The prognostic significance of CDKN2A homozygous deletion in IDH-mutant lower-grade glioma and glioblastoma: a systematic review of the contemporary literature

Abstract BACKGROUND recurring hotspot mutations in isocitrate dehydrogenase (IDH) 1 enzymes, and to a lesser extent IDH2, are the main oncogenic alteration in most of lower-grade diffuse gliomas and a subset of grade 4 gliomas. Although most commonly represented by the IDH1R132H mutation, non-canonical IDH1/2-nonR132H mutations are present in about 10% of cases. As the neomorphic enzymatic activity can vary depending on the type of the hotspot mutation, a different biological behaviour may be inferred. Nevertheless, the prognostic significance of the different IDH1/2 mutations remains a matter of debate. MATERIAL AND METHODS we queried the OncoNeuroTek tumor bank (Pitié-Salpêtrière Hospital, Paris) to identify all registered cases of IDH-mutated diffuse gliomas. Most relevant clinical and molecular data were collected. RESULTS We identified 1050 IDH mutated diffuse gliomas (481 grade 2 [46%], 459 grade 3 [44%], and 110 grade 4 [10%]), of which 1007 (96%) were IDH1 mutated (934 IDH1R132H [89%] and 73 IDH-nonR132H [7%]) and 43 (4%) were IDH2 mutated (24 IDH2R172K [2%] and 19 IDH2-nonR172K [2%]). The chromosomes 1p/19q codeletion was more frequent in IDH2-mutated tumors (25/42 [60%] versus 350/918 [38%] in IDH1-mutated cases, p=0.005). Nevertheless, only IDH2R172K mutation was associated with the codeletion (18/24 [75%], versus 7/18 [39%] in IDH2-nonR172K-mutated tumors, p=0.02). IDH1-nonR132H tumors showed the lowest rate of 1p/19q codeletion (9/69 [13%], versus 341/849 [40%] in IDH1R132H-mutated cases, p<0.001). At the time of observation, 536 patients were deceased (51%), with a median overall survival (OS) of 115 months (mo., 95% CI 108–125 mo.). Median follow up for censored patients was 77 mo. Codeleted patients had a significantly longer OS compared to non-codeleted ones (179 vs. 96 mo., p<0.001). No significant differences in survival were seen when stratifying according to IDH mutation type (115 mo. for IDH1R132H vs. 136 mo. for IDH1-nonR132H vs. 112 mo. for IDH2R172K vs. 150 mo. for IDH2-nonR172K, p=0.8). No differences were seen when restricting the analysis to codeleted or not-codeleted patients only, respectively. In a multivariate analysis including the main prognostic factors (age, sex, preoperative performance status, tumor grade, surgical resection, midline location, 1p/19q codeletion, and p16 homozygous deletion), no survival difference was associated with any of the IDH mutation subtype. CONCLUSION although significantly different rates of 1p/19q codeletion were seen according to the four main IDH mutation subgroups, these groups does not associate with different survival profiles in our cohort.

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A pan-cancer perspective analysis reveals the opposite prognostic significance of CD133 in lower grade glioma and papillary renal cell carcinoma

Science Progress ◽

10.1177/00368504211010938 ◽

2021 ◽

Vol 104 (2) ◽

pp. 003685042110109

Author(s):

Haiwei Wang ◽

Xinrui Wang ◽

Liangpu Xu ◽

Ji Zhang ◽

Hua Cao

Keyword(s):

Prognostic Factor ◽

Prognostic Significance ◽

Papillary Renal Cell Carcinoma ◽

High Expression ◽

Lower Grade ◽

Cd133 Expression ◽

The Poor ◽

Lower Grade Glioma ◽

Pan Cancer ◽

Perspective Analysis

CD133 is a valuable prognostic marker in multiple types of cancer. However, the expression, methylation levels, and prognostic relevance of CD133 have not been evaluated in a pan-cancer perspective. The expression and methylation levels of CD133 across different types of cancer were determined using The Cancer Genome Atlas (TCGA) dataset. Univariate cox regression and Kaplan-Meier survival were used to determine the prognostic significance of CD133 expression and methylation. CD133 was highly expressed in papillary renal cell carcinoma (PRCC) or pancreatic adenocarcinoma (PAAD). Correspondingly, PAAD and PRCC had low CD133 methylation levels. Through pan-cancer perspective analysis, we found that CD133 high expression was a poor prognostic factor in lower grade glioma (LGG), while, CD133 high expression was a good prognostic factor in PRCC. Moreover, genes positively correlated with CD133 expression were associated with the poor clinical outcomes of LGG. In PRCC, genes negatively correlated with CD133 expression were correlated with the poor overall survival. Furthermore, CD133 expression levels were highly correlated with the CD133 methylation levels in LGG or PRCC. Correspondingly, CD133 hypermethylation was a good prognostic factor in LGG. On the contrary, CD133 hypomethylation was a good prognostic factor in PRCC. We also found that CD133 was highly expressed and hypomethylated in wild type IDH subgroup of LGG. CD133 was highly expressed and hypomethylated in low stages and type1 of PRCC. CD133 high expression and hypomethylation were bad prognostic factors in LGG, while, CD133 high expression and hypomethylation were good prognostic factors in PRCC.

