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.
Project description:Breast cancers contain a minority population of cancer cells characterized by CD44 expression but low or undetectable levels of CD24 (CD44+CD24-/low) that have higher tumorigenic capacity than other subtypes of cancer cells. METHODS: We compared the gene-expression profile of CD44+CD24-/low tumorigenic breast-cancer cells with that of normal breast epithelium. Differentially expressed genes were used to generate a 186-gene invasiveness gene signature (IGS), which was evaluated for its association with overall survival and metastasis-free survival in patients with breast cancer or other types of cancer. RESULTS: There was a significant association between the IGS and both overall and metastasis-free survival (P<0.001, for both) in patients with breast cancer, which was independent of established clinical and pathological variables. When combined with the prognostic criteria of the National Institutes of Health, the IGS was used to stratify patients with high-risk early breast cancer into prognostic categories (good or poor); among patients with a good prognosis, the 10-year rate of metastasis-free survival was 81%, and among those with a poor prognosis, it was 57%. The IGS was also associated with the prognosis in medulloblastoma (P=0.004), lung cancer (P=0.03), and prostate cancer (P=0.01). The prognostic power of the IGS was increased when combined with the wound-response (WR) signature. CONCLUSIONS: The IGS is strongly associated with metastasis-free survival and overall survival for four different types of tumors. This genetic signature of tumorigenic breast-cancer cells was even more strongly associated with clinical outcomes when combined with the WR signature in breast cancer. Keywords: cell type comparison
Project description:In vitro cortex generated from embryonic stem cells (ESCs) is a model system to investigate corticogenesis and a promising tool for cortical therapy. A fundamental question that has implications for understanding corticogenesis and for using stem cells therapeutically is to determine whether in vitro cortex reproduces some fine-tuned epigenetic modifications that are important for corticogenesis and function in vivo such as parent-of-origin dependent DNA methylation and expression of imprinted genes (IGs). Here, we have compared at single-base resolution the parent-of-origin dependent DNA methylation and expression of IGs in hybrid cortices generated either in vivo or in vitro from ESCs using Reduced Representation Bisulfite Sequencing (RRBS) and RNA-seq. We report that in vitro cortex strictly reproduced the in vivo parental expression of 41 IGs, including those involved in corticogenesis such as Mest (paternal) and Cdkn1c (maternal). The expressed allele was set in ESCs and maintained during in vitro corticogenesis for most IGs but some switched from a biallelic expression in ESCs to the monoallelic expression observed in vivo. RRBS experiments revealed that parent-of-origin dependent methylation at imprinted loci were also largely similar in in vitro and in vivo cortices except at a few loci. The most discordant locus was Gpr1-Zdbf2: Zdbf2 RNA was paternal in vivo and biallelic in vitro, and this was concomitant with an aberrant gain of methylation on the maternal allele in vitro. Thus, we conclude that the epigenetic mechanisms at imprinted loci are largely but not strictly preserved in vitro. We propose that in vitro corticogenesis, with its set of IGs displaying faithful parent-of-origin dependent expression and methylation, helps to define the poorly known mechanisms regulating imprinting in the brain and roles of IGs during corticogenesis.