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Pediatric Oncology
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Stephen Lowis, Rachel Cox, John Moppett, Helen Rees
Alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene mutations in glioma are seen typically in young adults, and associate with other mutations including of IDH1 and TP53, but are mutually exclusive of 1p/19q-codeletion. ATRX loss is associated with a better prognosis within the group of IDH-mutant tumors.208
Oligoastrocytoma
Published in Dongyou Liu, Tumors and Cancers, 2017
Oligoastrocytoma that is classified by molecular diagnostic tests as astrocytoma is IDH mutant, alpha thalassemia mental retardation syndrome X linked (ATRX) mutant, and 1p/19q intact as well as TP53 mutant; that classified by molecular diagnostic tests as oligodendroglioma is IDH mutant, ATRX wild type, and 1p/19q codeleted. The presence of genetic mutations (e.g., deletions of chromosomes 1p and 19q and other changes) may lead to the production of unusual amounts of growth factors and gene proteins. This excess not only stimulates the aggressive growth of astrocytic and oligodendroglial cell populations to form tumor masses (which in turn may cause swelling or edema around the tumor and disrupt the normal function of these tissues through pressure and concussion) but also alters the functions of cells located elsewhere [6].
Neuroendocrine tumors of the gastrointestinal tract
Published in Demetrius Pertsemlidis, William B. Inabnet III, Michel Gagner, Endocrine Surgery, 2017
Bernard Khoo, Tricia Tan, Stephen R. Bloom
Mutations in menin therefore appear to cause the dysregulation of multiple cellular pathways, but the ultimate pathogenic links between menin and pancreatic NET tumorigenesis are still obscure. The key importance of menin in the pathogenesis of sporadic pancreatic NETs is reinforced by studies that show that 44% of 68 pancreatic NETs samples were shown to have mutations in MEN1, as opposed to none of the pancreatic adenocarcinoma samples. The same study showed that other key pathways were mutated in sporadic pancreatic NETs. DAXX (death-domain associated protein) and ATRX (alpha-thalassemia/mental retardation syndrome X-linked) mutations have been found to occur, collectively, in 43% of pancreatic NETs and none of pancreatic adenocarcinomas [8]. Mutations in both DAXX and ATRX appear to activate the so-called “alternative lengthening of telomeres” (ALT) pathway, which would be expected to immortalize cells. Indeed, 61% of sporadic pancreatic NETs show signs of ALT activity [9]. Notably, patients with pancreatic NETs that possessed mutations in MEN1, DAXX, or ATRX had prolonged survival compared with those patients whose pancreatic NETs did not possess these mutations. MEN1, DAXX, and ATRX mutations may therefore specify a class of pancreatic NETs with a relatively good prognosis; however, the robustness of this concept is yet to be tested prospectively.
ATRX immunohistochemistry can help refine ‘not elsewhere classified’ categorisation for grade II/III gliomas
Published in British Journal of Neurosurgery, 2019
C. Burford, R. Laxton, Z. Sidhu, M. Aizpurua, A. King, I. Bodi, K. Ashkan, S. Al-Sarraj
Following this protocol, tumours that are IDH-mutant but not 1p/19q codeleted, with a morphology resembling an oligodendroglioma, would be designated as ‘Diffuse glioma, IDH-mutant, NEC’. However, there is increasing evidence that tumours that are not 1p/19q codeleted have mutations in the alpha-thalassemia/mental retardation syndrome X-linked (ATRX) gene11–13 and this is associated with a less favourable prognosis, regardless of histology.11,14 Indeed, Reuss and colleagues (2015) have even suggested that ATRX immunohistochemistry could be used in place of fluorescence in situ hybridization (FISH) for 1p/19q co-deletion to produce a more rapid tumour diagnosis within 48 hours of tissue sampling15 and the second cIMPACT-NOW update16 now recommends tissue which shows IDH1/2 mutation and ATRX loss need not be further analysed for co-deletion status.
