Prospective Clinical Sequencing of Adult Glioma

Zheng, Siyuan; Alfaro-Munoz, Kristin; Wei, Wei; Wang, Xiaojing; Wang, Fang; Eterovic, Agda Karina; Shaw, Kenna; Meric‐Bernstam, Funda; Fuller, Gregory N.; Chen, Ken; Verhaak, Roel G.W.; Mills, Gordon B.; Yung, W. K. Alfred; Weathers, Shiao Pei; Groot, John F. de

doi:10.1158/1535-7163.mct-18-1122

Cited by 16 publications

(12 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Through a survey of more than 45,000 pan-cancer samples, we observed that IDH1 and IDH2 hotspot mutations are uncommon (2%) and extremely rare (0.4%), respectively, in human cancer, a finding in agreement with an independent pan-cancer analysis [37]. Therefore, despite being prevalent in glioma, as reported previously [10,11,14,38], these…”

Section: Discussionsupporting

confidence: 87%

Association of TP53 Alteration with Tissue Specificity and Patient Outcome of IDH1-Mutant Glioma

Murnyák

Huang

2021

Cells

View full text Add to dashboard Cite

Since the initial discovery of recurrent isocitrate dehydrogenase 1 (IDH1) mutations at Arg132 in glioma, IDH1 hotspot mutations have been identified in cholangiocarcinoma, chondrosarcoma, leukemia, and various other types of cancer of sporadic incidence. Studies in glioma and leukemia have helped promote the theory that IDH1 mutations are an oncogenic event that drives tumorigenesis in general. Through bioinformatic analysis of more than 45,000 human pan-cancer samples from three independent datasets, we show here that IDH1 mutations are rare events in human cancer but are exclusively prevalent in WHO grade II and grade III (lower-grade) glioma. Interestingly, alterations in the tumor-suppressor gene TP53 (tumor protein p53) co-occur significantly with IDH1 mutations and show a tendency of exclusivity to IDH2 mutations. The co-occurrence of IDH1 mutation and TP53 alteration is widespread in glioma, particularly in those harboring IDH1R132H, IDH1R132G, and IDH1R132S, whereas co-occurrence of IDH1R132C and TP53 alteration can be found sporadically in other cancer types. In keeping with the importance of p53 in tumor suppression, TP53 status is an independent predictor of overall survival irrespective of histological and molecular subgroups in lower-grade glioma. Together, these results indicate tissue specificity of IDH1 hotspot mutation and TP53 alteration and the importance of TP53 status as a predictor of patient outcome in lower-grade glioma.

show abstract

Section: Discussionsupporting

confidence: 87%

Association of TP53 Alteration with Tissue Specificity and Patient Outcome of IDH1-Mutant Glioma

Murnyák

Huang

2021

Cells

View full text Add to dashboard Cite

show abstract

“…In a separate study of 114 matched pre-and post-treatment GBMs, 17 (15%) showed a hypermutator profile at recurrence; among those 17 cases, 16 had mutations in MMR genes, and showed enrichment for MGMT methylation and IDH1 mutation [28]. Others have verified the association between IDH1 mutations and hypermutation after TMZ [15,27,32]. Among 157 pediatric gliomas, only 9 (6%) were hypermutated, and 7 contained mutations in DNA repair genes [14].…”

Section: Discussionmentioning

confidence: 99%

The efficacy of DNA mismatch repair enzyme immunohistochemistry as a screening test for hypermutated gliomas

