Molecular Study of Long-Term Survivors of Glioblastoma by Gene-Targeted Next-Generation Sequencing

Cantero, Diana; Lope, Andreu; Presa, Raquel Moreno de la; Sepúlveda, Juan Manuel; Borrás, José M.; Castresana, Javier S.; D’Haene, Nicky; Garcı́a, Juan F.; Salmon, Isabelle; Mollejo, Manuela; Rey, Juan A.; Hernández-Laín, Aurelio; Meléndez, Bárbara

doi:10.1093/jnen/nly048

Cited by 35 publications

(33 citation statements)

References 27 publications

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“…This was also the case for MGMT mRNA expression [65]. Moreover, an interesting observation is the involvement of alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene in longer survival of glioblastoma patients [6,70]. Using a gene-targeted next-generation sequencing panel, Cantero et al found better prognosis for glioblastoma patients whose tumors present with ATRX or DAXX mutations in the absence of IDH or H3F3A mutations [70].…”

Section: Long-term Glioblastoma Survivorsmentioning

confidence: 91%

“…Moreover, an interesting observation is the involvement of alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene in longer survival of glioblastoma patients [6,70]. Using a gene-targeted next-generation sequencing panel, Cantero et al found better prognosis for glioblastoma patients whose tumors present with ATRX or DAXX mutations in the absence of IDH or H3F3A mutations [70]. Similar findings were published by Chaurasia et al who reported significantly higher OS and progression-free survival (PFS) in glioblastoma patients with alpha thalassemia/mental retardation syndrome X-linked (ATRX) and IDH1 mutant protein expression (ATRX-and IDH+, respectively) [6].…”

Section: Long-term Glioblastoma Survivorsmentioning

confidence: 99%

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Genetic secrets of long-term glioblastoma survivors

Jovčevska

2018

Bosn J of Basic Med Sci

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Glioblastomas account for the majority of primary brain tumors. Although glioblastomas are considered as rare diseases, they represent 60%-70% of all gliomas and in most cases have fatal consequences. Genetic analyses show great heterogeneity both intratumor and intertumor. This notion opens up debates about glioblastoma origin. Different brain cells including astrocytes, neural stem cells, oligodendrocyte precursor cells and glioblastoma stem cells are proposed as capable of initiation and reseeding a tumor; however data is still inconclusive. Due to high mortality rate, long term glioblastoma survivors are defined as patients who live longer than 2 years post diagnosis. Extreme survivors, living 10 years or more after diagnosis, comprise less than 1% of all patients. Molecular testing suggests differences in the genetic profiles of glioblastoma between short and long term survivors. The most informative indicators are IDH mutations and MGMT promotor methylation. Other genes like FBLN4, EMP3, IGFBP-2, IGFBP-3, LGALS3, MAOB, PDPN, SERPING1 and TIMP1 have also been associated with glioblastoma prolonged survival. Emerging evidence proposes roles of different microRNAs in predicting patient survival. Moreover, clinical features like seizures as a symptom at presentation, age at diagnosis, and the extent of the surgical resection are also factors that influence the length of survival. Because of the small number of long term survivors, it is difficult to examine these samples and draw conclusions about the genetics of glioblastoma longevity. To aid in the clinical care, a thorough "omics" approach is necessary for identifying differences between short and long term glioblastoma survivors.

