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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 3  |  Issue : 4  |  Page : 168-174

Diagnostic and prognostic implications of molecular status in Chinese adults with diffuse glioma: An observational study


1 Department of Pathology, Xuanwu Hospital, Capital Medical University, Beijing, China
2 Department of Neurobiology, Xuanwu Hospital, Capital Medical University; Key Laboratory for Neurodegenerative Diseases, Ministry of Education, Beijing Geriatric Medical Research Centre, Beijing, China

Date of Submission03-Aug-2020
Date of Decision18-Sep-2020
Date of Acceptance30-Sep-2020
Date of Web Publication1-Feb-2021

Correspondence Address:
Dr. Yueshan Piao
45 Changchun Street, Xicheng District, Beijing 100053
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/glioma.glioma_21_20

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  Abstract 


Background and Aim: Mutations in isocitrate dehydrogenase (IDH), co-deletion of 1p and 19q, loss or expression of the transcription regulator ATRX, and mutations in telomerase reverse transcriptase (TERT) gene promoters are intimately linked with diffuse gliomas. We further explored the roles of the key molecules in adulthood diffuse gliomas and their prognosis. Materials and Methods: A total of 413 patients who underwent primary surgery between 2009 and 2015 at Xuanwu Hospital, Beijing, China, were included in this observational study. All specimens from the patients were fixed in 10% neutral buffered formalin and embedded in paraffin. The mutational status of IDH1/2 and the TERT promoter was determined using polymerase chain reaction-based direct sequencing. The assay for the 1p and 19q co-deletion was conducted using fluorescence in situ hybridization. Overall- and progression-free survival was calculated using the Kaplan–Meier method and the log-rank test. The study was approved by the Ethics Committee of Xuanwu Hospital, Capital Medical University, China (approval No. [2019]004) on May 22, 2019. Results: We found that tumors characterized by multiple lesions were predominantly free of IDH mutations (P < 0.001). Gliomas with IDH mutations arose more often in the frontal and insular lobes than in the other lobes (P < 0.001). Rates of IDH mutations were higher in patients who had seizures or were without discomfort than in those who had other clinical symptoms (P = 0.0003). Of 119 patients with complete molecular information according to the 2016 World Health Organization classification of central nervous system tumors, 5 had oligoastrocytomas that had multiple genotypes – IDH1 mutation, loss of ATRX expression, and 1p/19q co-deletion – but lacked TERT promoter mutations. Patients with seizures or without discomfort who had IDH mutations had better outcomes than did other patients (P < 0.001). Patients whose tumors had IDH and TERT promoter mutations had a better prognosis than did other patients (P < 0.001). Among patients whose tumors had wild-type IDH, those with loss of ATRX survived longer than did others (P = 0.005). Conclusions: The status of both ATRX and the TERT promoter can indicate the prognosis in patients with IDH wild-type gliomas. The diagnosis that is based on clinical symptoms, histologic findings, and molecular analysis should be implemented as the diagnostic standard for patients with oligoastrocytomas.

Keywords: 1p/19q co-deletion, ATRX, glioma, isocitrate dehydrogenase, telomerase reverse transcriptase gene


How to cite this article:
Wang L, Li Z, Liu C, Zhang L, Wang D, Ge H, Xu W, Fu Y, Cai Y, Lu D, Piao Y. Diagnostic and prognostic implications of molecular status in Chinese adults with diffuse glioma: An observational study. Glioma 2020;3:168-74

How to cite this URL:
Wang L, Li Z, Liu C, Zhang L, Wang D, Ge H, Xu W, Fu Y, Cai Y, Lu D, Piao Y. Diagnostic and prognostic implications of molecular status in Chinese adults with diffuse glioma: An observational study. Glioma [serial online] 2020 [cited 2022 Dec 8];3:168-74. Available from: http://www.jglioma.com/text.asp?2020/3/4/168/308484