McCord

Steffens

Javier

et al. 2020

acta neuropathol commun

View full text Add to dashboard Cite

A subset of gliomas has DNA repair defects that lead to hypermutated genomes. While such tumors are resistant to alkylating chemotherapies, they may also express more mutant neoantigens on their cell surfaces, and thus be more responsive to immunotherapies. A fast, inexpensive method of screening for hypermutated gliomas would therefore be of great clinical value. Since immunohistochemistry (IHC) for the DNA mismatch repair (MMR) proteins Msh2, Msh6, Mlh1, and Pms2 is already used to screen for hypermutated colorectal cancers, we sought to determine whether that panel might have similar utility in gliomas. MMR IHC was scored in 100 WHO grade I-IV gliomas (from 96 patients) with known tumor mutation burden (TMB), while blinded to TMB data. Cases included 70 grade IV GBMs, 13 grade III astrocytomas, 4 grade II astrocytomas (3 diffuse astrocytomas and 1 pleomorphic xanthoastrocytoma), 1 grade I pilocytic astrocytoma, 2 grade III oligodendrogliomas, 7 grade II oligodendrogliomas, and 3 grade I glioneuronal tumors. Eight of 100 tumors showed loss of one or more MMR proteins by IHC, and all 8 were hypermutated. Among the remaining 92 gliomas with intact MMR IHC, only one was hypermutated; that tumor had an inactivating mutation in another DNA repair gene, ATM. Overall accuracy, sensitivity, and specificity for DNA MMR IHC compared to the gold standard of TMB were 99, 89, and 100%, respectively. The strongest correlates with hypermutation were prior TMZ treatment, MGMT promoter methylation, and IDH1 mutation. Among the 8 MMR-deficient hypermutated gliomas, 4 (50%) contained both MMR-lost and MMR-retained tumor cells. Together, these data suggest that MMR IHC could be a viable front-line screening test for gliomas in which immunotherapy is being considered. They also suggest that not all cells in a hypermutated glioma may actually be MMR-deficient, a finding that might need to be considered when treating such tumors with immunotherapies.

show abstract

“…According to TCGA data, frequency of EGFR mutation in GBM and LGG is 26.97 and 6.86% respectively. However, recent research has revealed a higher EGFR mutation frequency of 23% in LGGs, attributing to the different population of patients and deeper sequencing depth [38]. It gave us one hint that frequency of EGFR mutation might be notably underestimated, and it also might be the potential explanation of some rapid progressed lower-grade glioma (histopathological diagnosis) which might essentially be higher-grade glioma in molecular level.…”

Section: Discussionmentioning

confidence: 99%

EGFR mutation: novel prognostic factor associated with immune infiltration in lower-grade glioma; an exploratory study

Hao

Guo

2019

BMC Cancer

View full text Add to dashboard Cite

BackgroundGlioma is one of the most common type of primary central nervous system tumors. EGFR mutation, a common alteration occurs in various tumors, is not brought to the forefront in understanding and treating glioma at present.MethodsIn the present study, we demonstrated an immune infiltration related pattern of EGFR mutation in lower-grade glioma. In silico analyses were performed to investigate EGFR mutation and its biological effects and clinical values. GO and GSEA process were used as enrichment analysis. Infiltration levels of specific types of immune cells were estimated at TIMER database. Clinical data of patients were obtained from TCGA and were employed for survival analyses.ResultsHere we revealed that EGFR mutation leads to an up-regulation of immune response related pathways and dismal prognosis in lower-grade glioma. Infiltration of CD4+ T cells, neutrophils, macrophages, and dendritic cells were significantly increased in EGFR-mutant cases. Infiltration of specific types of immune cells were correlated with shorter survival time. PD-L1 was elevated in EGFR-mutant cases and correlated with infiltration level of CD4+ T cells, neutrophils and dendritic cells.ConclusionEGFR mutation indicates increasing infiltration of specific types of immune cells and poor prognosis in lower-grade glioma. Alteration of immune microenvironment since the EGFR mutation might influence the survival of glioma. We also provided a novel evidence and indicator of PD-1 inhibitor application in glioma.

show abstract

Prospective Clinical Sequencing of Adult Glioma

Cited by 16 publications

References 33 publications

Association of TP53 Alteration with Tissue Specificity and Patient Outcome of IDH1-Mutant Glioma

Association of TP53 Alteration with Tissue Specificity and Patient Outcome of IDH1-Mutant Glioma

The efficacy of DNA mismatch repair enzyme immunohistochemistry as a screening test for hypermutated gliomas

EGFR mutation: novel prognostic factor associated with immune infiltration in lower-grade glioma; an exploratory study

Contact Info

Product

Resources

About