1p19q co-deletion is an independent prognostic factor in glioma with TERT promoter mutations

doi:10.21203/rs.3.rs-4516259/v1

Download PDF

Article

1p19q co-deletion is an independent prognostic factor in glioma with TERT promoter mutations

https://doi.org/10.21203/rs.3.rs-4516259/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Various genetic variants, such as telomerase reverse transcriptase (TERT) promoter mutations (TERTmut) and 1p/19q co-deletion, are linked to gliomas; however, their prognostic significance remains uncertain. Here, we investigated the prevalence of TERTmut in gliomas, their correlation with clinicopathological features and molecular abnormalities, and prognostic implications of molecular abnormalities. Clinicopathological data were retrospectively collected from 161 patients diagnosed with glioma. An increased incidence of TERTmut was found in patients older than 50 years. Oligodendrogliomas and glioblastomas exhibited a higher susceptibility to TERT promoter mutations than astrocytomas. TERT promoter mutation rates were higher in WHO grade 3 and 4 tumors than in grade 1 and 2 tumors. The TERTmut group demonstrated a higher incidence of 1p19q co-deletion than the TERT wild-type group. Prognosis within the TERTmut group was closely correlated with histological type and glioma grade, along with IDH1/2 mutation, 1p19q co-deletion, and MGMT methylation, all indicative of a favorable prognosis. 1p19q co-deletion, and not IDH1/2 mutation, was identified as an independent prognostic factor for TERTmut glioma. The ensemble prognostic signature, incorporating 1p19q co-deletion, could aid in risk stratification and survival prediction in gliomas with TERTmut. Our findings establish a reliable and practical protocol for developing individualized surgical and treatment strategies.

Biological sciences/Cancer/Cns cancer

Biological sciences/Neuroscience/Diseases of the nervous system/Cancer in the nervous system

Glioma

TERT promoter mutation

1p/19q co-deletion

prognostic factor

Gliomas are complex diseases involving multiple genes. The discovery of molecular markers provides a foundation for the targeted treatment and molecular typing of gliomas^1,2. Gliomas are categorized into five molecular groups based on three tumor markers: mutations in the telomerase reverse transcriptase (TERT) promoter, mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), and co-deletion of chromosome arms 1p and 19q (1p/19q co-deletion)³. These groups exhibit variations in overall survival (OS), age at onset, and associations with germline variants, suggesting distinct underlying pathogenic mechanisms³. The 2021 World Health Organization (WHO) Classification of Central Nervous System Tumors incorporates numerous molecular markers closely related to diagnosis and prognosis⁴. However, the factors influencing the prognosis of patients with glioma are unclear.

TERT activation represents the rate-limiting step in telomerase production. Following mutation, TERT can generate two promoter-binding domains with identical structures, thereby doubling transcriptional activity. It can undergo reverse transcription to synthesize telomere repeat sequences at the chromosome ends, playing a crucial role in the onset and progression of glioma⁵.

The 1p/19q co-deletion has long been recognized as a characteristic molecular marker of oligodendroglioma⁶. Moreover, compared with those lacking the 1p/19q variant, patients with glioma harboring 1p/19q co-deletion exhibit substantially increased sensitivity to chemotherapy⁷. However, the association between 1p/19q co-deletion and survival in gliomas remains debatable. TERT promoter mutations (TERTmut) are predominantly identified in glioblastomas and oligodendroglioma, typically associated with an unfavorable prognosis. The OS of patients with oligodendroglioma (IDH mutation) presenting TERTmut and 1p/19q co-deletion is considerably higher than that of patients lacking these mutations⁸. An association between TERTmut and 1p/19q co-deletion has been suggested in certain glioma types. Nonetheless, the clinical significance of TERTmut and 1p/19q co-deletion in gliomas remains unclear.

The objective of our study was to examine the prognostic implications of TERTmut in patients with glioma and its interactions with other molecular markers, particularly 1p/19q co-deletion, with the aim of contributing insights that may facilitate personalized treatment strategies and enhance overall patient outcomes.

