Copy Number Variation (CNV) analysis of grade III 1p/19q co-deleted glioma
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Shai Rosenberg
PROVIDER: E-MTAB-5669 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:BACKGROUND: Recent reports indicate that anaplastic oligodendrogliomas frequently show allelic losses on chromosome arms 1p and 19q, and that these deletions are associated with better chemotherapeutic response and overall patient survival. Because of the diversified genetic makeup of the population and the centralized provincial referral system for brain tumor patients in Manitoba, the epidemiological features of such tumors sometimes differ from the published data acquired from non-community based settings. In this study, we assessed the prevalence of allelic deletions for chromosome arms 1p and 19q in anaplastic and in low-grade oligodendrogliomas in the Manitoba population. METHODS: Loss of heterozygosity (LOH) analysis of brain tumors was carried out using 4 microsatellite markers (D1S508, D1S2734, D19S219 and D19S412) and a PCR based assay. The tumors were consecutively acquired during the period September 1999-March 2001 and a total of 63 tumors were assessed. RESULTS: We found that allelic loss of chromosome 1p and 19q was higher in oligodendrogliomas than in other diffuse gliomas and that for anaplastic oligodendrogliomas, younger patients exhibited significantly more deletions than older patients (>60 years of age). CONCLUSIONS: These studies suggest that age may be a factor in the genetic alterations of oligodendrogliomas. In addition, these studies demonstrate that this assay can easily be carried out in a cost-effective manner in a small tertiary center.
| S-EPMC317335 | biostudies-literature
Project description:Although 1p/19q codeletion is the genetic hallmark defining oligodendrogliomas, approximately 30-40% of oligodendroglial tumors have intact 1p/19q in the literature and they demonstrate a worse prognosis. This group of 1p/19q intact oligodendroglial tumors is frequently suggested to be astrocytic in nature with TP53 and ATRX mutations but actually remains under-investigated. In the present study, we provided evidence that not all 1p/19q intact oligodendroglial tumors are astrocytic through histologic and molecular approaches. We examined 1p/19q status by FISH in a large cohort of 337 oligodendroglial tumors and identified 39.8% lacking 1p/19q codeletion which was independently associated with poor prognosis. Among this 1p/19q intact oligodendroglial tumor cohort, 58 cases demonstrated classic oligodendroglial histology which showed older patient age, better prognosis, association with grade III histology, PDGFRA expression, TERTp mutation, as well as frequent IDH mutation. More than half of the 1p/19q intact oligodendroglial tumors showed lack of astrocytic defining markers, p53 expression and ATRX loss. TP53 mutational analysis was additionally conducted in 45 cases of the 1p/19q intact oligodendroglial tumors. Wild-type TP53 was detected in 71.1% of cases which was associated with classic oligodendroglial histology. Importantly, IDH and TERTp co-occurred in 75% of 1p/19q intact, TP53 wild-type oligodendrogliomas, highlighting the potential of the co-mutations in assisting diagnosis of oligodendrogliomas in tumors with clear cell morphology and non-codeleted 1p/19q status. In summary, our study demonstrated that not all 1p/19q intact oligodendroglial tumors are astrocytic and co-evaluation of IDH and TERTp mutation could potentially serve as an adjunct for diagnosing 1p/19q intact oligodendrogliomas.
| S-EPMC5323103 | biostudies-literature
Project description:Accurate identification of molecular alterations in gliomas is crucial for their diagnosis and treatment. Although, fluorescence in situ hybridization (FISH) allows for the observation of diverse and heterogeneous alterations, it is inherently time-consuming and challenging due to the limitations of the molecular method. Here, we report the development of 1p/19qNET, an advanced deep-learning network designed to predict fold change values of 1p and 19q chromosomes and classify isocitrate dehydrogenase (IDH)-mutant gliomas from whole-slide images. We trained 1p/19qNET on next-generation sequencing data from a discovery set (DS) of 288 patients and utilized a weakly-supervised approach with slide-level labels to reduce bias and workload. We then performed validation on an independent validation set (IVS) comprising 385 samples from The Cancer Genome Atlas, a comprehensive cancer genomics resource. 1p/19qNET outperformed traditional FISH, achieving R2 values of 0.589 and 0.547 for the 1p and 19q arms, respectively. As an IDH-mutant glioma classifier, 1p/19qNET attained AUCs of 0.930 and 0.837 in the DS and IVS, respectively. The weakly-supervised nature of 1p/19qNET provides explainable heatmaps for the results. This study demonstrates the successful use of deep learning for precise determination of 1p/19q codeletion status and classification of IDH-mutant gliomas as astrocytoma or oligodendroglioma. 1p/19qNET offers comparable results to FISH and provides informative spatial information. This approach has broader applications in tumor classification.