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Prognostic significance of age related genes in patients with lower grade glioma

Journal of Cancer ◽

10.7150/jca.41123 ◽

2020 ◽

Vol 11 (13) ◽

pp. 3986-3999 ◽

Cited By ~ 2

Author(s):

Haiwei Wang ◽

Xinrui Wang ◽

Liangpu Xu ◽

Ji Zhang ◽

Hua Cao

Keyword(s):

Prognostic Significance ◽

Lower Grade ◽

Age Related ◽

Lower Grade Glioma

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Construction of Immune-related lncRNA Prognosis Models and Development Related Networks and Drugs in LGG

10.21203/rs.3.rs-757554/v1 ◽

2021 ◽

Author(s):

Xiaoyu Zhang ◽

Xiaoqin He ◽

Lin Xiong ◽

Yangtao Xu ◽

Wenliang Chen ◽

...

Keyword(s):

Immune Cells ◽

Prognostic Significance ◽

Clinical Staging ◽

Lower Grade ◽

Lasso Regression ◽

Malignant Tumours ◽

Lower Grade Glioma ◽

Patient Prognosis ◽

Core Genes

Abstract Glioma is the most important tumor of the nervous system. LncRNA plays an important role in the occurrence, development, and metastasis of glioma. The immune status of glioma plays an important role in its treatment and prognosis. In lower-grade glioma (LGG), based on the results of the Weighted correlation network analysis (WCGNA) of lncRNA, we used lasso regression, random forest model, and stepwise regression to establish the lncRNA prognostic model: 0.58349*CYTOR + 0. 47804*LINC01831 + 0. 24933*HOTAIRM1 + 0. 73600*AC022034 + 0. 62351*AC104407 = lncRNA model prognosis score (LMPS). Concomitantly, we explored the correlation of LMPS with the Estimation of STromal and Immune cells in MAlignant Tumours using Expression data (ESTIMATE), Tumor IMmune Estimation Resource (TIMER) infiltrating immune cells. We also established the reciprocal network of the model and verified the significant prognostic significance of the hub genes of the network and the significant impact on immunity. Finally, by connectivity Map (cMap) analysis, we obtained the drugs about the WCGNA module where the model is. Our study highlights the close role of the lncRNA model with patient prognosis, immunity, and clinical staging, and can guide immunotherapy. The network is constructed with the model as the core. Its core genes also have a guiding role in patient prognosis, immunity, and treatment. We identified loratadine and fidaxomicin as possible drugs.

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Homozygous deletion of CDKN2A by fluorescence in situ hybridization is prognostic in grade 4, but not grade 2 or 3, IDH-mutant astrocytomas

Acta Neuropathologica Communications ◽

10.1186/s40478-020-01044-y ◽

2020 ◽

Vol 8 (1) ◽

Author(s):

Daniel F. Marker ◽

Thomas M. Pearce

Keyword(s):

In Situ Hybridization ◽

Fluorescence In Situ Hybridization ◽

Medical Center ◽

Prognostic Significance ◽

Homozygous Deletion ◽

Cox Proportional Hazards ◽

Histologic Grade ◽

Lower Grade ◽

Primary Tumors

Abstract IDH-mutant astrocytomas have a more indolent natural history and better prognosis than their IDH-wild type counterparts, but are still graded according to schemes developed prior to the recognition of this type of neoplasm as a distinct entity. Homozygous deletion of CDKN2A has been proposed as a molecular correlate of aggressive behavior in these tumors, and may be incorporated into future grading systems in an effort to improve prognostic stratification. Fluorescence in situ hybridization (FISH) is a common ancillary testing modality used to assess CDKN2A status, but the specifics of how to best interpret FISH results for prognostication of gliomas have not been clearly defined in the literature. To address this issue, we performed a retrospective analysis of prospectively collected CDKN2A FISH data from 108 primary and 43 recurrent IDH-mutant astrocytomas diagnosed between 2007–2020 at the University of Pittsburgh Medical Center. High level CDKN2A homozygous deletion was rare in primary tumors and was identified more frequently in recurrent tumors. Multivariate Cox Proportional-Hazards analysis demonstrated that histologic grade and CDKN2A status are independent predictors of survival, and the prognostic value of CDKN2A is maximized by applying a threshold of ≥ 30% of tumor cells with homozygous deletion by FISH to define a positive result. At this threshold, CDKN2A deletion significantly stratified survival of histologic grade 4 tumors, but grade 2 and 3 tumors rarely exceeded this cutoff value and did not show worse survival. Lower thresholds identified additional lower grade tumors, but were not prognostically useful. Compared to prior studies, the lack of prognostic significance of CDKN2A homozygous deletion by FISH in grade 2–3 IDH-mutant astrocytomas may reflect differences in cohort populations or technical differences between testing modalities. Definitive criteria for determining CDKN2A homozygous deletion by various methodologies will be critical if this is to be included in future grading schemes.