Glioma samples and patient characteristics

This study was conducted with the approval of the Institutional Review Board of Ruijin Hospital (ID:2020 − 192), and written informed consent was obtained from all patients or their families. We confirmed that all methods were performed in accordance with the relevant guidelines and regulations. Patients with a clear pathological diagnosis of glioma and those who have undergone TERTmut testing were included in this experiment. Samples from patients who died of other diseases and were younger than 15 years of age were excluded. We enrolled 161 patients with gliomas, comprising 90 men and 71 women, admitted to Ruijin Hospital affiliated with Shanghai Jiao Tong University, between January 2018 and December 2022. The median age was 53.9 years (15–85 years). Following the fifth edition of the WHO classification criteria for central nervous system tumors in 2021⁴, the distribution included five cases classified as grade 1, 33 cases as grade 2, 17 cases as grade 3, and 106 cases as grade 4 tumors.

DNA extraction

Five to ten sections of paraffin-embedded tissue were cut 3–4-µm thick and then dewaxed and hydrated. One section was stained with hematoxylin and eosin to observe the tumor enrichment area. The corresponding area of the remaining white slices was scraped into an Eppendorf test tube, and lysate, protease K, and RNA enzyme were added. A DNA extraction kit (QIAamp DNA FFPE Tissue Handbook, catalog number 56404) was used to extract DNA through an automated extraction instrument, as per the manufacturer’s instructions. A NanoDrop2000 ultramicro spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA) was used to detect its concentration and optical density value.

Sanger sequencing

The extracted DNA was amplified using polymerase chain reaction (PCR) for IDH1 exon 4, IDH2 exon 4, and TERT core promoter fragments (including C288T and C250T sites). The PCR volume was 25 µL, and the reaction conditions were as follows: pre-denaturation at 94°C for 10 min, denaturation at 94°C for 45 s, annealing at 59°C for 45 s, extension at 72°C for 45 s for 40 cycles, extension at 72°C for 7 min, and termination at 4°C. Five microliters of the product was used for agarose gel electrophoresis and purified using PCR. The purified product was sequenced using a sequencing kit (GenomePrecision, Beijing, China) according to the product manual. Each PCR product was sequenced bidirectionally, and the sequencing results were analyzed using Chromas software.

Fluorescence in situ hybridization

After dewaxing and hydration, the 3–4-µm paraffin specimens were pretreated in pure water at 88–92°C for 30 min and then digested using pepsin for 15–20 min. Next, two-color probe hybridization was performed using 1p36 and 19q13 probe kits (FISH kit for the detection of 1p36/1q21 and 19q13/19p13 gene, Beijing GP Medical Technologies, Ltd., Beijing, China). Denaturation was conducted for 5 min at 73°C, followed by incubation in a water tank at 45–50°C; the specimens were removed before hybridization. After hybridization, specimens were washed and dried. Subsequently, 15 µL 4,6-diamidino-2-phenylindole was added to the specimens, and they were incubated at room temperature for 10–20 min. The results were observed under a fluorescence microscope. At least 100 qualified cells were counted, the red and green signals in the cells were observed, and the ratios of red and green signals were calculated. When the total number of red signals divided by the number of green signals was less than 0.75, the result was established as positive.

Real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR)

According to the instructions of the human MGMT methylation test kit (Genetech, Shanghai, China), the extracted DNA samples were transformed by heavy sulfite, and the products were purified. The RTFQ-PCR solution was prepared according to the dosage and amplified in the RTFQ-PCR instrument. The following amplification parameters were used: 95°C for 3 min; 95°C for 15 s, 60°C for 60 s, with 45 cycles; and fluorescent signal detection. The interpretation criteria were as follows: when the ΔCt value was ≤ 7, the MGMT methylation content in the sample was ≥ 1%, indicating positive MGMT methylation; when no FAM signal was detected in the MGMT reaction tube of the sample and Ct ≤ 32 in the control group, it was indicated that MGMT methylation was negative; when the ΔCt > 7, the MGMT methylation content in the sample was less than 1%, indicating that it was lower than the lower limit of detection by the kit.

