Multi-platform molecular profiling of a large cohort of glioblastomas reveals potential therapeutic strategies

Xiu, Joanne; Piccioni, David; Juarez, Tiffany; Pingle, Sandeep C.; Hu, Jethro; Rudnick, Jeremy; Fink, Karen; Spetzler, David; Maney, Todd; Ghazalpour, Anatole; Bender, Ryan; Gatalica, Zoran; Reddy, Sandeep K.; Sanai, Nader; Idbaïh, Ahmed; Glantz, Michael; Kesari, Santosh

doi:10.18632/oncotarget.7722

Cited by 27 publications

(27 citation statements)

References 56 publications

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“…Survival data, which were available for 102 patients operated after 2007, after introduction of temozolomide in standard treatment protocols, showed that younger age, IDH1-mutations, MGMT methylation and combined radiation and chemotherapy (temozolomide) were associated with longer survival. This is also in line with previous studies, clearly separating the IDH-wildtype and IDH-mutated subgroups (9,(25)(26)(27).…”

Section: Discussionsupporting

confidence: 93%

Low co-expression of epidermal growth factor receptor and its chaperone heat shock protein 90 is associated with worse prognosis in primary glioblastoma, IDH-wild-type

et al. 2017

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Epidermal growth factor receptor (EGFR) is a major oncogenic driver in glioblastoma (GBM) without mutations in the isocitrate dehydrogenase gene (IDH-wildtype). Heat shock protein 90 (HSP90) is a regulator of the stability of oncogenic proteins including EGFR, thereby acting as a molecular chaperone. We investigated the expression of EGFR and its chaperone HSP90 in GBM, IDH-wildtype. Tissue availability permitted analysis of 237/449 consecutive GBM cases, among them 214 IDH-wildtype (90.3%). The expression of EGFR and HSP90 was analysed by immunohistochemistry on a tissue microarray containing various tumour regions. The expression intensity (EI), and an expression score (ES) combining the percentage of stained cells with EI were determined for both markers. Overall, there was a positive correlation between EGFR and HSP90 expression (EI; r=0.275, P<0.001; ES, r=0.333, P<0.001). The expression of EGFR and HSP90 was significantly higher in the tumour centre, compared to the infiltration front (EI, P=0.002; ES, P<0.001). Survival data were available in 96 IDH-wildtype cases, and high expression of EGFR (ES only) was in trend associated with better outcome, but failed to meet statyistical significance (P=0.061). A combination of EGFR and HSP90, however, discriminated between different prognostic groups, with EGFRlow/HSP90low tumours showing the worst prognosis in univariate analysis (P=0.001), and in multivariate analysis including the other relevant prognostic factors age, MGMT status and postoperative treatment [n=76; hazard ratio (HR)=0.571; 95% confidence interval (CI) 0.328-0.996; P=0.048]. EGFR expression stratified most pronounced among HSP90low tumours, where the EGFRhigh phenotype was associated with longer survival. Our results reveal a variable reliance on the signalling pathway by EGFR in GBM, IDH-wildtype. Low co-expression was associated with worse prognosis.

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Section: Discussionsupporting

confidence: 93%

Low co-expression of epidermal growth factor receptor and its chaperone heat shock protein 90 is associated with worse prognosis in primary glioblastoma, IDH-wild-type

et al. 2017

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“…Reference genome used was hg19 from the UCSC Genome Browser database (http://hgdownload.cse.ucsc.edu/goldenPath/hg19/bigZips). Specific regions of 47 genes (panel of pan‐cancer genes of interest related to cancer genomics based on current literature) were amplified using the customized Illumina TruSeq Amplicon Cancer Hotspot panel 11. All variants reported were detected with >99% confidence based on the mutation frequency present.…”

Section: Methodsmentioning

confidence: 99%

“…Specific regions of 47 genes (panel of pan-cancer genes of interest related to cancer genomics based on current literature) were amplified using the customized Illumina TruSeq Amplicon Cancer Hotspot panel. 11 All variants reported were detected with >99% confidence based on the mutation frequency present. Mutations including PTEN, TP53 and BRAF and were evaluated by Nextgeneration sequencing (NGS; Illumina MiSeq platform) (Supporting Information Table S3).…”

