PCR-Based Simple Subgrouping Is Validated for Classification of Gliomas and Defines Negative Prognostic Copy Number Aberrations in IDH Mutant Gliomas

Nakae, Shunsuke; Sasaki, Hidenao; Hayashi, Shoryo; Hattori, Naoko; Kumon, Masanobu; Nishiyama, Yuya; Adachi, Kazuhide; Nagahisa, Shinya; Hayashi, Takuro; Inamasu, Joji; Abe, Masato; Hasegawa, Mitsuhiro; Hirose, Yuichi

doi:10.1371/journal.pone.0142750

Cited by 11 publications

(14 citation statements)

References 26 publications

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“…In contrast to tumors with gain on chromosome 7, there is a lack of evidence to indicate that tumors with 1p/19q codel are composed of multiple lineages. In addition, we recently published a study showing IDH1/2 ‐mutated gliomas without 1p/19q codel were mostly characterized by TP53 mutation, but +7 tumors did not show this mutation . Thus, again, +7q tumors and +7 tumors are genetically distinct in terms of both IDH1/2 and TP53 status, and IDH1/2 ‐mutated tumors could be divided into two groups, 1p/19q‐codeleted TP53 wild‐type tumors and 1p/19q non‐deleted TP53 ‐mutant tumors.…”

Section: Discussionmentioning

confidence: 98%

“…Thick lines to the right of chromosome scheme represent region of relative copy number gain. The +7q tumors and +7 tumors are genetically distinct in terms of both IDH 1/2 and TP 53 status, and show clearly distinct clinical aspects. (b) Schematic illustration of hypothetical genetic pathways associated with glioma development.…”

Section: Discussionmentioning

confidence: 99%

“…Gain of whole chromosome 7 occurs in IDH 1/2 wild type tumors. Note that +7q tumor and +7 (whole) belong to two distinct lineages defined by the IDH 1/2 and TP 53 status …”

Section: Discussionmentioning

confidence: 99%

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World Health Organization grade II–III astrocytomas consist of genetically distinct tumor lineages

et al. 2016

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Recent investigations revealed genetic analysis provides important information in management of gliomas, and we previously reported grade II–III gliomas could be classified into clinically relevant subgroups based on the DNA copy number aberrations (CNAs). To develop more precise genetic subgrouping, we investigated the correlation between CNAs and mutational status of the gene encoding isocitrate dehydrogenase (IDH) of those tumors. We analyzed the IDH status and CNAs of 174 adult supratentorial gliomas of astrocytic or oligodendroglial origin by PCR‐based direct sequencing and comparative genomic hybridization, respectively. We analyzed the relationship between genetic subclassification and clinical features. We found the most frequent aberrations in IDH mutant tumors were the combined whole arm‐loss of 1p and 19q (1p/19q codeletion) followed by gain on chromosome arm 7q (+7q). The gain of whole chromosome 7 (+7) and loss of 10q (−10q) were detected in IDH wild‐type tumors. Kaplan–Meier estimates for progression‐free survival showed that the tumors with mutant IDH, −1p/19q, or +7q (in the absence of +7p) survived longer than tumors with wild‐type IDH, +7, or −10q. As tumors with +7 (IDH wild‐type) showed a more aggressive clinical nature, they are probably not a subtype that developed from the slowly progressive tumors with +7q (IDH mutant). Thus, tumors with a gain on chromosome 7 (mostly astrocytic) comprise multiple lineages, and such differences in their biological nature should be taken into consideration during their clinical management.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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World Health Organization grade II–III astrocytomas consist of genetically distinct tumor lineages

et al. 2016

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“…Gliomas, which are diagnosed based on pathological and genetic ndings, are among the most common brain tumors [1][2][3][4]. Extensive, surgical resection is the preferred initial therapeutic strategy to improve prognosis [5,6]; however, such an approach also increases the risk of brain dysfunction because either the border between the tumor and normal brain tissue is unclear or because tumors in ltrate invasively into adjacent healthy brain tissue.…”

Section: Introductionmentioning

confidence: 99%

Myoinositol to total choline ratio in IDH wild-type gliomas as a prognostic factor on preoperative magnetic resonance spectroscopy