Statistical analysis

The χ2 test was used to detect both the relationships between TERT expression and clinicopathological features and the relationships between TERT expression and other molecular markers. Kaplan–Meier survival curves were used to analyze the OS, and the log-rank test was used to analyze the relationship between clinicopathological features, TERT, other molecular indicators, and OS. The Cox regression model was used for performing multivariate prognostic analyses. Factors identified as significant in univariate analyses were included in the model. OS referred to the time from the initial surgery date to the death of the patient, with a longer OS indicating a higher survival benefit for the patient group. Data processing and statistical analyses were conducted using SPSS (version 26.0) and GraphPad Prism 5. Statistical significance was set at P < 0.05.

Relationship between TERT and clinicopathological features of patients with glioma

The TERTmut status, assessed using Sanger sequencing in 161 patients, revealed positive rates of 40.74% (22/54) in patients younger than 50 years and 68.22% (73/107) in those older than 50 years, with a significant difference (P < 0.05, Table 1). Mutation rates in the TERT promoter were elevated in oligodendroglioma (94.44%) and glioblastoma (65.14%) compared with those in astrocytoma (23.08%; P < 0.05, Table 1). Additionally, the TERTmut rate was higher in patients with WHO grade 3 and 4 tumors than in patients with grade 1 and 2 tumors, with no significant difference observed based on gender (P > 0.05, Table 1).

Table 1

Correlations between *TERT*mut and clinicopathological characteristics in patients with glioma
Characteristics	TERTmut	TERTwt	χ²	P-value
Sex			1.005	0.316
Male	50	40
Female	45	26
Age in years			11.207	0.001
< 50	22	32
≥ 50	73	34
Tumor histological type			35.141	< 0.001
Astrocytoma	6	20
Oligodendroglioma	17	1
Glioblastoma	71	38
Others	1	7
WHO grade
1	0	5	13.585	0.004
2	15	18
3	10	7
4	70	36

Correlations between TERT and other molecular markers

Patients were categorized into a TERT mutation group (TERTmut; n = 95) and a TERT wild-type group (TERTwt; n = 66). In the TERTmut group, the incidence of 1p19q co-deletion was 20.9%, whereas in the TERTwt group, it was 4.8%, indicating a significant difference (P < 0.05, Table 2). No significant correlations were observed between TERTmut and IDH1 mutations, IDH2 mutations, MGMT promoter methylation, or BRAF mutations (P > 0.05, Table 2).

Table 2

Comparison of molecular pathological indicator mutations between *TERT*mut and *TERT*wt groups
Molecular characteristics	TERTmut	TERTwt	χ²	P-value
IDH1 mut			1.397	0.237
+	22	21
-	72	45
NA	1	0
IDH2 mut			1.413	0.512
+	2	0
-	92	66
NA	1	0
1p19q co-deletion			7.897	0.005
+	19	3
-	72	60
NA	4	3
MGMTmet			0.734	0.392
+	41	33
-	54	33
NA	0	0
BRAF			1.845	0.309
+	1	3
-	88	61
NA	6	2

NA: Not available.

Univariate analysis of prognostic factors in patients with glioma

Kaplan–Meier survival analysis of relationships between TERTmut, 1p19q co-deletion, and prognosis revealed that TERTmut was not associated with OS (P = 0.9925, Fig. 1a), whereas patients with 1p19q co-deletion exhibited significantly higher OS than those without the co-deletion (P = 0.0007, Fig. 1b). Subsequently, we analyzed the associations between various factors (including age, histological type, WHO grade, IDH1/2 mutation status, 1p19q co-deletion status, and MGMT methylation status) and prognosis in the TERTmut (Fig. 2) and TERTwt groups (Fig. 3). In the TERTmut group, prognosis was closely correlated with histological type (P = 0.0031, Fig. 2b) and glioma grade (P = 0.0031, Fig. 2c). Favorable prognostic indicators included IDH 1/2 mutation (P < 0.0001, Fig. 2d), 1p19q co-deletion (P = 0.0010, Fig. 2e), and MGMT methylation (P = 0.0019, Fig. 2f). In the TERTwt group, patient prognosis was significantly related to age (P = 0.0488, Fig. 3a) and grade (P = 0.0132, Fig. 3c), whereas molecular changes, such as IDH1/2 mutation (P = 0.1010, Fig. 3d), 1p19q co-deletion (P = 0.3861, Fig. 3e), and MGMT methylation (P = 8158, Fig. 3f), were not significantly associated with prognosis.