| S-EPMC10505231 | biostudies-literature
Project description:Approximately 50-80% of oligodendrogliomas demonstrate a combined loss of chromosome 1p and 19q. Chromosome 1p/19q deletion, appearing early in tumorigenesis, is associated with improved clinical outcomes, including response to chemotherapy and radiation. Although many hypotheses have been proposed, the molecular mechanisms underlying improved clinical outcomes with 1p/19q deletion in oligodendrogliomas have not been characterized fully. To investigate the molecular differences between oligodendrogliomas, we employed an unbiased proteomic approach using microcapillary liquid chromatography mass spectrometry, along with a quantitative technique called isotope-coded affinity tags, on patient samples of grade II oligodendrogliomas. Following conventional biochemical separation of pooled tumor tissue from five samples of undeleted and 1p/19q deleted grade II oligodendrogliomas into nuclei-, mitochondria-, and cytosol-enriched fractions, relative changes in protein abundance were quantified. Among the 442 total proteins identified, 163 nonredundant proteins displayed significant changes in relative abundance in at least one of the three fractions between oligodendroglioma with and without 1p/19q deletion. Bioinformatic analyses of differentially regulated proteins supported the potential importance of metabolism and invasion/migration to the codeleted phenotype. A subset of altered proteins, including the pro-invasive extracellular matrix protein BCAN, was further validated by Western blotting as candidate markers for the more aggressive undeleted phenotype. These studies demonstrate the utility of proteomic analysis to identify candidate biological motifs and molecular mechanisms that drive differential malignancy related to 1p19q phenotypes. Future analysis of larger patient samples are warranted to further refine biomarker panels to predict biological behavior and assist in the identification of deleted gene products that define the 1p/19q phenotype.
| S-EPMC3119493 | biostudies-literature
Project description:The aim of this study was to identify relevant biomarkers for the prognosis of glioma considering current molecular changes such as IDH mutation and 1p19q deletion. Gene expression profiling was performed using the TaqMan Low Density Array and hierarchical clustering using 96 selected genes in 64 patients with newly diagnosed glioma. The expression dataset was validated on a large independent cohort from The Cancer Genome Atlas (TCGA) database. A differential expression panel of 26 genes discriminated two prognostic groups regardless of grade and molecular groups of tumors: Patients having a poor prognosis with a median overall survival (OS) of 23.0 ± 9.6 months (group A) and patients having a good prognosis with a median OS of 115.0 ± 6.6 months (group B) (p = 0.007). Hierarchical clustering of the glioma TCGA cohort supported the prognostic value of these 26 genes (p < 0.0001). Among these genes, CHI3L1 and NTRK2 were identified as factors that can be associated with IDH status and 1p/19q co-deletion to distinguish between prognostic groups of glioma from the TCGA cohort. Therefore, CHI3L1 associated with NTRK2 seemed to be able to provide new information on glioma prognosis.
