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The Intratumoral Heterogeneity Reflects the Intertumoral Subtypes of Glioblastoma Multiforme: A Regional Immunohistochemistry Analysis.

ABSTRACT: Glioblastoma multiforme (GBM) is the most frequent and aggressive primary brain tumor in adults. Despite extensive therapy the prognosis for GBM patients remains poor and the extraordinary therapy resistance has been attributed to intertumoral heterogeneity of glioblastoma. Different prognostic relevant GBM tumor subtypes have been identified based on their molecular profile. This approach, however, neglects the heterogeneity within individual tumors, that is, the intratumoral heterogeneity. Here, we detected the regional immunoreactivity by immunohistochemistry and immunofluorescence using nine different markers on resected GBM specimens (IDH wildtype, WHO grade IV). We found repetitive expression profiles, that could be classified into clusters. These clusters could then be assigned to five pathophysiologically relevant groups that reflect the previously described subclasses of GBM, including mesenchymal, classical, and proneural subtype. Our data indicate the presence of tumor differentiations and tumor subclasses that occur within individual tumors, and might therefore contribute to develop adapted, individual-based therapies.

SUBMITTER: Bergmann N

PROVIDER: S-EPMC7193089 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The Intratumoral Heterogeneity Reflects the Intertumoral Subtypes of Glioblastoma Multiforme: A Regional Immunohistochemistry Analysis.

Bergmann Natalie N Delbridge Claire C Gempt Jens J Feuchtinger Annette A Walch Axel A Schirmer Lucas L Bunk Wolfram W Aschenbrenner Thomas T Liesche-Starnecker Friederike F Schlegel Jürgen J

Frontiers in oncology 20200424

Glioblastoma multiforme (GBM) is the most frequent and aggressive primary brain tumor in adults. Despite extensive therapy the prognosis for GBM patients remains poor and the extraordinary therapy resistance has been attributed to intertumoral heterogeneity of glioblastoma. Different prognostic relevant GBM tumor subtypes have been identified based on their molecular profile. This approach, however, neglects the heterogeneity within individual tumors, that is, the intratumoral heterogeneity. Her ...[more]

PMID: 32391260

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Project description:BackgroundA major barrier to effective treatment of glioblastoma (GBM) is the large intertumoral heterogeneity at the genetic and cellular level. In early phase clinical trials, patient heterogeneity in response to therapy is commonly observed; however, how tumor heterogeneity is reflected in individual drug sensitivities in the treatment-naïve glioblastoma stem cells (GSC) is unclear.MethodsWe cultured 12 patient-derived primary GBMs as tumorspheres and validated tumor stem cell properties by functional assays. Using automated high-throughput screening (HTS), we evaluated sensitivity to 461 anticancer drugs in a collection covering most FDA-approved anticancer drugs and investigational compounds with a broad range of molecular targets. Statistical analyses were performed using one-way ANOVA and Spearman correlation.ResultsAlthough tumor stem cell properties were confirmed in GSC cultures, their in vitro and in vivo morphology and behavior displayed considerable tumor-to-tumor variability. Drug screening revealed significant differences in the sensitivity to anticancer drugs (p < 0.0001). The patient-specific vulnerabilities to anticancer drugs displayed a heterogeneous pattern. They represented a variety of mechanistic drug classes, including apoptotic modulators, conventional chemotherapies, and inhibitors of histone deacetylases, heat shock proteins, proteasomes and different kinases. However, the individual GSC cultures displayed high biological consistency in drug sensitivity patterns within a class of drugs. An independent laboratory confirmed individual drug responses.ConclusionsThis study demonstrates that patient-derived and treatment-naïve GSC cultures maintain patient-specific traits and display intertumoral heterogeneity in drug sensitivity to anticancer drugs. The heterogeneity in patient-specific drug responses highlights the difficulty in applying targeted treatment strategies at the population level to GBM patients. However, HTS can be applied to uncover patient-specific drug sensitivities for functional precision medicine.

Project description:BackgroundNext-generation sequencing is revealing genomic heterogeneity in localized prostate cancer (CaP). Incomplete sampling of CaP multiclonality has limited the implications for molecular subtyping, stratification, and systemic treatment.ObjectiveTo determine the impact of genomic and transcriptomic diversity within and among intraprostatic CaP foci on CaP molecular taxonomy, predictors of progression, and actionable therapeutic targets.Design, setting, and participantsFour consecutive patients with clinically localized National Comprehensive Cancer Network intermediate- or high-risk CaP who did not receive neoadjuvant therapy underwent radical prostatectomy at Roswell Park Cancer Institute in June-July 2014. Presurgical information on CaP content and a customized tissue procurement procedure were used to isolate nonmicroscopic and noncontiguous CaP foci in radical prostatectomy specimens. Three cores were obtained from the index lesion and one core from smaller lesions. RNA and DNA were extracted simultaneously from 26 cores with ≥90% CaP content and analyzed using whole-exome sequencing, single-nucleotide polymorphism arrays, and RNA sequencing.Outcome measurements and statistical analysisSomatic mutations, copy number alternations, gene expression, gene fusions, and phylogeny were defined. The impact of genomic alterations on CaP molecular classification, gene sets measured in Oncotype DX, Prolaris, and Decipher assays, and androgen receptor activity among CaP cores was determined.Results and limitationsThere was considerable variability in genomic alterations among CaP cores, and between RNA- and DNA-based platforms. Heterogeneity was found in molecular grouping of individual CaP foci and the activity of gene sets underlying the assays for risk stratification and androgen receptor activity, and was validated in independent genomic data sets. Determination of the implications for clinical decision-making requires follow-up studies.ConclusionsGenomic make-up varies widely among CaP foci, so care should be taken when making treatment decisions based on a single biopsy or index lesions.Patient summaryWe examined the molecular composition of individual cancers in a patient's prostate. We found a lot of genetic diversity among these cancers, and concluded that information from a single cancer biopsy is not sufficient to guide treatment decisions.

Dataset Information

The Intratumoral Heterogeneity Reflects the Intertumoral Subtypes of Glioblastoma Multiforme: A Regional Immunohistochemistry Analysis.

Publications

The Intratumoral Heterogeneity Reflects the Intertumoral Subtypes of Glioblastoma Multiforme: A Regional Immunohistochemistry Analysis.

Similar Datasets

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