Multivariate analysis of prognostic factors in patients with glioma

Factors identified as statistically significant in univariate analyses were subjected to a multivariate Cox regression analysis. The 1p19q co-deletion was identified as an independent prognostic factor for TERTmut glioma (Table 3), whereas WHO grade was identified as an independent prognostic factor for TERTwt glioma (Table 4).

Table 3

Results of a multivariate Cox regression analysis of the prognosis of patients with *TERT*mut glioma
Prognostic factor	β	SE	Wald	P-value	Exp(β)	95% CI
Histological type	0.743	0.417	3.172	0.075	2.103	0.928–4.765
WHO grade	0.036	0.265	0.019	0.891	1.037	0.617–1.742
1p19q co-deletion	-1.393	0.576	5.848	0.016	0.248	0.080–0.768
MGMT status	-0.264	0.338	0.608	0.435	0.768	0.396–1.491
IDH status	-0.064	0.486	0.017	0.895	0.938	0.361–2.433

Table 4

Results of a multivariate COX regression analysis of the prognosis of patients with *TERT*wt glioma
Prognostic factor	β	SE	Wald	P-value	Exp(β)	95% CI
Age	0.003	0.013	0.050	0.823	1.003	0.978–1.028
WHO grade	0.644	0.278	5.349	0.021	1.904	1.103–3.287

Glioma, constituting 45–50% of all intracranial tumors, is a prevalent malignant tumor of the central nervous system. Glioma is characterized by aggressive growth, frequent recurrence, challenges in treatment, and high mortality rates. Despite therapeutic interventions, including surgery, radiotherapy, and chemotherapy, the median survival time for patients with glioma remains at 15 months^9,10. The WHO classification of central nervous system tumors integrates molecular markers that are closely related to diagnosis and prognosis¹¹, with TERT being a pivotal marker, thereby highlighting the need for an accurate analysis of its association with pathological features and other molecular changes. While numerous studies have indicated the predictive role of TERT mutations in survival^12,13, its correlation with clinicopathological features and its impact on patient prognosis remain unclear^14,15. In our retrospective analysis of 161 patients with glioma, TERTmut frequency was observed to be notably higher in patients older than 50 years than in patients younger than 50 years, in oligodendroglioma and glioblastoma than in astrocytoma, and in WHO grade 3 and 4 tumors than in grade 1 and 2 tumors (Table 1). Univariate survival analyses revealed that the prognosis of the TERTmut group was closely associated with the histological type (P = 0.0031, Fig. 2b) and grade (P = 0.0031, Fig. 2c) of glioma but not age (P = 0.1276, Fig. 2a).

