TRB Richness and CTC as prognostic factors in the INTEGA trial
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB55475 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR10748000_1.fastq.gz | Fastqsanger.gz | |||
| ERR10748000_2.fastq.gz | Fastqsanger.gz | |||
| ERR10748001_1.fastq.gz | Fastqsanger.gz | |||
| ERR10748001_2.fastq.gz | Fastqsanger.gz | |||
| ERR10748002_1.fastq.gz | Fastqsanger.gz |
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Project description:Introduction: The EORTC22033-26033 clinical trial investigated whether initial temozolomide (TMZ) chemotherapy confers survival advantage compared to radiotherapy (RT) in low grade glioma patients. In this study we performed gene expression profiling on tissues from this trial in order to identify markers associated with progression free survival and treatment response in this well-defined cohort of patients. Methods: Gene expression profiling, performed on 195 samples, was used to assign tumors to one of six intrinsic glioma subtypes (IGS; molecularly similar tumors predefined by unsupervised gene expression analysis) and to extract the cellular composition of immune infiltrates. DNA copy number changes were determined on samples assigned to IGS-16. Results: We confirm that IGS-subtypes are prognostic in EORTC22033-26033 clinical trial samples. Specific genetic changes segregate in distinct IGS subtypes: most samples assigned to IGS-9 have IDH-mutations combined with 1p19q codeletion, samples assigned to IGS-17 have IDH-mutations with intact 1p19q chromosomal arms and samples assigned to other intrinsic subtypes often are IDH-wildtype and 1p19q intact. A trend towards benefit from RT compared to TMZ was observed for samples assigned to IGS-9 (HR for TMZ is 1.90, 95% CI [0.95, 3.80], P=0.065), but not for samples assigned to IGS-17 (HR for TMZ vs RT is 0.87, 95% CI[0.50, 1.51], P=0.62). We did not identify genes significantly associated with progression free survival (PFS) within intrinsic subtypes, though follow-up time is limited. We also show that LGGs and GBMs differ in their immune-infiltrate with LGGs having higher suppressor and lower effector cell populations compared to GBMs. This suggests that LGGs are less amenable to checkpoint inhibitor type immune therapies than GBMs. Gene expression analysis and copy number analysis also identified one patient with a pilocytic astrocytoma (PA). Conclusion: Intrinsic glioma subtypes are prognostic for PFS in EORTC22033-26033 clinical trial samples.
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Project description:Background. We aimed to develop a gene expression-based prognostic signature for isocitrate dehydrogenase (IDH) wild-type glioblastoma using clinical trial datasets representative of glioblastoma clinical trial populations. Results. NanoString data were available from 512 patients in the discovery ATE dataset. Elastic net identified a prognostic signature of nine genes (CHEK1, GPR17, IGF2BP3, MGMT, MTHFD1L, PTRH2, SOX11, S100A9, and TFRC). Translating weighted elastic net scores to an average z-score signature conserved the prognostic value of the ATE signature. The z-score signature was prognostic for OS in the ATE dataset (P < 0.0001), as expected, and in the validation cohorts (AVAglio, P < 0.0001; GLARIUS, P = 0.021; UCLA, P = 0.0037). The signature remained prognostic following adjustment for MGMT promoter methylation status or corticosteroid use at baseline. A positive correlation between the signature and proneural/proliferative subtypes was observed in patients with MGMT non-methylated promoter status. Conclusions. The ATE signature showed prognostic value and may enable clinical trial stratification for IDH wild-type glioblastoma.
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