Pediatric-type high-grade gliomas with PDGFRA amplification in adult patients with Li-Fraumeni syndrome: clinical and molecular characterization of three cases

Abstract

Li-Fraumeni syndrome (LFS) is an autosomal dominant tumor predisposition syndrome caused by heterozygous germline mutations or deletions in the TP53 tumor suppressor gene. Central nervous system tumors, such as choroid plexus tumors, medulloblastomas, and diffuse gliomas, are frequently found in patients with LFS. Although molecular profiles of diffuse gliomas that develop in pediatric patients with LFS have been elucidated, those in adults are limited. Recently, diffuse gliomas have been divided into pediatric- and adult-type gliomas, based on their distinct molecular profiles. In the present study, we investigated the molecular profiles of high-grade gliomas in three adults with LFS. These tumors revealed characteristic histopathological findings of high-grade glioma or glioblastoma and harbored wild-type IDH1/2 according to whole exome sequencing (WES). However, these tumors did not exhibit the key molecular alterations of glioblastoma, IDH-wildtype such as TERT promoter mutation, EGFR amplification, or chromosome 7 gain and 10 loss. Although WES revealed no other characteristic gene mutations or copy number alterations in high-grade gliomas, such as those in histone H3 genes, PDGFRA amplification was found in all three cases together with uniparental disomy of chromosome 17p, where the TP53 gene is located. DNA methylation analyses revealed that all tumors exhibited DNA methylation profiles similar to those of pediatric-type high-grade glioma H3-wildtype and IDH-wildtype (pHGG H3-/IDH-wt), RTK1 subtype. These data suggest that high-grade gliomas developed in adult patients with LFS may be involved in pHGG H3-/IDH-wt. PDGFRA and homozygous alterations in TP53 may play pivotal roles in the development of this type of glioma in adult patients with LFS.

Keywords: PDGFRA amplification; H3-wildtype and IDH-wildtype; Li-Fraumeni syndrome; Pediatric-type high-grade glioma.

Fig. 1

MRI of primary and recurrent tumors in the three cases. A FLAIR (left) and contrast-enhanced T1-weighted (right) images showing the primary tumor in Case 1. B FLAIR (left) and contrast-enhanced T1-weighted (right) images showing the recurrent tumor in Case 1. C FLAIR (left) and contrast-enhanced T1-weighted (right) images showing the primary tumor in Case 2. D Contrast-enhanced T1-weighted image showing the first recurrent tumor in Case 2. E Contrast-enhanced T1-weighted image showing the second recurrent tumor in Case 2. F FLAIR (left) and contrast-enhanced T1-weighted (right) images showing the primary tumor in Case 3. G Contrast-enhanced T1-weighted images showing a recurrent intracranial tumor (left) and cervical tumor (right) in Case 3. T1CE: contrast-enhanced T1-weighted imaging

Fig. 2

HE and IHC of the three tumors. A HE staining findings in Case 1 (left), Case 2 (middle), and Case 3 (right). Scale bar indicates 100 μm. B IHC using anti-GFAP antibody (top), anti-p53 antibody (middle), and anti-Ki-67 antibody (bottom) in Cases 1 (left), 2 (middle), and 3 (right). Scale bar indicates 100 μm

Fig. 3

Gene mutations, copy number alterations, and chromosomal alterations in the three cases. WES data and methylation classifier data were used for mutation analysis and CNV analysis, respectively. Gene mutations (green box), focal gene amplification (red square), and homozygous deletion (blue square) of cyclins/Rb-related genes, mismatch repair genes, TP53-related genes, RTK/Ras/PI3K/AKT genes, chromatin modifiers, histone H3, IDH, and chromosomal alterations (1p/19q codeletion and chromosome 7 gain and 10 loss) in Case 1 (left), Case 2 (middle), and Case 3 (right). Right bar graph indicates the number of cases exhibiting alterations

Fig. 4

Status of TP53 gene and chromosome 17 in the three cases. A Summary of TP53 mutation patterns (germline and tumor), VAF (variant allele frequency) and copy numbers of TP53 in Case 1 (left), Case 2 (middle), and Case 3 (right). B–D Dot plots indicating B allele frequency (BAF) of common SNPs on chromosome 17p and 17q in Case 1 (B), Case 2 (C), and Case 3 (D). Higher and lower mismatch ratios of the SNPs are shown as yellow and blue dots, respectively. A red line indicates TP53 gene. All figures were obtained using WES data

Fig. 5

DNA methylation status of the three cases. A Table indicating methylation classes and calibrated scores obtained at the DKFZ classifier of Case 1, 2 and 3. B t-SNE plot indicating DNA methylation status of diffuse midline glioma, H3 K27-altered (DMG_K27; n = 20), diffuse hemispheric glioma, H3 G34-mutant (DHG_G34; n = 20), glioblastoma, IDH-wildtype (GBM_RTK1; n = 62, GBM_RTK2; n = 143) and pediatric-type high-grade diffuse gliomas (pHGGs), IDH-wildtype and H3 wildtype (pHGG_MYCN; n = 20 pHGG_RTK1; n = 20 and pHGG_RTK2; n = 20) including Case 1 (red), Case 2 (orange), and Case 3 (yellow)