Coexistence of TERT C228T mutation and MALAT1 dysregulation in primary glioblastoma: new prognostic and therapeutic targets
Published in Neurological Research, 2021
Secil Ak Aksoy, Melis Mutlu, Berrin Tunca, Hasan Kocaeli, Mevlut Ozgur Taskapilioglu, Ahmet Bekar, Cagla Tekin, Omer Gokay Argadal, Muhammet Nafi Civan, İsmail Seckin Kaya, Pınar Eser Ocak, Sahsine Tolunay
GBs are classified as per their clinical and molecular formation as follows: primary GBs that arise de novo and secondary GBs that arise from low-grade glioma [7]. Although different genetic changes are detected in the primary and secondary groups, Isocitrate dehydrogenase 1 and 2 (IDH1/2), alpha thalassemia/mental retardation syndrome X-linked (ATRX), and telomerase reverse transcriptase (TERT) are frequently used to differentiate these tumors [8,9]. Changes in IDH, TERT, and ATRX are associated not only with specific histological subgrouping but also with variable prognosis [9,10]. In this context, it investigates the prognostic and predictive roles of these genes, and it is predicted that they can guide the clinical treatment of glioma patients. However, to our knowledge, no study has analyzed the changes in IDH, TERT, and ATRX/DAXX and their relationship with prognosis with respect to the classification of adult and pediatric primary GB patients. In addition to this classification, there is no information about the molecular etiology and identification of non-coding RNAs in genetic subtypes of primary pediatric and adult GB. Long non-coding RNAs (LncRNAs) are groups of transcripts that are longer than 200 nucleotides and do not have protein coding potential; however, they regulate gene expression through direct interactions with DNA, proteins, and other RNAs [11]. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a cancer-supportive LncRNA found on chromosome 11q13 and in non-small cell lung cancer that promotes brain metastasis [12]. Recent studies suggest that MALAT1 can be used as both a prognostic marker and a therapeutic target in GB [13,14]. Our research team previously found that the MALAT1 expression was upregulated significantly in these patients in a study on 75 adult primary GB patients. Further, high MALAT1 expression is an unfavorable prognostic factor for overall survival in IDH wild-type primary GB tumors [15].
Potential of IDH mutations as immunotherapeutic targets in gliomas: a review and meta-analysis
Published in Expert Opinion on Therapeutic Targets, 2021
Nazareno Gonzalez, Antonela S. Asad, José Gómez Escalante, Jorge A. Peña Agudelo, Alejandro J. Nicola Candia, Matías García Fallit, Adriana Seilicovich, Marianela Candolfi
In 2016, the WHO typification combined the histopathological features with the genetic lesions to classify gliomas [4], introducing the concept of layered diagnosis [32]. While Grade II diffuse gliomas were tumors with nuclear atypia, with focal or dispersed anaplasia, Grade III gliomas showed more celullarity and cytologic pleomorphism, as well as mitotic figures. Grade IV diffuse gliomas and glioblastomas (GBM) additionally showed microvascular proliferation and/or pseudopalizading necrosis. According to that classification, a subset of these tumors were defined based on the status of IDH mutation and 1p/19q codeletion (Table 1). Oligodendrogliomas were characterized by the presence of mIDH and 1p/19q deletion. Non-codeleted Grade II–III gliomas that exhibited tumor suppressor protein 53 (TP53) inactivation and loss-of-function mutations of the ATRX (alpha thalassemia/mental retardation syndrome X-linked) gene showed an astrocytic phenotype. These Astrocytomas can harbor mutated (80%) or wild-type (20%) IDH [33–35]. These alterations were also present in those GBM that were considered to be originated from Low Grade Glioma (LGG, secondary GBM), which represented 10% of GBM [9,18]. This classification has recently changed and the 2021 WHO classification of tumors of the CNS [36] gives a central role to the mutation status of IDH and uses Arabic numerals instead of Roman numerals to identify histological grades (Table 1). Diffuse gliomas with mIDH can exhibit 1p/19q codeletion or combination of p53 mutation with ATRX loss, which are mutually exclusive and identify Oligodendrogliomas and Astrocytomas, all of which can be graded 2 or 3 (Table 1). Grade 4 Astrocytomas, which were previously considered secondary GBM, also exhibit CDKN2A/B homozygous deletion and are associated with a much lower survival than lower grade Astrocytomas. In fact, the presence of CDKN2A/B deletion categorizes these tumors as grade 4 Astrocytomas even in the absence of microvascular proliferation or necrosis. On the other hand, wtIDH gliomas comprise diffuse gliomas displaying histological features of GBM, such as necrosis and microvascular proliferation, as well as wtIDH diffuse gliomas that do not show these histological features but exhibit TERT promoter mutation, EFGR amplification or +7/-10 copy number changes [36]. Please note that the latter tumors were previously classified as grade II–III wtIDH Astrocytomas in the former 2016 WHO Classification of CNS tumors [5]. Thus, in order to identify wtIDH gliomas that exhibited a different histopathology than traditional grade 4 GBM and considering that we have used this characteristic to stratify these two entities, we are now naming these tumors ‘wtIDH gliomas with grade 2–3 histopathology (wtIDH 2–3)’ throughout the manuscript and analyzed them as a separate entity.