  Introduction Top


The classification of diffuse gliomas was based on histopathological features for more than a century.[1],[2] Many molecular markers have been discovered in diffuse gliomas, some of which are related to the prognosis of patients with glioma.[3] Therefore, they have been incorporated into the 2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System.[2],[4] Mutations involving isocitrate dehydrogenase (IDH; either IDH1 or IDH2) are closely associated with diffuse gliomas.[5] These mutations occur during the early stage of tumor development, before the loss of expression of the transcription regulator ATRX, and co-deletion of 1p and 19q. Patients who had tumors with mutations involving IDH were shown to have a better prognosis than did patients who had tumors without such mutations.[6] The 1p/19q co-deletion, caused by a nonbalanced t(1:19)(q10:p10) translocation with subsequent loss of one of the derivative chromosomes, occurs in many oligodendrogliomas.[1] Loss of ATRX expression occurs in cells with alternative lengthening of telomeres (ALT),[7] which rely on homologous recombination to maintain chromosome ends.[7] Recent studies have shown that loss of ATRX expression occurs in pilocytic astrocytoma with anaplastic features.[8],[9] In addition to the ALT pathway, the telomerase pathway itself is activated in some cancer cells through mutations in the telomerase reverse transcriptase gene (TERT) promoter, mostly C228T and C250T.[10] For example, TERT promoter mutations have been discovered in oligodendrogliomas and glioblastomas.[11] According to the 2016 WHO classification, most WHO Grades II and III astrocytic tumors exhibit ATRX loss and TP53 mutations, whereas WHO Grades II and III oligodendrogliomas exhibit 1p/19q co-deletion. However, the data have also implied that in rare cases of oligoastrocytomas, no specific molecular pattern has been found.

In this study, we evaluated the prognostic value of key molecular changes, including IDH mutations, 1p/19q co-deletion, loss of ATRX expression, and TERT promoter mutations in 413 adults with gliomas. We also investigated the clinical, histological, and molecular genetic correlations.


  Materials and Methods Top


Materials

A total of 413 patients, including 239 males and 174 females, who underwent primary surgery between 2009 and 2015 at Xuanwu Hospital, Beijing, China, were included in this observational study. The eligible criteria were as follows: (1) specimens must be pathologically diagnosed as diffuse gliomas (Grades II–IV) according to the 2016 WHO central nervous system tumor classification;[2] (2) the patient was older than 18 years; and (3) the pathology library had complete and adequate paraffin specimens. Samples were excluded if tissues were of poor quality and if they were classified as WHO Grade I glioma and H3K27M mutant diffuse midline gliomas. Their median age at surgery was 48 years. The histological diagnoses were 26 astrocytomas, 20 anaplastic astrocytomas, 62 oligodendrogliomas, 45 anaplastic oligodendrogliomas, 55 oligoastrocytomas, 27 anaplastic oligoastrocytomas, and 178 glioblastomas. These gliomas were also classified into groups according to some molecular alterations, such as those with IDH mutation, 1p/19q co-deletion TERT promoter mutations, and loss of ATRX expression. The signed informed consent was obtained from each patient. The study was approved by the Ethics Committee of Xuanwu Hospital, Capital Medical University (approval No. (2019)004) on May 22, 2019 and was conducted in full compliance with all principles of the Declaration of Helsinki.

Immunohistochemical studies

All specimens were fixed in 10% neutral buffered formalin and embedded in paraffin. Sections were immunostained with a commercially available antibodies reactive against ATRX (rabbit polyclonal antibody, dilution 1:400; HPA001906; Sigma-Aldrich, Darmstadt, Germany) and p53 (mouse monoclonal antibody, 1:500; DO7, Cell Signaling Technology, USA) as described previously.[12],[13] Only specimens that demonstrated nuclear staining were considered for evaluation. Cases with more than 10% positive tumor cells were scored positive. To evaluate ATRX, nontumor cells of the patients, including endothelial cells, cortical neurons, and infiltrating inflammatory cells, were used as internal positive controls.[14]

Molecular testing

The mutational status of IDH1, IDH2, and the TERT promoter was determined with Sanger sequencing.[15] DNA was extracted from formalin-fixed, paraffin-embedded specimens. Primers and polymerase chain reaction (PCR) conditions used for IDH1 (R132 codon), IDH2 (R172 codon), and the TERT promoter were the same as a previous study.[15] The assay for the 1p/19q co-deletion was conducted with fluorescence in situ hybridization according to the manufacturer's instructions and as previously reported.[15]

Statistical analysis

Statistical analysis was performed with SPSS 16.0 (SPSS, Chicago, IL, USA). Student's t-test was used to assess the median age of the patients with and without ATRX loss, IDH mutations, 1p/19q co-deletion, and TERT promoter mutations. Fisher's exact test and the Chi-square test were used to test associations or differences among ATRX loss, IDH1/2 mutations, 1p/19q co-deletion, and TERT promoter mutations. Overall survival and progression-free survival, calculated as the time between surgery and either death or the last follow-up visit, were compared among groups through the use of the Kaplan–Meier method and the log-rank test.