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Section: Long-term Glioblastoma Survivorsmentioning

confidence: 91%

Section: Long-term Glioblastoma Survivorsmentioning

confidence: 99%

Genetic secrets of long-term glioblastoma survivors

Jovčevska

2018

Bosn J of Basic Med Sci

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“…Therefore, we sought to identify other variables that could potentially predict clinical outcomes prior to vaccination initiation. Because 3-y survival is a very common cutoff to define LTS in GBM clinical studies, [8][9][10][11] we first stratified patients into long-term survivors (LTS, >3 y) and short-term survivors (STS, ≤3 y).…”

Section: Baseline Clinical Characteristics Of Long-and Short-term Surmentioning

confidence: 99%

T cell receptor repertoire as a prognosis marker for heat shock protein peptide complex-96 vaccine trial against newly diagnosed glioblastoma

Zhang

Mudgal²,

Wang

et al. 2020

OncoImmunology

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Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults with a dismal prognosis. We previously reported that vaccination with heat shock protein peptide complex-96 (HSPPC-96) improves survival in patients with newly diagnosed GBM (NCT02122822). Especially for patients with a strong antitumor immune response after vaccination, a durable survival benefit can be achieved. Here, we conducted T cell receptor (TCR) sequencing to retrospectively examine the TCR repertoires of tumor-infiltrating lymphocytes in long-term survivors (LTS) and short-term survivors (STS). We found that LTS exhibit lower TCR repertoire diversity compared with STS, indicating the prevalence of dominant TCR clones in LTS tumors. Accordingly, the LTS group showed increased inter-patient similarity, especially among high-frequency TCR clones, implying some of these dominant clones are shared among LTS. Indeed, we discovered four TCR clones significantly enriched in the LTS group: the presence of these clones has predictive value for stratifying patients prior to vaccination. Together, these findings uncover a group of preexisting TCR clones shared in LTS that can be utilized as candidate biomarkers to select GBM patients most likely to durably respond to HSPPC-96 treatment.

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“…We used a custom Ampliseq (PCR-based) gene-targeted NGS panel that analyze 30 genes that were previously demonstrated to be frequently mutated in gliomas 12 . DNA from formalinfixed paraffin-embedded (FFPE) tumor tissues was extracted using the QIAamp DNA FFPE Tissue Kit (Qiagen).…”

Section: Molecular Characterization Of the Tumorsmentioning

confidence: 99%

Immune profiling of gliomas reveals a connection with Tau function and the tumor vasculature

Cejalvo

Gargini

Segura-Collar

et al. 2020

Preprint

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BackgroundGliomas remain refractory to all attempted treatments, including those using immune checkpoint inhibitors. The characterization of the tumor (immune) microenvironment has been recognized as an important challenge to get a mechanistic explanation for this lack of response and to improve the therapy of glial tumors.MethodsWe designed a prospective analysis of the hematopoietic cells of gliomas by flow cytometry. Tumors with or without isocytrate dehydrogenase 1/2 (IDH1/2) mutations were included in the study. The genetic profile and the presence of different molecular and cellular features of the gliomas were analyzed in parallel. The findings were validated in mouse glioma models.ResultsWe observed that few immune cells infiltrate mutant IDH1/2 gliomas and we distinguished two different profiles in their IDH1/2 wild-type counterparts. The first one has an important immune component, particularly enriched in myeloid cells with immunosuppressive features. The second group is more similar to mutant IDH1/2 gliomas, with few immune cells and a less immunosuppressive profile. Notably, we observed a direct correlation between the immune content and the presence of vascular alterations, which were associated with a reduced expression of Tau, a microtubule-binding-protein that controls the formation of tumor vessels in gliomas. Furthermore, overexpression of Tau was able to reduce the immune content in orthotopic mouse glioma models, delaying tumor growth.ConclusionsThere is a correlation between vascular alterations and the immune profile of gliomas, which could be exploited for the design of more successful clinical trials with immunomodulatory molecules.

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Molecular Study of Long-Term Survivors of Glioblastoma by Gene-Targeted Next-Generation Sequencing

Cited by 35 publications

References 27 publications

Genetic secrets of long-term glioblastoma survivors

Genetic secrets of long-term glioblastoma survivors

T cell receptor repertoire as a prognosis marker for heat shock protein peptide complex-96 vaccine trial against newly diagnosed glioblastoma

Immune profiling of gliomas reveals a connection with Tau function and the tumor vasculature

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