Kumon

Nakae²,

Murayama

et al. 2020

Preprint

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Background: Isocitrate dehydrogenase (IDH) wild-type gliomas tend to be pathologically defined as glioblastomas. We previously reported that, unlike IDH-mutant gliomas, IDH wild-type gliomas showed significantly lower ratios of myoinositol to total choline (i.e., the Ins/Cho ratio) on magnetic resonance (MR) spectroscopy. Given that IDH-mutant gliomas also have much better prognoses than IDH wild-type gliomas, we hypothesized that this lower Ins/Cho ratio is associated with malignancy in adults with supratentorial gliomas. Therefore, we calculated the Ins/Cho ratios of patients with supratentorial IDH wild-type gliomas and investigated their progression free survival (PFS) and overall survival (OS) to determine its utility as a prognostic marker.Methods: We classified IDH wild-type gliomas (n = 30) into two groups based on the Ins/Cho ratios, and compared patient backgrounds, pathological findings, PFS, OS, and copy number aberrations.Results: Compared with the group with high Ins/Cho ratios, the group with low Ins/Cho ratios had shorter PFS (P = 0.020) and OS (P = 0.037) durations. Multivariate analysis demonstrated that the Ins/Cho ratio correlated significantly with PFS (hazard ratio 0.34, P = 0.027). Conclusion: We conclude that the preoperative Ins/Cho ratio can be used as a novel prognostic factor for IDH wild-type gliomas.

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“…However, genetic and chromosomal markers that are strongly associated with patient prognosis such as isocitrate dehydrogenase ( IDH ) 1/2 , TERT promoter, 1p/19 co-deletions, TP53 , and ATRX , have been reported, and their validity has been shown previously [ 1 - 11 ]. Based on these studies, most adult supratentorial gliomas can be genetically classified into IDH wild-type gliomas, IDH mutant gliomas with TP53 or ATRX mutations, or IDH mutant gliomas with 1p/19q co-deletions [ 6 , 8 ]. In the revised WHO classification, an IDH mutation and 1p/19q co-deletions are crucial for a diagnosis of adult supratentorial glioma.…”

Section: Introductionmentioning

confidence: 99%

Remote intracranial recurrence of IDH mutant gliomas is associated with TP53 mutations and an 8q gain

et al. 2017

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Most IDH mutant gliomas harbor either 1p/19q co-deletions or TP53 mutation; 1p/19q co-deleted tumors have significantly better prognoses than tumors harboring TP53 mutations. To investigate the clinical factors that contribute to differences in tumor progression of IDH mutant gliomas, we classified recurrent tumor patterns based on MRI and correlated these patterns with their genomic characterization. Accordingly, in IDH mutant gliomas (N = 66), 1p/19 co-deleted gliomas only recurred locally, whereas TP53 mutant gliomas recurred both locally and in remote intracranial regions. In addition, diffuse tensor imaging suggested that remote intracranial recurrence in the astrocytomas, IDH-mutant with TP53 mutations may occur along major fiber bundles. Remotely recurrent tumors resulted in a higher mortality and significantly harbored an 8q gain; astrocytomas with an 8q gain resulted in significantly shorter overall survival than those without an 8q gain. OncoScan® arrays and next-generation sequencing revealed specific 8q regions (i.e., between 8q22 and 8q24) show a high copy number. In conclusion, only tumors with TP53 mutations showed patterns of remote recurrence in IDH mutant gliomas. Furthermore, an 8q gain was significantly associated with remote intracranial recurrence and can be considered a poor prognostic factor in astrocytomas, IDH-mutant.

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PCR-Based Simple Subgrouping Is Validated for Classification of Gliomas and Defines Negative Prognostic Copy Number Aberrations in IDH Mutant Gliomas

Cited by 11 publications

References 26 publications

World Health Organization grade II–III astrocytomas consist of genetically distinct tumor lineages

World Health Organization grade II–III astrocytomas consist of genetically distinct tumor lineages

Myoinositol to total choline ratio in IDH wild-type gliomas as a prognostic factor on preoperative magnetic resonance spectroscopy

Remote intracranial recurrence of IDH mutant gliomas is associated with TP53 mutations and an 8q gain

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