| S-EPMC6521129 | biostudies-literature
Project description:AimsTo determine whether testing for isolated 1p or 19q losses, or as a codeletion, has any significance in the workup of glioblastomas (GBMs).MethodsUpfront 1p/19q testing by fluorescence in situ hybridization (FISH) and/or polymerase chain reaction (PCR)-based loss of heterozygosity (LOH) was done in 491 gliomas that were histologically diagnosed as GBMs. Outcomes were determined and measured against 1p/19q results.ResultsTwenty-eight showed apparent 1p/19q codeletion by either FISH and/or PCR-based LOH, but only 1/26 showed codeletion by both tests. Over 90% of tumours with apparent codeletion by either FISH or LOH also had 10q LOH and/or EGFR amplification, features inversely related to true whole-arm 1p/19q codeletion. Furthermore, only 1/28 tumours demonstrated an R132H IDH1 mutation. Neither 1p/19q codeletion by FISH nor LOH had an impact on GBM survival. Isolated losses of 1p or 19q also had no impact on survival.ConclusionsThese data suggest that (i) 1p/19q testing is not useful on gliomas that are histologically GBMs; (ii) codeletion testing should be reserved only for cases with compatible morphology; and (iii) EGFR, 10q, and IDH1 testing can help act as safeguards against a false-positive 1p/19q result.
| S-EPMC4095883 | biostudies-literature
Project description:The prognosis of small-cell lung cancer (SCLC) is poor despite reports suggesting modest improvement in survival. To date, chemotherapy remains the cornerstone treatment for SCLC patients, and many studies have focused on identifying the molecular characteristics of SCLC, which serve as the basis for precision treatments that improve the prognosis of SCLC. For instance, the therapeutic effect of temozolomide, recommended for patients with relapsed SCLC, is linked to 1p/19q codeletion in anaplastic oligodendroglial tumors. A subpopulation of SCLC patients may derive benefit from tyrosine kinase inhibitors targeting RET. In order to identify 1p/19q codeletion and RET rearrangement in SCLC patients, 32 SCLC resected specimens were retrospectively collected between 2008 and 2014 from the Zhejiang Cancer Hospital in People's Republic of China. Fluorescence in situ hybridization was used to detect 1p/19q codeletion and RET rearrangement in the specimens. A 1p single deletion was detected in eight specimens, 19q single deletion was detected in three specimens, and only three specimens had a 1p/19q codeletion. None of the specimens had a RET rearrangement. The three patients whose specimens had a 1p/19q codeletion were alive after 58, 50, and 30 months of follow-up care. There was a trend toward prolonged overall survival for the patients with codeletion compared to no codeletion, 1p single deletion, 19q single deletion, and without 1p and 19q deletion (P=0.113, 0.168, 0.116, and 0.122, respectively). Our data showed that RET rearrangement may be not an ideal molecular target for SCLC therapies in People's Republic of China. Instead, 1p/19q codeletion is a promising marker for a good prognosis and treatment with temozolomide in SCLC.
| S-EPMC4913998 | biostudies-literature
Project description:Background: Chromosome 1p/19q codeletion is one of the most important genetic alterations for low grade gliomas (LGGs), and patients with 1p/19q codeletion have significantly prolonged survival compared to those without the codeletion. And the tumor immune microenvironment also plays a vital role in the tumor progression and prognosis. However, the effect of 1p/19q codeletion on the tumor immune microenvironment in LGGs is unclear. Methods: Immune cell infiltration of 281 LGGs from The Cancer Genome Atlas (TCGA) and 543 LGGs from the Chinese Glioma Genome Atlas (CGGA) were analyzed for immune cell infiltration through three bioinformatics tools: ESTIMATE algorithm, TIMER, and xCell. The infiltrating level of immune cells and expression of immune checkpoint genes were compared between different groups classified by 1p/19q codeletion and IDH (isocitrate dehydrogenase) mutation status. The differential biological processes and signaling pathways were evaluated through Gene Set Enrichment Analysis (GSEA). Correlations were analyzed using Spearman correlation. Results: 1p/19q codeletion was associated with immune-related biological processes in LGGs. The infiltrating level of multiple kinds of immune cells and expression of immune checkpoint genes were significantly lower in 1p/19q codeletion LGGs compared to 1p/19q non-codeletion cohorts. There are 127 immune-related genes on chromosome 1p or 19q, such as TGFB1, JAK1, and CSF1. The mRNA expression of these genes was positively correlated with their DNA copy number. These genes are distributed in multiple immune categories, such as chemokines/cytokines, TGF-β family members, and TNF family members, regulating immune cell infiltration and expression of the immune checkpoint genes in tumors. Conclusion: Our results indicated that 1p/19q codeletion status is closely associated with the immunosuppressive microenvironment in LGGs. LGGs with 1p/19q codeletion display less immune cell infiltration and lower expression of immune checkpoint genes than 1p/19q non-codeletion cases. Mechanistically, this may be, at least in part, due to the deletion of copy number of immune-related genes in LGGs with 1p/19q codeletion. Our findings may be relevant to investigate immune evasion in LGGs and contribute to the design of immunotherapeutic strategies for patients with LGGs.