As per the WHO 2021 standards¹¹, IDH1/2 wild-type diffuse astrocytic glioma with TERTmut is classified as glioblastoma, highlighting the association of TERTmut with tumor aggressiveness. However, the pathogenesis of glioma is complex, and the molecular changes influencing prognosis have been extensively debated. While most studies suggest that TERTmut is associated with poor prognosis in gliomas, research in mouse tumor transplantation models has shown that RAS, TERT, and p53 mutations or abnormal expression are implicated in glioma occurrence. These genes contribute to a fully malignant and rapid transformation, with mutations and specific combinations of susceptible cell types playing pivotal roles in the development of gliomas¹⁶. Fujimoto et al.¹⁷ analyzed 46 patients with IDH wild-type/TERTmut low-grade gliomas and 85 patients with IDH wild-type/TERTwt low-grade gliomas, demonstrating that the analysis of TERTmut status is necessary and sufficient to diagnose IDH wild-type diffuse astrocytic gliomas with the molecular features of glioblastoma. Further studies have indicated that mutations near TERT and TERC impact telomere length, increasing the risk of high-grade gliomas¹⁷. Similarly, variants near TERT and TERC, influencing telomere length, are associated with the risk of high-grade gliomas¹⁸. However, Muench et al.¹⁹ proposed that TERTmut cannot serve as a prognostic factor for IDH wild-type gliomas. They provided evidence that TERTmut in diffuse gliomas without further morphological or molecular signs of high-grade glioma should be interpreted in the context of clinicopathological presentation, as well as the epigenetic profile, and TERTmut may not be suitable as a standalone marker for IDH wild-type glioblastoma. Our Kaplan–Meier survival analysis revealed that OS was shorter in the TERTmut group than in the IDH wild-type and IDH mutant groups (P < 0.0001, Fig. 2d). Additionally, we observed no significant difference between the IDH mutation status and prognosis of patients with TERTwt glioma (P = 0.1010, Fig. 3d). Multivariate Cox regression analyses demonstrated that the IDH mutation was not an independent prognostic factor for TERTmut or TERTwt glioma (Tables 3 and 4). Therefore, we believe that TERTmut cannot be used as an independent prognostic factor for IDH wild-type gliomas, consistent with the results of Muench et al.¹⁹

As mentioned earlier, TERTmut, a predictor of highly aggressive gliomas in most studies, typically relies on a histological diagnosis of diffuse astrocytoma or anaplastic astrocytoma with IDH wild-type and without 1p19q co-deletion¹⁷. However, the significance of TERTmut with 1p19q co-deletion in the integrative diagnosis of glioma remains unclear. 1p19q serves as a crucial marker for the classification, treatment, and prognosis of glioma^3,20,21. 1p19q co-deletion is prevalent in all glioma subtypes, especially in patients with oligodendroglioma. Following an IDH mutation, the tumor progresses to oligodendroglioma in cases where 1p19q combined deletion occurs. This co-deletion holds significance in differentiating oligodendrogliomas from astrocytomas and serves as a basis for differential diagnosis. Killela et al.²² reported that 78% (35/45) of oligodendrogliomas exhibited TERTmut. In our study, 17 of 18 oligodendrogliomas had TERTmut (Table 1). Furthermore, among the 22 patients with glioma harboring a 1p19q co-deletion, 19 cases were accompanied by TERTmut (Table 2). Simultaneously, we observed no correlation between TERTmut and patient survival (Fig. 1a). The OS of patients with 1p19q co-deletion was significantly longer than that of patients without 1p19q co-deletion, consistent with previously reported results^6,23,24. However, in the TERTmut group, 1p19q co-deletion was identified as an independent prognostic factor in patients with glioma (Fig. 2 and Table 3). Conversely, in the TERTwt group, 1p19q co-deletion was not an independent prognostic factor for patients with glioma (Fig. 3 and Table 4). Therefore, when TERT is not mutated, the increased survival associated with 1p19 co-deletion disappears. We propose that improved survival in patients with 1p19q co-deletion is dependent on TERT promoter mutations. However, the mechanism by which 1p19 co-deletion affects the prognosis of patients with gliomas is complex. According to Lv et al. ²⁵, the effect of 1p/19q co-deletion on the immune microenvironment in low-grade glioma plays a crucial role in tumor progression and prognosis. Immune cell infiltration of 281 low-grade gliomas from The Cancer Genome Atlas and 543 low-grade gliomas from the Chinese Glioma Genome Atlas were analyzed for immune cell infiltration using the ESTIMATE algorithm, TIMER, and xCell. Low-grade gliomas with 1p/19q co-deletion exhibit lesser immune cell infiltration and lower expression of immune checkpoint genes than those in 1p/19q non-co-deletion cases. Similarly, some studies have shown that a higher risk is associated with an increase in various factors in the tumor microenvironment, such as protein acetylation and inflammatory responses²⁶. Furthermore, pathway analysis suggested that prostaglandins, N-terminal acetyltransferases, and responses to copper ions may be involved in 1p/19q glioma progression^27–29. Collectively, we propose that better survival of patients with 1p19q co-deletion is dependent on TERT promoter mutations; however, the specific mechanism remains to be further investigated.