  Results Top


Clinical characteristics

We investigated the relationships among the patients' ages, tumor locations, clinical histories and outcomes, histological classifications, and molecular alterations. [Table 1] provides an overview of all glioma samples subjected to various analyses according to IDH mutations.
Table 1: Clinical characteristics of the sample set according to isocitrate dehydrogenase mutation, loss of ATRX expression, and 1p/19q co-deletion status

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Molecular alterations and integrated diagnosis

IDH gene mutations were present in 183 of the 413 tumors; 174 had IDH1 mutations and 9 had IDH2 mutations. Patients whose initial symptoms were seizures or who had no discomfort had a higher rate of IDH mutations than did those in whom the initial symptoms were headaches; changes in mental status, motor function, and movement; or sensory and visual changes [P < 0.001; Table 1].

To investigate the relationship between molecular markers and tumor location, we classified the glioma locations into four categories: gliomas with IDH mutations in multiple regions, gliomas without IDH mutations in multiple regions, gliomas in a single lobe with IDH mutations (frontal, temporal, parietal, occipital, or insular lobe or midline structures), and gliomas in a single lobe without IDH mutations. The gliomas identified showed mutation-specific patterns of tumor location in the central nervous system. Tumors in multiple regions were predominantly without IDH mutations [P = 0.001; Table 1]. Furthermore, gliomas with IDH mutations arose more often in the frontal and insular lobes than in the temporal, occipital, and parietal lobes [P < 0.0001; Table 1].

Loss of ATRX expression was observed in 97 (23.49%) of all 413 diffuse gliomas analyzed. This was observed frequently in astrocytomas: 11 (42.31%) of 26 diffuse astrocytomas, 24 (43.64%) of 55 oligoastrocytomas, 10 (50.00%) of 20 anaplastic astrocytomas, and 13 (48.15%) of 27 anaplastic oligoastrocytomas. However, it was observed infrequently in other gliomas: 24 (13.48%) of 178 glioblastomas, 10 (16.13%) of 62 oligodendrogliomas, and 5 (11.11%) of 45 anaplastic oligodendrogliomas. Among the tumors showing loss of ATRX expression, 71 (57.69%) harbored concomitant IDH mutations (P < 0.0001). Of the other 26, 15 (57.69%) had been diagnosed as glioblastomas according to their structure.

Data from 13 tumors were lost as a result of PCR failure. Of the remaining 400, 225 exhibited TERT promoter mutations; of these, 159 (70.67%) had a C228T mutation and 66 (29.33%) had a C250T mutation. TERT promoter mutations were significantly more frequent in the 170 glioblastomas (105 [61.76%]) and the 105 oligodendroglial tumors, including oligodendrogliomas and anaplastic oligodendrogliomas (76 [72.38%]; P < 0.0001). At the same time, TERT promoter mutations were significantly correlated with IDH mutations in oligodendrogliomas but inversely correlated with IDH mutations in glioblastomas. Furthermore, most tumors had either TERT promoter mutations or loss of ATRX expression, but not both; only 5 tumors displayed both loss of ATRX immunoreactivity and TERT promoter mutations. Of the 5 tumors without IDH mutations, 3 (60%) were diagnosed as glioblastomas. Glioblastomas seemed to be more common among the 124 gliomas without IDH mutations, with TERT promoter mutations, and without a loss of ATRX expression (99 [79.84%]) than among the 77 “triple wild-type” gliomas (no IDH mutation, presence of ATRX expression, and no TERT promoter mutations; 43 [55.84%], P < 0.0001).

A total of 119 tumors were categorized according to the 2016 WHO classification; 27 were astrocytomas with IDH mutations (Grades II and III); 16 were astrocytomas with no IDH mutations; 53 were oligodendrogliomas with IDH mutation and 1p/19q co-deletion (Grades II and III); 2 were glioblastomas with IDH mutations; and 10 were glioblastomas with no IDH mutations. Of these 119 tumors [Figure 1], 68 (57.14%) had the 1p/19q co-deletion. Loss of ATRX expression showed a significant inverse correlation with 1p/19q co-deletion (P < 0.0001). However, 5 morphologically oligoastrocytoma-like tumors had both loss of ATRX expression and 1p/19q co-deletion, which we termed an “oligoastrocytoma dual-genotype” [Figure 2].[16] All 5 lacked TERT promoter mutations, and 3 of 5 overexpressed p53.
Figure 1: Morphological and integrated diagnosis of Chinese adult diffuse gliomas

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Figure 2: The diagnosis of dual-genotype oligoastrocytoma. (A) Hematoxylin and eosin staining showed the morphological features of oligoastrocytoma-like tumors. (B) Immunohistochemical staining showed ATRX loss of expression in tumor cells. (C and D) Fluorescence in situ hybridization showed 1p/19q co-deletion in the tumor . Original magnifications: 200× in A and B, 1000×in C and D

