Predicting the likelihood of an isocitrate dehydrogenase 1 or 2 mutation in diagnoses of infiltrative glioma

Chen, Li; Voronovich, Zoya; Clark, Kenneth; Hands, Isaac; Mannas, Jonathan P.; Walsh, Meggen; Nikiforova, Marina N.; Durbin, Eric B.; Weiss, Heidi L.; Horbinski, Craig

doi:10.1093/neuonc/nou097

Cited by 70 publications

(46 citation statements)

References 16 publications

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“…ATRX loss is caused by corresponding gene mutations, while s trong p53 immunostaining in > 10% neoplastic cells is highly correlated with TP53 mutation in diffuse gliomas . In this study, 41% of IDH mutant astrocytomas had no ATRX mutation/protein loss, which is in line with ATRX retention previously found in IDH mutant diffuse gliomas from patients at ≥ 55 years in other studies . Conversely, although ATRX loss is considered to be mutually exclusive with 1p/19q codeletion, two ODs had ATRX mutation.…”

Section: Discussionsupporting

confidence: 89%

“…The incidence of IDH mutations in diffuse gliomas is strongly associated with the age of patients, and it was reported to be very low in patients ≥ 55 years (around 2%) . Therefore, in this era of heightened cost‐consciousness, it has been questioned whether immunohistochemistry against IDH1 R132H or DNA sequencing for other IDH1 or IDH2 mutations should be performed in all diffuse gliomas of patients of 55 years or over . Due to the very low prevalence (< 1%) of GBMs with non‐canonical IDH mutations in patients ≥ 55 years, WHO suggests that immunohistochemistry against IDH1 R132H is sufficient to classify these tumors as IDH wild‐type .…”

Section: Introductionmentioning

confidence: 99%

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Diffuse gliomas in patients aged 55 years or over: A suggestion for IDH mutation testing

et al. 2019

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Diffuse gliomas are defined on the isocitrate dehydrogenase (IDH) gene (IDH) mutational mutational status. The most frequent IDH mutation is IDH1 R132H, which is detectable by immunohistochemistry; other IDH mutations are rare (10%). IDH mutant gliomas have better prognosis. Further, IDH wild-type low-grade (II/III) gliomas have clinical behaviors similar to those of glioblastoma (GBM) and it was suggested that they are submitted to similar post-surgical treatment. The incidence of IDH mutant gliomas (2%) and that of GBMs with non-canonical IDH mutations (< 1%) are very low in patients ≥ 55 years. For this reason, it was suggested that immunohistochemistry against IDH1 R132H is sufficient to classify GBM as IDH wild-type in this age group. However, no indication was provided for IDH mutational testing in low-grade diffuse gliomas. To address this issue, 273 diffuse gliomas were tested for IDH1 R132H immunohistochemistry. 2/4 diffuse astrocytomas (DAs), 4/9 anaplastic astrocytomas (AAs), 2/256 GBMs, and 4/4 oligodendrogliomas had positive staining. No other IDH mutations were found in immuno-negative low-grade cases by DNA sequencing. To validate our findings, we considered 311 diffuse gliomas in patients ≥ 55 years in The Cancer Genome Atlas database. Fifty-five out of 311 gliomas had IDH R132H mutations (9/16 DAs; 8/48 AAs; 3/211 GBMs; 35/36 oligodendrogliomas), one DA, and one oligodendroglioma had other IDH mutations. IDH mutant gliomas had significantly higher frequency of O-6-methylguanine-DNA methyltransferase promoter methylation (P = 0.0008) and longer overall survival (P < 0.0001).In conclusion, low-grade gliomas are a minor part of gliomas (117/584) in patients ≥ 55 years, albeit they represent most IDH mutant gliomas in this age group (64/69 cases). IDH non-canonical mutations can be found in immunonegative low-grade gliomas (2/54). In view of its significance for prognosis and therapeutic management, our results suggest that IDH mutational status is assessed in all diffuse gliomas in patients ≥ 55 years by immunohistochemistry, followed by IDH sequencing in low-grade immunonegative cases.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Diffuse gliomas in patients aged 55 years or over: A suggestion for IDH mutation testing

et al. 2019

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“…In diffuse glioma, the IDH status is essential for integrated diagnosis by the WHO classification system (2016). [14][15][16] In cerebellar high-grade gliomas, IDH mutations are rarely reported. The majority of these mutations in diffuse glioma are IDH1 R132H, 13 and IDH mutations other than IDH1 R132H are rare in patients older than 55 years.…”