| S-EPMC8322528 | biostudies-literature
Project description:PurposeThe present study aimed to preoperatively predict the status of 1p/19q based on radiomics analysis in patients with World Health Organization (WHO) grade II gliomas.MethodsThis retrospective study enrolled 157 patients with WHO grade II gliomas (76 patients with astrocytomas with mutant IDH, 16 patients with astrocytomas with wild-type IDH, and 65 patients with oligodendrogliomas with mutant IDH and 1p/19q codeletion). Radiomic features were extracted from magnetic resonance images, including T1-weighted, T2-weighted, and contrast T1-weighted images. Elastic net and support vector machines with radial basis function kernel were applied in nested 10-fold cross-validation loops to predict the 1p/19q status. Receiver operating characteristic analysis and precision-recall analysis were used to evaluate the model performance. Student's t-tests were then used to compare the posterior probabilities of 1p/19q co-deletion prediction in the group with different 1p/19q status.ResultsSix valuable radiomic features, along with age, were selected with the nested 10-fold cross-validation loops. Five features showed significant difference in patients with different 1p/19q status. The area under curve and accuracy of the predictive model were 0.8079 (95% confidence interval, 0.733-0.8755) and 0.758 (0.6879-0.8217), respectively, and the F1-score of the precision-recall curve achieved 0.6667 (0.5201-0.7705). The posterior probabilities in the 1p/19q co-deletion group were significantly different from the non-deletion group.ConclusionCombined radiomics analysis and machine learning showed potential clinical utility in the preoperative prediction of 1p/19q status, which can aid in making customized neurosurgery plans and glioma management strategies before postoperative pathology.
| S-EPMC8290517 | biostudies-literature
Project description:BackgroundIDH-mutant gliomas are separate based on the codeletion of the chromosomal arms 1p and 19q into oligodendrogliomas IDH-mutant 1p/19q-codeleted and astrocytomas IDH-mutant. While nuclear loss of ATRX expression excludes 1p/19q codeletion, its limited sensitivity prohibits to conclude on 1p/19q status in tumors with retained nuclear ATRX expression.MethodsEmploying mass spectrometry based proteomic analysis in a discovery series containing 35 fresh frozen and 72 formalin fixed and paraffin embedded tumors with established IDH and 1p/19q status, potential biomarkers were discovered. Subsequent validation immunohistochemistry was conducted on two independent series (together 77 oligodendrogliomas IDH-mutant 1p/19q-codeleted and 92 astrocytomas IDH-mutant).ResultsWe detected highly specific protein patterns distinguishing oligodendroglioma and astrocytoma. In these patterns, high HIP1R and low vimentin levels were observed in oligodendroglioma while low HIP1R and high vimentin levels occurred in astrocytoma. Immunohistochemistry for HIP1R and vimentin expression in 35 cases from the FFPE discovery series confirmed these findings. Blinded evaluation of the validation cohorts predicted the 1p/19q status with a positive and negative predictive value as well as an accuracy of 100% in the first cohort and with a positive predictive value of 83%; negative predictive value of 100% and an accuracy of 92% in the second cohort. Nuclear ATRX loss as marker for astrocytoma increased the sensitivity to 96% and the specificity to 100%.ConclusionsWe demonstrate that immunohistochemistry for HIP1R, vimentin, and ATRX predict 1p/19q status with 100% specificity and 95% sensitivity and therefore, constitutes a simple and inexpensive approach to the classification of IDH-mutant glioma.
| S-EPMC9713528 | biostudies-literature