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Background <p>The non-canonical <i>isocitrate dehydrogenase 1</i> (<i>IDH1</i>) R132C mutation is rare in diffuse gliomas but appears to be enriched in tumors associated with Li-Fraumeni syndrome (LFS), which is caused by germline tumor protein p53 (<i>TP53</i>) mutations. However, the molecular relationship between <i>TP53</i> alterations and <i>IDH1</i> R132C, as well as the prevalence of LFS among patients with R132C–mutant gliomas, remains unclear.</p> Methods <p>We analyzed 93 consecutive patients retrospectively with <i>IDH1</i>–mutant diffuse gliomas (Central Nervous System World Health Organization (CNS WHO) Grades 2 and 3) treated at our institution between 2005 and 2025. <i>IDH, TP53</i>, and <i>ATRX</i> status were assessed by immunohistochemistry, Sanger sequencing, multiplex ligation-dependent probe amplification, and targeted next-generation sequencing. Germline <i>TP53</i> mutations were assessed using peripheral blood samples. DNA methylation profiling was performed using the Methylscape platform and the DKFZ methylation classifier.</p> Results <p>Three of 90 <i>IDH1</i>-mutant gliomas (3%) harbored the R132C variant. All three tumors were astrocytomas with concurrent <i>TP53</i> mutation, <i>ATRX</i> alteration, and 1p/19q non-codeletion. Exploratory cancer cell fraction analysis suggested that both <i>IDH1</i> R132C and <i>TP53</i> mutations were present in the major tumor cell population, supporting a biological association between <i>TP53</i> alterations and the occurrence of the <i>IDH1</i> R132C variant. One patient harbored a pathogenic germline <i>TP53</i> mutation despite lacking a family history or fulfilling the established clinical diagnostic criteria for LFS. DNA methylation analysis demonstrated partial overlap with conventional <i>IDH</i>–mutant astrocytoma and also revealed atypical clustering patterns.</p> Conclusions <p><i>IDH1</i> R132C-mutant gliomas are characterized by concurrent <i>TP53</i> mutation, <i>ATRX</i> alteration, and 1p/19q non-codeletion. Although based on a small cohort, our findings support a biological association between <i>TP53</i> alterations and the rare <i>IDH1</i> R132C variant and suggest that germline <i>TP53</i> testing may be considered in selected patients, particularly younger individuals, to identify previously unrecognized Li-Fraumeni syndrome.</p>

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Molecular characteristics of isocitrate dehydrogenase 1 R132C–mutant diffuse gliomas: association with TP53 alterations and Li-Fraumeni syndrome

  • 期刊论文

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  • 发表日期：

    2026年7月3日

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  • Shinji Yamashita,
  • Fumitaka Matsumoto,
  • Kiyotaka Saito,
  • Masato Hidaka,
  • Souma Arikawa,
  • Tomoki Kawano,
  • Tomohiro Kawano,
  • Mitsuru Tamura,
  • Hironobu Okuyama,
  • Nayuta Higa,
  • Ryosuke Hanaya,
  • Toshiaki Akahane,
  • Akihide Tanimoto,
  • Yuichiro Sato,
  • Yoshiko Okita

摘要

Background

The non-canonical isocitrate dehydrogenase 1 (IDH1) R132C mutation is rare in diffuse gliomas but appears to be enriched in tumors associated with Li-Fraumeni syndrome (LFS), which is caused by germline tumor protein p53 (TP53) mutations. However, the molecular relationship between TP53 alterations and IDH1 R132C, as well as the prevalence of LFS among patients with R132C–mutant gliomas, remains unclear.

Methods

We analyzed 93 consecutive patients retrospectively with IDH1–mutant diffuse gliomas (Central Nervous System World Health Organization (CNS WHO) Grades 2 and 3) treated at our institution between 2005 and 2025. IDH, TP53, and ATRX status were assessed by immunohistochemistry, Sanger sequencing, multiplex ligation-dependent probe amplification, and targeted next-generation sequencing. Germline TP53 mutations were assessed using peripheral blood samples. DNA methylation profiling was performed using the Methylscape platform and the DKFZ methylation classifier.

Results

Three of 90 IDH1-mutant gliomas (3%) harbored the R132C variant. All three tumors were astrocytomas with concurrent TP53 mutation, ATRX alteration, and 1p/19q non-codeletion. Exploratory cancer cell fraction analysis suggested that both IDH1 R132C and TP53 mutations were present in the major tumor cell population, supporting a biological association between TP53 alterations and the occurrence of the IDH1 R132C variant. One patient harbored a pathogenic germline TP53 mutation despite lacking a family history or fulfilling the established clinical diagnostic criteria for LFS. DNA methylation analysis demonstrated partial overlap with conventional IDH–mutant astrocytoma and also revealed atypical clustering patterns.

Conclusions

IDH1 R132C-mutant gliomas are characterized by concurrent TP53 mutation, ATRX alteration, and 1p/19q non-codeletion. Although based on a small cohort, our findings support a biological association between TP53 alterations and the rare IDH1 R132C variant and suggest that germline TP53 testing may be considered in selected patients, particularly younger individuals, to identify previously unrecognized Li-Fraumeni syndrome.