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A Pan-Cancer Analysis of Clinical Prognosis and Immune Infiltration of CKS1B in Human Tumors

BioMed Research International ◽

10.1155/2021/5862941 ◽

2021 ◽

Vol 2021 ◽

pp. 1-25

Author(s):

Yan Jia ◽

Quan Tian ◽

Kaitai Yang ◽

Yi Liu ◽

Yanfeng Liu

Keyword(s):

Prognostic Significance ◽

Tumor Infiltrating Lymphocytes ◽

Small Scale ◽

Lower Grade ◽

Clinical Prognosis ◽

Bladder Urothelial Carcinoma ◽

Lower Grade Glioma ◽

Infiltrating Lymphocytes ◽

First Time ◽

Pan Cancer

Although more and more evidence supports CDC28 protein kinase subunit 1B (CKS1B) is involved significantly in the development of human cancers, most of the researches have focused on a single disease, and pan-cancer studies conducted from a holistic perspective of different tumor sources have not been reported yet. Here, for the first time, we investigated the potential oncogenic and prognostic role of CKS1B across 33 tumors based on public databases and further verified it in a small scale by RNA sequencing or quantitative real-time PCR. CKS1B was generally highly expressed in a majority of tumors and had a notable correlation with the prognosis of patients, but its prognostic significance in different tumors was not exactly the same. In addition, CKS1B expression was also closely related to the infiltration of cancer-associated fibroblasts in tumors such as breast invasive carcinoma, kidney chromophobe, lung adenocarcinoma, and tumor-infiltrating lymphocytes in tumors such as glioblastoma multiforme, bladder urothelial carcinoma, and brain lower grade glioma. Moreover, reduced CKS1B methylation was observed in certain tumors, for example, adrenocortical carcinoma. Cell cycle and kinase activity regulation and PI3K-Akt signaling pathway were found to be involved in the functional mechanism of CKS1B. In conclusion, our first pan-cancer analysis of CKS1B contributes to a better overall understanding of CKS1B and may provide a new target for future cancer therapy.

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Prognostic significance of X‐linked inhibitor of apoptosis protein in solid tumors: A systematic review and meta‐analysis

Journal of Cellular Physiology ◽

10.1002/jcp.28443 ◽

2019 ◽

Vol 234 (10) ◽

pp. 18111-18122 ◽

Cited By ~ 2

Author(s):

Shimeng Li ◽

Baoxiang Pan ◽

Lihong Li ◽

Bo Shi ◽

Feng Xie ◽

...

Keyword(s):

Systematic Review ◽

Solid Tumors ◽

Meta Analysis ◽

Prognostic Significance ◽

Inhibitor Of Apoptosis ◽

Inhibitor Of Apoptosis Protein ◽

Apoptosis Protein

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Prognostic significance of CD30 expression in diffuse large B cell lymphoma: A systematic review with meta‐analysis

Journal of Oral Pathology and Medicine ◽

10.1111/jop.13208 ◽

2021 ◽

Author(s):

Carla Isabelly Rodrigues‐Fernandes ◽

Lucas Guimarães Abreu ◽

Raghu Radhakrishnan ◽

Danyel Elias da Cruz Perez ◽

Gleyson Kleber Amaral‐Silva ◽

...

Keyword(s):

Systematic Review ◽

B Cell ◽

Cell Lymphoma ◽

Meta Analysis ◽

Prognostic Significance ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

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RUNX1 and REXO2 are associated with the heterogeneity and prognosis of IDH wild type lower grade glioma

Scientific Reports ◽

10.1038/s41598-021-91382-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Haiwei Wang ◽

Xinrui Wang ◽

Liangpu Xu ◽

Ji Zhang ◽

Hua Cao

Keyword(s):

Transcription Factor ◽

Low Frequency ◽

Tumor Grade ◽

The Cancer Genome Atlas ◽

Lower Grade ◽

Wild Type ◽

Lower Grade Glioma ◽

Cancer Genome Atlas ◽

Worse Prognosis ◽

Genome Atlas

AbstractBased on isocitrate dehydrogenase (IDH) alterations, lower grade glioma (LGG) is divided into IDH mutant and wild type subgroups. However, the further classification of IDH wild type LGG was unclear. Here, IDH wild type LGG patients in The Cancer Genome Atlas and Chinese Glioma Genome Atlas were divided into two sub-clusters using non-negative matrix factorization. IDH wild type LGG patients in sub-cluster2 had prolonged overall survival and low frequency of CDKN2A alterations and low immune infiltrations. Differentially expressed genes in sub-cluster1 were positively correlated with RUNX1 transcription factor. Moreover, IDH wild type LGG patients with higher stromal score or immune score were positively correlated with RUNX1 transcription factor. RUNX1 and its target gene REXO2 were up-regulated in sub-cluster1 and associated with the worse prognosis of IDH wild type LGG. RUNX1 and REXO2 were associated with the higher immune infiltrations. Furthermore, RUNX1 and REXO2 were correlated with the worse prognosis of LGG or glioma. IDH wild type LGG in sub-cluster2 was hyper-methylated. REXO2 hyper-methylation was associated with the favorable prognosis of LGG or glioma. At last, we showed that, age, tumor grade and REXO2 expression were independent prognostic factors in IDH wild type LGG.

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