Section: Mutational Analysismentioning

confidence: 98%

Profiles of brain metastases: Prioritization of therapeutic targets

Ferguson

Zheng

Xiu

et al. 2018

Intl Journal of Cancer

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We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational treatment strategies. Tumor samples were collected from both the primary and metastatic sites of nonsmall cell lung cancer, breast cancer and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next‐generation sequencing with a targeted 47‐gene panel), protein expression (assayed by immunohistochemistry) and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification and mutations among brain metastases, extracranial metastases and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8,178 nonsmall cell lung cancers (5,098 primaries; 2,787 systemic metastases; 293 brain metastases), 7,064 breast cancers (3,496 primaries; 3,469 systemic metastases; 99 brain metastases) and 1,757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1 and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication and/or repair.

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“…Indeed, several recent studies have provided convincing evidence for molecular drifts occurring during glioblastoma progression after (or under) standard therapy. Xiu et al have compared 12 pairs of patient-matched ndGBs and recGBs and found profound changes in the spectrum of biomarkers including MGMT methylation in 94% of samples analyzed [31]. Importantly, loss of MGMT methylation was found to be a more frequent event than acquisition in recGBs.…”

Section: Glioblastoma: General Factsmentioning

confidence: 99%

“…The past decade has been marked by an explosion of exploratory investigations that have applied high-throughput omics to characterizing (epi)genome, transcriptome and metabolome in ndGBs [42][43][44]. For recGBs, high-throughput profiling data are considerably scarcer [25,[31][32][33]. One of the constraining factors is the limited availability of recGB tissue samples due to the fact that only around 25% of patients are considered for open surgery after recurrence [20] and that diagnostic biopsy is not routinely justified for recGBs due to lack of effective treatment options that can be derived from such a biopsy.…”

Section: Molecular Stratification Of Recurrent Glioblasoma: Challengementioning

confidence: 99%

Assessment of Anti-Proliferative Activities of Selected Medicinal Plant Extracts Used for Management of Diseases around Lake Victoria Basin

Swaya¹,

Aduma²,

Chelimo³

et al. 2017

J Carcinog Mutagen

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Glioblastoma is the most common and most malignant type of intrinsic brain tumor in adults. The standard of care for glioblastoma consists of surgical debulking followed by combined radiochemotherapy. The clinical efficacy of standard therapies for newly diagnosed glioblastomas is rather modest with the highest survival rate at 5-years being less than 10%. Inevitable recurrence after cytotoxic therapies poses the major challenge in the clinical management of high grade gliomas. For recurrent glioblastomas, there is no standard therapy with lack of level one evidence for treatment efficacy. Recent evidence indicates that post-therapy recurrence in gliomas is a consequence of a plethora of molecular and cellular factors including intratumoural heterogeneity, functional hierarchy of distinct types of glioma cells, dynamic changes in the molecular landscapes and cellular composition of the tumour during therapy and the impact of particular treatment modalities. There is an emerging consensus that molecular distinctions within and between individual tumours is an important factor determining clinical outcomes. Consequently, integrated approaches based on the combination of molecular profiling with traditional methods such as immunohistochemical phenotyping, karyotyping and/or non-quantitative methylation-specific PCR have emerged as a promising venue towards increasing the predictive value of diagnostics for malignant brain tumors. The high level of inter-and intra-tumoural molecular diversity in gliomas underscores the need of integrating high throughput molecular profiling and pharmacogenomics into a diagnostic paradigm for gliomas and raises the possibility that molecular-instructed personalized treatments may provide clinical benefit to patients with glioblastoma, particularly in the setting of post-treatment recurrence. Here we discuss potential prospects and challenges of patient-tailored diagnostics and personalized treatment strategies for recurrent glioblastomas.

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Multi-platform molecular profiling of a large cohort of glioblastomas reveals potential therapeutic strategies

Cited by 27 publications

References 56 publications

Low co-expression of epidermal growth factor receptor and its chaperone heat shock protein 90 is associated with worse prognosis in primary glioblastoma, IDH-wild-type

Low co-expression of epidermal growth factor receptor and its chaperone heat shock protein 90 is associated with worse prognosis in primary glioblastoma, IDH-wild-type

Profiles of brain metastases: Prioritization of therapeutic targets

Assessment of Anti-Proliferative Activities of Selected Medicinal Plant Extracts Used for Management of Diseases around Lake Victoria Basin

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