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Prognostic analysis of gliomas according to molecular classification

Of the 413 patients, 164 (39.71%) had tumor recurrence and 130 (31.48%) were deceased at the time of analysis. The results of Kaplan–Meier survival analysis are shown in [Figure 3].
Figure 3: Prognostic analysis of gliomas according to molecular classification. (A) The Kaplan–Meier curves clearly showed different prognoses among the three groups. (B and C) The OS and PFS of IDH mutant-patients with different clinical symptoms. (D and E) The OS and PFS based on IDH mutations and TERT promoter mutations. (F and G) The OS and PFS based on TERT promoter mutations and loss of ATRX expression in IDH wild-type groups. IDH: Isocitrate dehydrogenase, OS: Overall survival, PFS: Progression-free survival, TERT: Telomerase reverse transcriptase gene

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We also investigated the prognostic implications of the molecular classification in Grades II and III gliomas. These gliomas were classified into three groups: those with IDH mutation and 1p/19q co-deletion (n = 53); those with IDH mutation but no 1p/19q co-deletion (n = 27); and those with neither IDH mutation nor 1p/19q co-deletion (n = 16). The Kaplan–Meier curves clearly showed different prognosis among the three groups: Group A had the best prognosis, followed by Groups B and C [P = 0.045; [Figure 3]A].

We investigated the overall survival and progression-free survival of patients with different clinical histories. Of the patients who had seizures or were without discomfort, the 72 with IDH mutations survived substantially longer survival than did the 50 without IDH mutations [P < 0.0001; [Figure 3]B], and of the patients whose initial symptoms were headaches, changes in mental status, motor or movement changes, or sensory and visual changes, the 81 who had IDH mutations survived longer than did the 152 without IDH mutations [P < 0.0001; [Figure 3]C].

Kaplan–Meier curves based on IDH mutations and TERT promoter mutations, which included diffuse gliomas with mutations in both IDH and TERT promoters (n = 98), mutations in IDH but not in TERT promoters (n = 82), mutations in TERT promoters but not in IDH (n = 127), and mutations in neither IDH nor TERT promoters (n = 100), demonstrated significant differences in prognosis, whereby the prognosis was best in patients with both types of mutations, followed by those with only IDH mutations. The patients with only TERT promoter mutations had the worst prognosis (IDH mutation/TERT mutation vs. IDH mutation/TERT wildtype vs. IDH wildtype/TERT mutation. Overall survival: P < 0.0001, [Figure 3]D; progression-free survival: P < 0.0001, [Figure 3]E).

More than half the tumors (15 [57.69%]) that showed loss of ATRX expression but had IDH mutations were diagnosed as glioblastomas on the basis of structure. Because more than 10% of gliomas without IDH mutations lost ATRX expression, we compared the survival of patients without IDH mutations according to loss or retention of ATRX expression. Kaplan–Meier curves did not show a statistically significant difference between the two groups; however, they did demonstrate significant differences in prognosis when we classified gliomas without IDH mutations into three groups according to the presence or absence of TERT promoter mutations and loss of ATRX expression. The 124 patients whose gliomas had IDH-wildtype/TERT-mut/ATRX intact had substantially shorter survival than did those whose gliomas had no IDH or TERT mutations, regardless of whether ATRX expression was intact (n = 77) or lost (n = 23); the latter group had the best prognosis [overall survival: P = 0.003, [Figure 3]F; progression-free survival: P = 0.001, [Figure 3]G].


  Discussion Top


Approximately 85% of cancers depend on abnormal activation of the telomerase pathway and consequently, have TERT promoter mutations.[17],[18] The results of our study of these mutations in diffuse gliomas showed that TERT promoter mutations were frequent in glioblastomas (61.76%) and oligodendrogliomas (72.38%). This finding corroborated other findings that TERT promoter mutations are present in these types of tumors.[19],[20] Moreover, we provide evidence that TERT promoter mutations had completely opposite influences on clinical outcomes, depending on IDH mutation status: patients with oligodendroglial tumors with IDH-mut and TERT-mut had a better prognosis than did those whose tumors had IDH-mut/TERT-wildtype. In contrast, patients with tumors that had TERT-mut/IDH-wildtype, most of which were diagnosed as glioblastomas, had a poorer prognosis than patients whose tumors had IDH-mut/TERT-wildtype.[21],[22]

