Molecular Subtypes of Glioblastoma Are Relevant to Lower Grade Glioma

Guan, Xiaowei; Vengoechea, Jaime; Zheng, Siyuan; Sloan, Andrew E.; Chen, Yanwen; Brat, Daniel J.; O’Neill, Brian Patrick; Groot, John de; Yust‐Katz, Shlomit; Yung, W. K. Alfred; Cohen, Mark L.; Aldape, Kenneth; Rosenfeld, Steven S.; Verhaak, Roeland; Barnholtz‐Sloan, Jill S.

doi:10.1371/journal.pone.0091216

Cited by 82 publications

(90 citation statements)

References 32 publications

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“…Our observation of high divergence between PBMC and TIL repertoires in LGG and some GBM provides evidence of tumor-associated T-cell responses in glioma. This overall approach may offer new insight into the coevolution of antitumor reactivity with tumor progression (41) independent and synergistically with gene expression-based immune profiling (45).…”

Section: Discussionmentioning

confidence: 99%

Diversity and divergence of the glioma-infiltrating T-cell receptor repertoire

Sims

Grinshpun

Feng

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Although immune signaling has emerged as a defining feature of the glioma microenvironment, how the underlying structure of the glioma-infiltrating T-cell population differs from that of the blood from which it originates has been difficult to measure directly in patients. High-throughput sequencing of T-cell receptor (TCR) repertoires (TCRseq) provides a population-wide statistical description of how T cells respond to disease. We have defined immunophenotypes of whole repertoires based on TCRseq of the α-and β-chains from glioma tissue, nonneoplastic brain tissue, and peripheral blood from patients. Using information theory, we partitioned the diversity of these TCR repertoires into that from the distribution of VJ cassette combinations and diversity due to VJ-independent factors, such as selection due to antigen binding. Tumor-infiltrating lymphocytes (TILs) possessed higher VJ-independent diversity than nonneoplastic tissue, stratifying patients according to tumor grade. We found that the VJ-independent components of tumor-associated repertoires diverge more from their corresponding peripheral repertoires than T-cell populations in nonneoplastic brain tissue, particularly for low-grade gliomas. Finally, we identified a "signature" set of TCRs whose use in peripheral blood is associated with patients exhibiting low TIL divergence and is depleted in patients with highly divergent TIL repertoires. This signature is detectable in peripheral blood, and therefore accessible noninvasively. We anticipate that these immunophenotypes will be foundational to monitoring and predicting response to antiglioma vaccines and immunotherapy.T-cell receptor | immunoprofiling | glioma | glioblastoma | immunooncology T he potential for immunotherapy to alleviate progression and recurrence in glioma has inspired intense study of the immunological phenotypes underlying the regulation and selection of tissue-infiltrating lymphocytes (TILs). Motivated by the prospect of targeted therapy, previous studies of glioma have undertaken large-scale genomic and gene expression analysis. These studies revealed distinct phenotypic states or subtypes that stratify gliomas and resemble different glial lineages (1-3). Although immunological gene expression classifications have been associated with clinical outcomes and prognosis (4, 5), precision immunotherapy will ultimately rely on manipulation of the T-cell population that infiltrates gliomas and its underlying repertoire of T-cell receptors (TCRs). However, the structure and intertumoral heterogeneity of the TIL population in gliomas has not been described. Here, we use whole repertoire sequencing of TCRs from glioma tissue and matched peripheral blood to discover novel immunological phenotypes with implications for noninvasive patient monitoring.Local antitumor potential is, in part, a function of the TCR repertoire expressed by T cells that surveil the CNS beyond the bloodbrain barrier. Through somatic V(D)J recombination including random nucleotide insertion in each T-cell, the α-and β-cha...

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Section: Discussionmentioning

confidence: 99%

Diversity and divergence of the glioma-infiltrating T-cell receptor repertoire

Sims

Grinshpun

Feng

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Global gene expression of gliomas has been extensively studied over the past decade [31,40,105,108,146]. The best known expression-based molecular classification subdivides glioblastoma and anaplastic astrocytoma into 3 classes (Proneural, Mesenchymal or Proliferative) or glioblastomas into 4 subtypes (Proneural, Neural, Classical and Mesenchymal), which are largely comparable [40,108,146].…”

Section: Comprehensive Genome Analysismentioning

confidence: 99%

“…The best known expression-based molecular classification subdivides glioblastoma and anaplastic astrocytoma into 3 classes (Proneural, Mesenchymal or Proliferative) or glioblastomas into 4 subtypes (Proneural, Neural, Classical and Mesenchymal), which are largely comparable [40,108,146]. The latter has been shown to be applicable to astrocytomas and oligodendrogliomas as well [40].…”

Section: Comprehensive Genome Analysismentioning

confidence: 99%

Diffusely infiltrating astrocytomas: pathology, molecular mechanisms and markers

Ichimura¹,

Narita²,

Hawkins

2015

Acta Neuropathol

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Diffusely infiltrating astrocytomas include diffuse astrocytomas WHO grade II and anaplastic astrocytomas WHO grade III and are classified under astrocytic tumours according to the current WHO Classification. Although the patients generally have longer survival as compared to those with glioblastoma, the timing of inevitable malignant progression ultimately determines the prognosis. Recent advances in molecular genetics have uncovered that histopathologically diagnosed astrocytomas may consist of two genetically different groups of tumours. The majority of diffusely infiltrating astrocytomas regardless of WHO grade have concurrent mutations of IDH1 or IDH2, TP53 and ATRX. Among these astrocytomas, no other genetic markers that may distinguish grade II and grade III tumours have been identified. Those astrocytomas without IDH mutation tend to have a distinct genotype and a poor prognosis comparable to that of glioblastomas. On the other hand, diffuse astrocytomas that arise in children do not harbour IDH/TP53 mutations, but instead display mutations of BRAF or structural alterations involving MYB/MYBL1 or FGFR1. A molecular classification may thus help delineate diffusely infiltrating astrocytomas into distinct pathogenic and prognostic groups, which could aid in determining individualised therapeutic strategies.

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“…Codeletion of chromosomes 1p and 19q, long identifi ed as a favorable prognostic feature in oligodendroglial tumors, was found in many grade II and III tumors as well. The combination of IDH-1 mutation/CIMP+ and 1p;19q codeleted molecular signature predicted longer survival when compared to IDH-1 wild-type/ CIMP− and 1p;19q non-deleted tumors independent of tumor histology [ 7 ].…”

Section: Classifi Cation and Gradingmentioning

confidence: 89%