Section: Discussionmentioning

confidence: 99%

“…The majority of these mutations in diffuse glioma are IDH1 R132H, 13 and IDH mutations other than IDH1 R132H are rare in patients older than 55 years. [14][15][16] In cerebellar high-grade gliomas, IDH mutations are rarely reported. 1,4,[6][7][8] In addition, there are only a few reports of IDH-mutated diffuse gliomas of infratentorial origin.…”

Section: Discussionmentioning

confidence: 99%

Cerebellar high‐grade astrocytoma with IDH mutations in the elderly: A report of two cases

et al. 2018

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Cerebellar high-grade gliomas are rare, and likely to affect younger patients compared with those of cerebral origin. Recent genetic analyses have revealed that isocitrate dehydrogenase (IDH) 1/2 mutations are rare in infratentorial gliomas. In this paper, we report two elderly cases of IDH-mutated cerebellar high-grade glioma with unusual histological features and uncommon patient ages. One case was an 83-year-old man, whose tumor was predominantly composed of densely packed round-to-polygonal epithelioid cells. The other was a 75-year-old woman's high-grade astrocytoma characterized by cord-like structures and the perivascular papillary arrangements with varying amounts of myxoid matrix. The former harbored IDH1 R132H mutation, whereas the latter had IDH2 R172K mutation. According to our literature review, eight cases of IDH-mutated infratentorial gliomas including the present cases have been reported, and four had mutations other than IDH1 R132H. Moreover, we herein report the first elderly case of IDH2-mutation. Although the number is limited, IDH-mutant infratentorial diffuse gliomas may have clinical, histological and genetic features different from supratentorial cases.

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“…With IDH1 IHC, when the result is clearly immunopositive (and in our experience the immunostain has high fidelity and is usually easy to interpret, with either all tumor cells positive or negative), then no additional mutational confirmation is necessary. If IDH1 IHC is negative, then mutational testing for IDH1/ IDH2 mutation should be done in select patient groups including younger patients to rule out the rare types of IDH1/IDH2 mutation not detected by the antibody; a predictive algorithm has been recently developed and is online for directing IDH1/2 testing [23]. …”

Section: Discussionmentioning

confidence: 99%

BRAF VE1 Immunoreactivity Patterns in Epithelioid Glioblastomas Positive for BRAF V600E Mutation

Kleinschmidt‐DeMasters

Aisner²,

Foreman

2015

American Journal of Surgical Pathology

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Background Epithelioid glioblastomas (E-GBMs) manifest BRAF V600E mutation in up to fifty percent of cases, compared to a small percentage of ordinary GBMs, suggesting they are best considered variants rather than a different pattern of GBM. Availability of a targeted therapy, vemurafenib, may make testing BRAF status important for treatment. It is unclear whether BRAF VE1 immunohistochemistry (IHC) can substitute for Sanger sequencing in these tumors. Design BRAF VE1 IHC was correlated with Sanger sequencing results on our original cohort of E-GBMs, and then new E-GBM cases were tested with both techniques (n=20). Results were compared to those in similarly-assessed giant cell GBMs, anaplastic pleomorphic xanthoastrocytomas (A-PXAs). Results All tumors tested showed 1:1 correlation between BRAF V600E mutational results and IHC. However, heavy background immunostaining in some negatively-mutated cases resulted in equivocal results that required repeat IHC testing and additional mutation testing using a different methodology to confirm lack of detectable BRAF mutation. Mutated/ BRAF VE1 IHC+ E-GBMs and A-PXAs tended to manifest strong, diffuse cytoplasmic immunoreactivity, compared to previously-studied GGs which demonstrate more intense immunoreactivity in the ganglion, than glial, tumor component. One of our E-GBM patients with initial gross total resection quickly recurred within 4 months, required a second resection, and then was placed on vemurafenib; she remains tumor-free 21 months after second resection without neuroimaging evidence of residual disease, adding to the growing number of reports of successful treatment of BRAF-mutated glial tumors with drug. Conclusions E-GBMs show good correlation between mutational status and IHC, albeit with limitations to IHC. E-GBMs can respond to targeted therapy.

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Predicting the likelihood of an isocitrate dehydrogenase 1 or 2 mutation in diagnoses of infiltrative glioma

Abstract: We have integrated multiple variables to generate a probability of an IDH1/2 mutation. The associated web-based application can help triage diffuse gliomas that would benefit from mutation testing in both clinical and research settings.

Cited by 70 publications

References 16 publications

Diffuse gliomas in patients aged 55 years or over: A suggestion for IDH mutation testing

Diffuse gliomas in patients aged 55 years or over: A suggestion for IDH mutation testing

Cerebellar high‐grade astrocytoma with IDH mutations in the elderly: A report of two cases

BRAF VE1 Immunoreactivity Patterns in Epithelioid Glioblastomas Positive for BRAF V600E Mutation

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