NF1 expression profiling in IDH-wildtype glioblastoma: genomic associations and survival outcomes.

IF 6.2 2区 医学 Q1 NEUROSCIENCES Acta Neuropathologica Communications Pub Date : 2024-10-29 DOI:10.1186/s40478-024-01875-z
Michael Chang, Mohamed Sherief, Maria Ioannou, Viveka Chinnasamy, Lucy Chen, Michael Frost, Michelle Mattson-Hoss, Herb Sarnoff, David O Kamson, Matthias Holdhoff, Debraj Mukherjee, Chetan Bettegowda, Jordina Rincon-Torroella, Victoria Croog, Peng Huang, Fausto J Rodriguez, Calixto-Hope G Lucas, Karisa C Schreck
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引用次数: 0

Abstract

Background: NF1 inactivation is associated with sensitivity to MEK inhibitor targeted therapy in low-grade and some high-grade gliomas. NF1 loss may also be a harbinger of exploitable vulnerabilities in IDH-wildtype glioblastoma (GBM). Accurate and consistent detection of NF1 loss, however, is fraught given the large gene size, challenges with complete coverage and variant calling upon sequencing, and mechanisms of mRNA and protein regulation that result in early degradation in the absence of genomic alterations. Here, we seek to perform a composite analysis for NF1 loss accounting for genomic alterations and protein expression via immunohistochemistry. We also characterize the landscape of NF1 alterations in GBM.

Methods: We assembled a single-institution, retrospective cohort of 542 IDH-wildtype GBM with somatic next generation sequencing to investigate the frequency and nature of detected NF1 alterations. We selected 69 GBMs from which to build a tissue microarray (TMA) of 44 NF1-wildtype and 25 NF1-mutant cases. We performed NF1 immunohistochemistry using two different NF1 antibodies (NFC, Sigma-Aldrich; and iNF-07E, iNFixion Bioscience) and correlated results with clinical, genomic, and other immunohistochemical features.

Results: In our retrospective cohort, we identified 88 IDH-wildtype GBM with NF1 alterations (16%). NF1 alterations were mutually exclusive with EGFR and MDM2 alterations (p-adj < 0.001, 0.05, respectively), but co-occurred with PIK3R1 alterations (Log2(OR) = - 1.6, p-adj = 0.03). Of the 63 scorable sporadic GBMs in the TMA, 14 harbored NF1 inactivating alterations and of those, 12 (86%) demonstrated minimal NF1 immunoreactivity by NFC antibody, compared to 8 (57%) by iNF-07E antibody. Among the 42 scorable NF1-wildtype GBM in the TMA, NF1 immunostaining was minimal in 18 (43%) by NFC antibody compared to 4 (10%) by iNF-07E antibody, potentially reflecting false positives or differential protein regulation. Minimal immunoreactivity by NFC antibody was associated with decreased median overall survival (8.5 vs. 16.4 months, p = 0.011). Cox proportional hazards model correcting for prognostic variables in this subset revealed HR 3.23 (95% CI 1.29-8.06, p = 0.01) associated with decreased NF1 expression by IHC.

Conclusion: NF1 immunostaining may serve as a sensitive surrogate marker of NF1 genomic inactivation and a valuable extension to next-generation sequencing for defining NF1 status. Minimal NF1 immunoreactivity is a poor prognostic marker, even in IDH-wildtype glioblastoma without apparent NF1 genomic alterations, but the underlying molecular mechanism requires further investigation.

