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

IF 5.3 2区医学 Q1 GENETICS & HEREDITY

NPJ Genomic Medicine Pub Date : 2025-10-30 DOI:10.1038/s41525-025-00526-z

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

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Abstract

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.

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基于全基因组测序的成人胶质母细胞瘤遗传易感性分析。

成人胶质母细胞瘤的种系遗传易感性尚不清楚。随着广泛分子检测的选择，临床医生意识到在胶质母细胞瘤患者中发现种系易感性的先验概率是至关重要的。在这里，我们研究了成人胶质母细胞瘤的遗传易感性，使用配对肿瘤-正常WGS数据，在未选择的92例WHO 4级胶质瘤患者的平均队列中。在10例患者（11%）中，在与家族性胶质母细胞瘤（MSH6 （3x）、PMS2 （5x）、MSH2、NF1、BRCA1）或髓母细胞瘤（SUFU）密切相关的基因中发现了12种致病性种系变异（PGVs）。在这些患者中的6例（60%）中，因果关系得到了第二个（体细胞）事件和/或匹配的全基因组突变特征的支持。因此，种系易感性确实在成人胶质母细胞瘤的发展中发挥作用，错配修复缺陷是主要机制。我们的研究结果还强调了肿瘤正常WGS对胶质母细胞瘤患者及其家属的益处，除了确定可操作的治疗突变。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

NPJ Genomic Medicine Biochemistry, Genetics and Molecular Biology-Molecular Biology

CiteScore

9.40

自引率

1.90%

发文量

审稿时长

17 weeks

期刊介绍： npj Genomic Medicine is an international, peer-reviewed journal dedicated to publishing the most important scientific advances in all aspects of genomics and its application in the practice of medicine. The journal defines genomic medicine as "diagnosis, prognosis, prevention and/or treatment of disease and disorders of the mind and body, using approaches informed or enabled by knowledge of the genome and the molecules it encodes." Relevant and high-impact papers that encompass studies of individuals, families, or populations are considered for publication. An emphasis will include coupling detailed phenotype and genome sequencing information, both enabled by new technologies and informatics, to delineate the underlying aetiology of disease. Clinical recommendations and/or guidelines of how that data should be used in the clinical management of those patients in the study, and others, are also encouraged.