligoastrocytoma having oligodendroglioma cells that outnumbered the astrocytoma cells and where the astrocytoma cells becoming more dominant over the episodes of recurrence. With the recognition of the possibility of lineage conversion, our study suggests that molecular examination should be performed to adjust therapeutic strategies in recurrent gliomas. Indeed, our observation of lineage conversion in glioma recurrence calls into question the current distinction drawn between oligodendroglioma, astrocytoma and oligoastrocytoma, rather than simply bidding "farewell to oligoastrocytoma."
ATRX
Isocitrate dehydrogenase
Oligodendroglial Tumor
Lineage (genetic)
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Abstract Introduction The updated 2016 classification of gliomas incorporates well-established molecular parameters into the classification of diffuse gliomas, taking into account isocitrate dehydrogenase 1 (IDH1) mutation, α-thalassemia/mental retardation syndrome X-linked (ATRX) loss, and 1p/19q co-deletion. Aim and Objectives To study IDH1 and ATRX mutations in gliomas, 1p/19q co-deletion by fluorescent in situ hybridization (FISH) in oligodendroglioma, and to correlate IDH1, ATRX, and 1p/19q with tumor type and grade. Material and Methods Total 73 cases of gliomas were diagnosed on histology and graded as astrocytoma (grades 2–4), oligodendroglioma (grades 2–3), and oligoastrocytoma (grades 2–3) by two pathologists independently. IDH mutation and ATRX expression were analyzed using immunohistochemistry in all cases whereas 1p/19q co-deletion was studied using FISH in cases with oligodendroglioma and oligoastrocytoma morphology. Results Total 48 cases of astrocytoma, 9 cases of oligoastrocytoma, and 16 cases of oligodendroglioma were included. The maximum number of IDH1 mutation cases were seen in diffuse astrocytoma (7/10; 70%) as compared with anaplastic astrocytoma (5/15; 33.33%), glioblastoma multiforme (GBM) (3/23; 13.04%) grade II oligoastrocytoma (3/6; 50%), anaplastic oligoastrocytoma (2/3; 66.67%), and oligodendroglioma grade II (7/10; 70%). ATRX loss was seen in diffuse astrocytoma grade II (6/10; 60%), anaplastic astrocytoma (6/15; 40%), oligoastrocytoma grade II (2/6; 33.33%), and anaplastic oligoastrocytoma (1/3; 33.33%). 1p/19q co-deletion was seen in oligoastrocytoma (2/2; 100%), anaplastic oligoastrocytoma (1/2; 50%), oligodendroglioma (3/4; 75%), and anaplastic oligodendroglioma (1/3; 33.33%). Six of the seven cases with 1p/19q co-deletion also showed IDH1 mutation. One of seven 1p/19q co-deleted cases had loss of expression of ATRX. Conclusion Incorporation of IDH1 mutation, ATRX loss, and 1p/19q co-deletion molecular studies help in a more accurate diagnosis and classification of gliomas.
ATRX
Anaplastic astrocytoma
Oligodendroglial Tumor
Isocitrate dehydrogenase
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