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<p>Polymorphous low-grade neuroepithelial tumors of the young (PLNTY) are slow- or non-progressing epileptogenic tumors, typically occurring in young adults. These tumors are highly calcified and exhibit both diffuse growth and oligodendroglioma-like patterns. Epithelioid glioblastomas (E-GB) are rare and aggressive variants of isocitrate dehydrogenase wildtype glioblastomas (GB), associated with poor overall survival. Both PLNTY and E-GB often carry oncogenic <i>BRAF</i> V600E mutation (BRAF<sub>V600E</sub>). In this case study, we analyzed clinical and genetic data from a single patient who, based on extensive histological and molecular evaluation, was diagnosed to carry PLNTY-like tumor that progressed into E-GB years later. The aim of our study was to uncover the genetic drivers and the evolutionary history of these tumors. Progression of the PLNTY-like tumor into E-GB was investigated using histology, chromosomal karyotyping, whole-genome sequencing (WGS), and RNA sequencing. A typical immunohistochemical stain pattern of CD34 positivity was detected in the apparent PLNTY, whereas it was depleted in the E-GB sample, as expected. WGS analysis of the PLNTY and three E-GB samples revealed four genes with shared somatic protein-altering mutations: <i>BRAF</i> (carrying BRAF<sub>V600E</sub>)<i>,</i> clonal in both PLNTY and E-GB, as well as <i>GNS, FOXRED2</i>, and <i>SSTR5</i>, which were subclonal in PLNTY and clonal in E-GB. Both the PLNTY-like and E-GB tumors also carried highly similar copy number alteration profiles with a prominent loss of heterozygosity (LOH) in the majority of the chromosomes, suggesting their monoclonal origin. PLNTY-like tumor was mainly diploid, and the tumor underwent a genome-wide duplication event during the progression to E-GB. Furthermore, two focal rearrangements leading to homozygous deletion of <i>CDKN2A/B</i> were detected in E-GB samples. In conclusion, this study revealed unusually extensive LOH in the histologically and genetically supported PLNTY-like tumor that progressed into E-GB. Notably, only a limited set of genetic alterations was associated with malignant transformation beyond genome duplication, the <i>CDKN2A/B</i> inactivation representing the best-known oncogenic driver for malignant transformation. These findings suggest that genomic profiling may be a valuable tool for the diagnosis and prognostic assessment of low-grade neuroepithelial lesions.</p>

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Genomic analysis of PLNTY-like tumor progression into epithelioid glioblastoma: a case report

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月8日

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  • Sonja Mäntylä,
  • Anssi Nurminen,
  • Sanna Huovinen,
  • Serafiina Jaatinen,
  • Teppo Haapaniemi,
  • Riikka Nurminen,
  • Ismaïl Hermelo,
  • Stefanie Volz,
  • Kendra K. Maaß,
  • Kristian W. Pajtler,
  • Kristiina Nordfors,
  • Hannu Haapasalo,
  • Matti Nykter,
  • Joonas Haapasalo,
  • Kirsi J. Rautajoki

摘要

Polymorphous low-grade neuroepithelial tumors of the young (PLNTY) are slow- or non-progressing epileptogenic tumors, typically occurring in young adults. These tumors are highly calcified and exhibit both diffuse growth and oligodendroglioma-like patterns. Epithelioid glioblastomas (E-GB) are rare and aggressive variants of isocitrate dehydrogenase wildtype glioblastomas (GB), associated with poor overall survival. Both PLNTY and E-GB often carry oncogenic BRAF V600E mutation (BRAFV600E). In this case study, we analyzed clinical and genetic data from a single patient who, based on extensive histological and molecular evaluation, was diagnosed to carry PLNTY-like tumor that progressed into E-GB years later. The aim of our study was to uncover the genetic drivers and the evolutionary history of these tumors. Progression of the PLNTY-like tumor into E-GB was investigated using histology, chromosomal karyotyping, whole-genome sequencing (WGS), and RNA sequencing. A typical immunohistochemical stain pattern of CD34 positivity was detected in the apparent PLNTY, whereas it was depleted in the E-GB sample, as expected. WGS analysis of the PLNTY and three E-GB samples revealed four genes with shared somatic protein-altering mutations: BRAF (carrying BRAFV600E), clonal in both PLNTY and E-GB, as well as GNS, FOXRED2, and SSTR5, which were subclonal in PLNTY and clonal in E-GB. Both the PLNTY-like and E-GB tumors also carried highly similar copy number alteration profiles with a prominent loss of heterozygosity (LOH) in the majority of the chromosomes, suggesting their monoclonal origin. PLNTY-like tumor was mainly diploid, and the tumor underwent a genome-wide duplication event during the progression to E-GB. Furthermore, two focal rearrangements leading to homozygous deletion of CDKN2A/B were detected in E-GB samples. In conclusion, this study revealed unusually extensive LOH in the histologically and genetically supported PLNTY-like tumor that progressed into E-GB. Notably, only a limited set of genetic alterations was associated with malignant transformation beyond genome duplication, the CDKN2A/B inactivation representing the best-known oncogenic driver for malignant transformation. These findings suggest that genomic profiling may be a valuable tool for the diagnosis and prognostic assessment of low-grade neuroepithelial lesions.