In addition, we confirmed a strong association of the loss of ATRX expression with IDH mutations in astrocytomas. ATRX protein is frequently absent in cancer cells that depend on the ALT pathway to maintain telomere length,[23] even without obvious changes in the ATRX gene.[7],[24],[25] We found the loss of ATRX expression in 23.73% of diffuse gliomas in our adult patients. Alterations in ATRX expression significantly overlapped with mutations of IDH1 and IDH2. This molecular feature seemed to be specific for the Grades II and III astrocytic lineage, but it did not occur in oligodendrogliomas or glioblastomas. Our data suggested that astrocytomas with alterations in ATRX expression rely on the ALT mechanism. Numerous studies have shown that such alterations arise after IDH mutations;[26] however, we found several tumors with alterations in ATRX expression, but without concomitant IDH mutations, half of which were glioblastomas (without H3K27M mutations). Unfortunately, survival did not differ significantly between the two groups of gliomas without IDH mutations. We found that patients with such gliomas that had no TERT mutations but did have alterations in ATRX expression had the best prognosis, whereas those with gliomas that had normal ATRX expression with TERT promoter mutations had the worst prognosis; thus, lack of IDH mutations may be a further evaluative prognostic marker, such as EGFR amplification, combined whole chromosome 7 gain, and whole chromosome 10 loss in glioma.[27],[28]

IDH mutations, 1p/19q co-deletion, and loss of ATRX expression were recognized as definitive diagnostic molecular markers of diffuse gliomas in the 2016 WHO classification. Moreover, the association of the loss of ATRX expression with 1p/19q co-deletion has been studied widely.[14],[29] Loss of ATRX expression (a marker of astrocytoma) and 1p/19q co-deletion (a marker of oligodendroglioma) were found to be mutually exclusive; however, we found five tumors diagnosed as oligoastrocytoma on the basis of structure that also had IDH1 mutations but did not have TERT promoter mutations, which suggested that there exist true “oligoastrocytomas” with molecular features of both astrocytomas and oligodendrogliomas and that this subtype is rare. These five cases proved that these two elements shared the same tumor stem cell that relied on the ALT mechanism and had IDH1 mutations during the early stage of glioma development.[26] Unfortunately, there are some limitations in our study. The survival rate of patients with “oligoastrocytomas” could not be analyzed separately because the numbers of patients with either alteration were too small, the disease course in these patients was favorable, and the study period was too brief to cover the full trajectory of disease progression. Moreover, recent studies have found that homozygous deletion of CDKN2A/B in IDH mutant gliomas, EGFR amplification, and combined whole chromosome 7 gain and whole chromosome 10 loss in IDH wildtype gliomas are also associated with the prognosis of glioma patients.[27],[28] We did not detect these molecular changes to further determine more biomarkers on prognosis.

Nowadays, clinicians increasingly rely on the genetic classification to guide clinical decision-making. Our data showed that of patients whose gliomas had IDH mutations, those who had headaches, changes in mental status, changes in motor function and movement, or sensory and visual changes had shorter overall survival and progression-free survival than did those who had seizures or had no discomfort. In addition, our findings suggested that gliomas in the frontal and insular lobes had a higher incidence of IDH mutations, whereas tumors with multiple lesions predominantly lacked IDH mutations.


  Conclusions Top


A molecular classification based on the presence or absence of IDH mutations, loss of ATRX expression, TERT promoter mutations, and 1p/19q co-deletion enables a molecular diagnosis of oligoastrocytoma. Astrocytomas and oligodendrogliomas have mutually exclusive pathways for overcoming replicative senescence. At the same time, the status of ATRX expression combined with TERT promoter status can be indicative of the prognosis of patients who have gliomas without IDH mutations. A system based on clinical symptoms, histological features, and molecular analysis should become the standard diagnostic tool for this group of patients. Further follow-ups and histological studies are needed to elucidate the effects of molecular signatures on the outcomes of true “oligoastrocytomas.” [29]

Acknowledgment

We are thankful to Dr. Kun Yao from the Department of Pathology, Beijing Sanbo Brain Hospital, Capital Medical University, China, for her excellent technical assistance.

Financial support and sponsorship

This work was supported by the Capital Health Research and Development Special Program (2014-2-2013), High-level Teachers in Beijing Municipal Universities in the Period of 13th Five-year Plan (CIT and TCD201904091) and Beijing Municipal Science and Technology Commission Program (D131100005313017).

Institutional review board statement

The study was approved by the Ethics Committee of Xuanwu Hospital, Capital Medical University, China {approval No. (2019)004} on May 22, 2019, and was conducted in full compliance with the principles of the Declaration of Helsinki.

Declaration of participant consent

The authors certify that they have obtained the appropriate patient consent forms. In the forms, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published, and due efforts will be made to conceal their identity.

Conflicts of interest

The authors declare no conflicts of interest.



 
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