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<p>The germline genetic susceptibility to adult glioblastoma remains unclear. With the option of broad molecular testing, it is crucial that clinicians are aware of the a priori probability of finding germline predisposition in glioblastoma patients. Here, we studied the genetic predisposition to adult glioblastoma using paired tumor-normal WGS data in an unselected, average cohort of 92 glioma WHO grade 4 patients. In 10 patients (11%), 12 Pathogenic Germline Variants (PGVs) were found in genes strongly associated with familial glioblastoma (<i>MSH6</i> (3x), <i>PMS2</i> (5x), <i>MSH2</i>, <i>NF1</i>, <i>BRCA1</i>) or medulloblastoma (<i>SUFU</i>). In six of these patients (60%), causality was supported by a second (somatic) event and/or a matching genome-wide mutational signature. Thus, germline predisposition does play a role in the development of adult glioblastoma, with mismatch repair deficiency being the main mechanism. Our results also highlight the benefits of tumor-normal WGS for glioblastoma patients and their families, beyond identifying actionable mutations for therapy.</p>

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Whole genome sequencing-based analysis of genetic predisposition to adult glioblastoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月30日

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  • Mark P. van Opijnen,
  • Devin R. van Valkengoed,
  • Joep de Ligt,
  • Filip Y. F. de Vos,
  • Marike L. D. Broekman,
  • Edwin Cuppen,
  • Roelof Koster

摘要

The germline genetic susceptibility to adult glioblastoma remains unclear. With the option of broad molecular testing, it is crucial that clinicians are aware of the a priori probability of finding germline predisposition in glioblastoma patients. Here, we studied the genetic predisposition to adult glioblastoma using paired tumor-normal WGS data in an unselected, average cohort of 92 glioma WHO grade 4 patients. In 10 patients (11%), 12 Pathogenic Germline Variants (PGVs) were found in genes strongly associated with familial glioblastoma (MSH6 (3x), PMS2 (5x), MSH2, NF1, BRCA1) or medulloblastoma (SUFU). In six of these patients (60%), causality was supported by a second (somatic) event and/or a matching genome-wide mutational signature. Thus, germline predisposition does play a role in the development of adult glioblastoma, with mismatch repair deficiency being the main mechanism. Our results also highlight the benefits of tumor-normal WGS for glioblastoma patients and their families, beyond identifying actionable mutations for therapy.