Shreya Budhiraja, Graysen McManus, Shivani Baisiwala, Ella N Perrault, Sia Cho, Miranda Saathoff, Li Chen, Cheol H Park, Hasaan A Kazi, Crismita Dmello, Peiyu Lin, C David James, Adam M Sonabend, Dieter H Heiland, Atique U Ahmed
Background: Cellular functions hinge on the meticulous orchestration of protein transport, both spatially and temporally. Central to this process is retrograde trafficking, responsible for targeting proteins to the nucleus. Despite its link to many diseases, the implications of retrograde trafficking in glioblastoma (GBM) are still unclear.
Methods: To identify genetic drivers of TMZ resistance, we conducted comprehensive CRISPR-knockout screening, revealing ADP-ribosylation factor 4 (ARF4), a regulator of retrograde trafficking, as a major contributor.
Results: Suppressing ARF4 significantly enhanced TMZ sensitivity in GBM patient-derived xenograft (PDX) models, leading to improved survival rates (P < .01) in both primary and recurrent lines. We also observed that TMZ exposure stimulates ARF4-mediated retrograde trafficking. Proteomics analysis of GBM cells with varying levels of ARF4 unveiled the influence of this pathway on EGFR signaling, with increased nuclear trafficking of EGFR observed in cells with ARF4 overexpression and TMZ treatment. Additionally, spatially resolved RNA-sequencing of GBM patient tissues revealed substantial correlations between ARF4 and crucial nuclear EGFR (nEGFR) downstream targets, such as MYC, STAT1, and DNA-PK. Decreased activity of DNA-PK, a DNA repair protein downstream of nEGFR signaling that contributes to TMZ resistance, was observed in cells with suppressed ARF4 levels. Notably, treatment with DNA-PK inhibitor, KU-57788, in mice with a recurrent PDX line resulted in prolonged survival (P < .01), highlighting the promising therapeutic implications of targeting proteins reliant on ARF4-mediated retrograde trafficking.
Conclusions: Our findings demonstrate that ARF4-mediated retrograde trafficking contributes to the development of TMZ resistance, cementing this pathway as a viable strategy to overcome chemoresistance in GBM.
{"title":"ARF4-mediated retrograde trafficking as a driver of chemoresistance in glioblastoma.","authors":"Shreya Budhiraja, Graysen McManus, Shivani Baisiwala, Ella N Perrault, Sia Cho, Miranda Saathoff, Li Chen, Cheol H Park, Hasaan A Kazi, Crismita Dmello, Peiyu Lin, C David James, Adam M Sonabend, Dieter H Heiland, Atique U Ahmed","doi":"10.1093/neuonc/noae059","DOIUrl":"10.1093/neuonc/noae059","url":null,"abstract":"<p><strong>Background: </strong>Cellular functions hinge on the meticulous orchestration of protein transport, both spatially and temporally. Central to this process is retrograde trafficking, responsible for targeting proteins to the nucleus. Despite its link to many diseases, the implications of retrograde trafficking in glioblastoma (GBM) are still unclear.</p><p><strong>Methods: </strong>To identify genetic drivers of TMZ resistance, we conducted comprehensive CRISPR-knockout screening, revealing ADP-ribosylation factor 4 (ARF4), a regulator of retrograde trafficking, as a major contributor.</p><p><strong>Results: </strong>Suppressing ARF4 significantly enhanced TMZ sensitivity in GBM patient-derived xenograft (PDX) models, leading to improved survival rates (P < .01) in both primary and recurrent lines. We also observed that TMZ exposure stimulates ARF4-mediated retrograde trafficking. Proteomics analysis of GBM cells with varying levels of ARF4 unveiled the influence of this pathway on EGFR signaling, with increased nuclear trafficking of EGFR observed in cells with ARF4 overexpression and TMZ treatment. Additionally, spatially resolved RNA-sequencing of GBM patient tissues revealed substantial correlations between ARF4 and crucial nuclear EGFR (nEGFR) downstream targets, such as MYC, STAT1, and DNA-PK. Decreased activity of DNA-PK, a DNA repair protein downstream of nEGFR signaling that contributes to TMZ resistance, was observed in cells with suppressed ARF4 levels. Notably, treatment with DNA-PK inhibitor, KU-57788, in mice with a recurrent PDX line resulted in prolonged survival (P < .01), highlighting the promising therapeutic implications of targeting proteins reliant on ARF4-mediated retrograde trafficking.</p><p><strong>Conclusions: </strong>Our findings demonstrate that ARF4-mediated retrograde trafficking contributes to the development of TMZ resistance, cementing this pathway as a viable strategy to overcome chemoresistance in GBM.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11300013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140175774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: The mesenchymal (MES) subtype of glioblastoma (GBM) is believed to be influenced by both cancer cell-intrinsic alterations and extrinsic cellular interactions, yet the underlying mechanisms remain unexplored.