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IDH 野生型胶质母细胞瘤中 NF1 的表达谱分析:基因组关联与生存结果。
背景:NF1 失活与低级别和某些高级别胶质瘤对 MEK 抑制剂靶向治疗的敏感性有关。NF1 缺失也可能预示着 IDH 野生型胶质母细胞瘤(GBM)中存在可利用的漏洞。然而,由于 NF1 基因体积庞大、测序时的完全覆盖和变异调用面临挑战,以及 mRNA 和蛋白质调控机制导致基因组未发生改变时的早期降解,因此准确一致地检测 NF1 缺失充满了困难。在此,我们试图对 NF1 基因缺失进行综合分析,考虑基因组改变和免疫组化的蛋白表达。我们还描述了 NF1 在 GBM 中的改变情况:我们对 542 例 IDH 野生型 GBM 进行了体细胞新一代测序,建立了一个单一机构的回顾性队列,以研究检测到的 NF1 改变的频率和性质。我们选择了 69 例 GBM,并从中建立了一个组织芯片(TMA),其中包括 44 例 NF1 野生型病例和 25 例 NF1 突变病例。我们使用两种不同的 NF1 抗体(NFC,Sigma-Aldrich;iNF-07E,iNFixion Bioscience)进行了 NF1 免疫组化,并将结果与临床、基因组和其他免疫组化特征相关联:在我们的回顾性队列中,我们发现了 88 例伴有 NF1 改变的 IDH 野生型 GBM(16%)。NF1改变与表皮生长因子受体(EGFR)和MDM2改变相互排斥(p-adj 2(OR) = - 1.6,p-adj = 0.03)。在TMA中的63个可扫描散发性GBM中,14个存在NF1失活改变,其中12个(86%)通过NFC抗体显示出最小的NF1免疫反应,而8个(57%)通过iNF-07E抗体显示出最小的NF1免疫反应。在 TMA 中 42 个可扫描的 NF1 野生型 GBM 中,NFC 抗体显示 18 个(43%)的 NF1 免疫反应极低,而 iNF-07E 抗体显示 4 个(10%),这可能反映了假阳性或蛋白调控的差异。NFC 抗体的最小免疫反应与中位总生存期的降低有关(8.5 个月 vs. 16.4 个月,p = 0.011)。校正该子集预后变量的 Cox 比例危险模型显示,HR 3.23(95% CI 1.29-8.06,p = 0.01)与 IHC 表达的 NF1 减少有关:NF1免疫染色可作为NF1基因组失活的灵敏替代标记物,是下一代测序的重要延伸,可用于确定NF1状态。即使在没有明显NF1基因组改变的IDH-野生型胶质母细胞瘤中,NF1的最低免疫反应也是预后不良的标志物,但其潜在的分子机制还需要进一步研究。
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来源期刊
Acta Neuropathologica Communications
Acta Neuropathologica Communications Medicine-Pathology and Forensic Medicine
CiteScore
11.20
自引率
2.80%
发文量
162
审稿时长
8 weeks
期刊介绍: "Acta Neuropathologica Communications (ANC)" is a peer-reviewed journal that specializes in the rapid publication of research articles focused on the mechanisms underlying neurological diseases. The journal emphasizes the use of molecular, cellular, and morphological techniques applied to experimental or human tissues to investigate the pathogenesis of neurological disorders. ANC is committed to a fast-track publication process, aiming to publish accepted manuscripts within two months of submission. This expedited timeline is designed to ensure that the latest findings in neuroscience and pathology are disseminated quickly to the scientific community, fostering rapid advancements in the field of neurology and neuroscience. The journal's focus on cutting-edge research and its swift publication schedule make it a valuable resource for researchers, clinicians, and other professionals interested in the study and treatment of neurological conditions.
期刊最新文献
Diffuse pediatric high-grade glioma of methylation-based RTK2A and RTK2B subclasses present distinct radiological and histomolecular features including Gliomatosis cerebri phenotype. A primary intracranial neuroepithelial neoplasm with novel TCF3::BEND2 fusion: a case report. Correction: Revisiting gliomatosis cerebri in adult-type diffuse gliomas: a comprehensive imaging, genomic and clinical analysis. Host genetics and gut microbiota influence lipid metabolism and inflammation: potential implications for ALS pathophysiology in SOD1G93A mice. NF1 expression profiling in IDH-wildtype glioblastoma: genomic associations and survival outcomes.
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