We acknowledge that our study has certain limitations. Patients in our cohort were treated using various modalities, and treatment annotations were lacking for a substantial portion of the dataset. In the future, we plan to conduct a confirmatory study that replicates and validates the findings for patients with a consistent treatment strategy, accounting for other prognostic factors, such as tumor size, location, and degree of resection.

In summary, TERT promoter mutations exhibit distinct patterns in patients with glioma, associated with age, histological type, and WHO grade. TERTmut is positively correlated with 1p19q co-deletion and is insufficient as an independent prognostic factor for IDH wild-type gliomas. Notably, the ensemble prognostic signature featuring 1p19q co-deletion could serve as a valuable tool for risk stratification and survival prediction in gliomas with TERT promoter mutations. As our understanding of the optimal classification of adult diffuse gliomas evolves, biomarkers for risk-based classification may enhance clinical strategies. Collectively, our findings present a reliable protocol for neurosurgeons to devise personalized surgical and treatment strategies in patients with glioma.

Author information

Authors and Affiliations

Department of Pathology, The First People’s Hospital of Zigong, shang yi hao yi zhi lu 42#, Zigong 643099, Sichuan province, China.

Dan Wan & Yutao Zhang

Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.

Benyan Zhang & Jialing Xie & Xianwei Yang

Author contributions

Xianwei Yang and Dan Wan performed the sample collection and research and wrote the paper. Jialing Xie performed the experiments. Benyan Zhang contributed to the research design. Yutao Zhang and Benyan Zhang gave the final approval of the manuscript.

Corresponding author

Correspondence to Xianwei Yang.

Data availability

The raw sequencing data are available under controlled access at the National Center for Biotechnology Information (NCBI) database under accession number: PQ002189, PQ002190, PQ002191, and PQ002192.

Competing interests

The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Mörén, L. et al. Metabolomic screening of tumor tissue and serum in glioma patients reveals diagnostic and prognostic information. Metabolites 5, 502–520 (2015).
Dang, L., Yen, K. & Attar, E. C. IDH mutations in cancer and progress toward development of targeted therapeutics. Ann. Oncol. 27, 599–608 (2016).
Eckel-Passow, J. E. et al. Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N. Engl. J. Med. 372, 2499–2508 (2015).
WHO Classification of Tumours Editorial Board. Central nervous system tumours (2021). https://tumourclassification.iarc.who.int/chapters/45.
Huang, F. W. et al. TERT promoter mutations and monoallelic activation of TERT in cancer. Oncogenesis 4, e176 (2015).
Zhao, J., Ma, W. & Zhao, H. Loss of heterozygosity 1p/19q and survival in glioma: a meta-analysis. Neuro. Oncol. 16, 103–112 (2014).
Pandith, A. A. et al. Evaluation of chromosome 1p/19q deletion by fluorescence in situ hybridization (FISH) as prognostic factors in malignant glioma patients on treatment with alkylating chemotherapy. Cancer Genet. 278–279, 55–61 (2023).
Gao, K. et al. TERT promoter mutations and long telomere length predict poor survival and radiotherapy resistance in gliomas. Oncotarget 7, 8712–8725 (2016).
Reifenberger, G., Wirsching, H. G., Knobbe-Thomsen, C. B. & Weller, M. Advances in the molecular genetics of gliomas – implications for classification and therapy. Nat. Rev. Clin. Oncol. 14, 434–452 (2017).
Wei, Y. et al. EIF4A3-induced circular RNA ASAP1 promotes tumorigenesis and temozolomide resistance of glioblastoma via NRAS/MEK1/ERK1-2 signaling. Neuro. Oncol. 23, 611–624 (2021).
Louis, D. N. et al. The 2021 WHO Classification of Tumors of the central nervous system: a summary. Neuro. Oncol. 23, 1231–1251 (2021).
Gabler, L. et al. TERT expression is susceptible to BRAF and ETS-factor inhibition in BRAFV600E/TERT promoter double-mutated glioma. Acta Neuropathol. Commun. 7, 128 (2019).
Vuong, H. G. et al. The interaction between TERT promoter mutation and MGMT promoter methylation on overall survival of glioma patients: a meta-analysis. BMC Cancer 20, 897 (2020).
Patel, N. P., Lyon, K. A. & Huang, J. H. The effect of race on the prognosis of the glioblastoma patient: a brief review. Neurol. Res. 41, 967–971 (2019).
Vuong, H. G. et al. TERT promoter mutation and its interaction with IDH mutations in glioma: combined TERT promoter and IDH mutations stratifies lower-grade glioma into distinct survival subgroups-A meta-analysis of aggregate data. Crit. Rev. Oncol. Hematol. 120, 1–9 (2017).
Gong, M. et al. Loss of p53 Concurrent with RAS and TERT activation induces glioma formation. Mol. Neurobiol. 60, 3452–3463 (2023).
Fujimoto, K. et al. TERT promoter mutation status is necessary and sufficient to diagnose IDH-wildtype diffuse astrocytic glioma with molecular features of glioblastoma. Acta Neuropathol. 142, 323–338 (2021).
Walsh, K. M. et al. Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk. Nat. Genet. 46, 731–735 (2014).
Muench, A. et al. A novel type of IDH-wildtype glioma characterized by gliomatosis cerebri-like growth pattern, TERT promoter mutation, and distinct epigenetic profile. Am. J. Surg. Pathol. 47, 1364–1375 (2023).
van den Bent, M. J. et al. Bevacizumab and temozolomide in patients with first recurrence of WHO grade II and III glioma, without 1p/19q co-deletion (TAVAREC): a randomised controlled phase 2 EORTC trial. Lancet Oncol. 19, 1170–1179 (2018).
van den Bent, M. J. et al. Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet 390, 1645–1653 (2017) [published correction appears in Lancet 390, 1644 2017].
Killela, P. J. et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc. Natl. Acad. Sci. U. S. A. 110, 6021–6026 (2013).
Deluche, E. et al. CHI3L1, NTRK2, 1p/19q and IDH status predicts prognosis in glioma. Cancers (Basel) 11, 544 (2019).
Chai, R. C. et al. Systematically characterize the clinical and biological significances of 1p19q genes in 1p/19q non-codeletion glioma. Carcinogenesis 40, 1229–1239 (2019).
Lv, L. et al. Effects of 1p/19q Codeletion on Immune Phenotype in Low Grade glioma. Front. Cell. Neurosci. 15, 704344 (2021).
Hu, X. et al. Multigene signature for predicting prognosis of patients with 1p19q co-deletion diffuse glioma. Neuro. Oncol. 19, 786–795 (2017).
Menter, D. G. & Dubois, R. N. Prostaglandins in cancer cell adhesion, migration, and invasion. Int. J. Cell Biol. 2012, 723419 (2012).
Kalvik, T. V. & Arnesen, T. Protein N-terminal acetyltransferases in cancer. Oncogene 32, 269–276 (2013).
Goodman, V. L., Brewer, G. J. & Merajver, S. D. Copper deficiency as an anti-cancer strategy. Endocr. Relat. Cancer11, 255–263 (2004).

No competing interests reported.

Download PDF

Version 1

posted

You are reading this latest preprint version

1p19q co-deletion is an independent prognostic factor in glioma with TERT promoter mutations

Status:

Version 1

Abstract

Figures

Introduction

Materials and methods

Glioma samples and patient characteristics

DNA extraction

Sanger sequencing

Fluorescence in situ hybridization

Real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR)

Statistical analysis

Results

Univariate analysis of prognostic factors in patients with glioma

Multivariate analysis of prognostic factors in patients with glioma

Discussion

Declarations

References

Additional Declarations

Status:

Version 1