Methods: Identification of microglial heterogeneity by bioinformatics analysis. Transwell migration, invasion assays, and tumor models were used to determine gene function and the role of small molecule inhibitors. RNA sequencing, chromatin immunoprecipitation, and dual-luciferase reporter assays were performed to explore the underlying regulatory mechanisms.
Results: We identified the inflammatory microglial subtype of tumor-associated microglia (TAM) and found that its specific gene integrin beta 2 (ITGB2) was highly expressed in TAM of MES GBM tissues. Mechanistically, the activation of ITGB2 in microglia promoted the interaction between the SH2 domain of STAT3 and the cytoplasmic domain of ITGB2, thereby stimulating the JAK1/STAT3/IL-6 signaling feedback to promote the MES transition of GBM cells. Additionally, microglia communicated with GBM cells through the interaction between the receptor ITGB2 on microglia and the ligand ICAM-1 on GBM cells, while an increased secretion of ICAM-1 was induced by the proinflammatory cytokine leukemia inhibitory factor (LIF). Further studies demonstrated that inhibition of cyclin-dependent kinase 7 substantially reduced the recruitment of SNW1 to the super-enhancer of LIF, resulting in transcriptional inhibition of LIF. We identified notoginsenoside R1 as a novel LIF inhibitor that exhibited synergistic effects in combination with temozolomide.
Conclusions: Our research reveals that the epigenetic-mediated interaction of GBM cells with TAM drives the MES transition of GBM and provides a novel therapeutic avenue for patients with MES GBM.
背景:间质(MES)亚型胶质母细胞瘤(GBM)被认为受到癌细胞内在改变和外在细胞相互作用的影响,但其潜在机制仍未探明:方法:通过生物信息学分析确定小胶质细胞的异质性。方法:通过生物信息学分析确定小神经胶质细胞的异质性,利用透孔迁移、侵袭试验和肿瘤模型确定基因功能和小分子抑制剂的作用。我们还进行了 RNA 测序、染色质免疫沉淀和双荧光素酶报告实验,以探索潜在的调控机制:结果:我们确定了肿瘤相关小胶质细胞(TAM)这一炎性小胶质细胞亚型,并发现其特异性基因 ITGB2 在 MES GBM 组织的 TAM 中高表达。从机理上讲,ITGB2在小胶质细胞中的激活促进了STAT3的SH2结构域与ITGB2的胞浆结构域之间的相互作用,从而刺激了JAK1/STAT3/IL-6信号反馈,促进了GBM细胞的MES转化。此外,小胶质细胞通过小胶质细胞上的受体ITGB2和GBM细胞上的配体ICAM-1之间的相互作用与GBM细胞进行交流,而促炎细胞因子LIF会诱导ICAM-1分泌增加。进一步的研究表明,抑制 CDK7 可大大减少 SNW1 对 LIF 超级增强子的招募,从而导致 LIF 的转录抑制。我们发现鹅掌楸苷 R1 是一种新型 LIF 抑制剂,它与替莫唑胺联合使用可产生协同效应:我们的研究揭示了表观遗传学介导的 GBM 细胞与 TAM 的相互作用推动了 GBM 的 MES 转变,并为 MES GBM 患者提供了一种新的治疗途径。
{"title":"Super-enhancer-driven LIF promotes the mesenchymal transition in glioblastoma by activating ITGB2 signaling feedback in microglia.","authors":"Han Xie, Yanyi Jiang, Yufei Xiang, Baoming Wu, Jiajia Zhao, Ruixiang Huang, Mengting Wang, Yunlong Wang, Jun Liu, Dejun Wu, Dasheng Tian, Erbao Bian","doi":"10.1093/neuonc/noae065","DOIUrl":"10.1093/neuonc/noae065","url":null,"abstract":"<p><strong>Background: </strong>The mesenchymal (MES) subtype of glioblastoma (GBM) is believed to be influenced by both cancer cell-intrinsic alterations and extrinsic cellular interactions, yet the underlying mechanisms remain unexplored.</p><p><strong>Methods: </strong>Identification of microglial heterogeneity by bioinformatics analysis. Transwell migration, invasion assays, and tumor models were used to determine gene function and the role of small molecule inhibitors. RNA sequencing, chromatin immunoprecipitation, and dual-luciferase reporter assays were performed to explore the underlying regulatory mechanisms.</p><p><strong>Results: </strong>We identified the inflammatory microglial subtype of tumor-associated microglia (TAM) and found that its specific gene integrin beta 2 (ITGB2) was highly expressed in TAM of MES GBM tissues. Mechanistically, the activation of ITGB2 in microglia promoted the interaction between the SH2 domain of STAT3 and the cytoplasmic domain of ITGB2, thereby stimulating the JAK1/STAT3/IL-6 signaling feedback to promote the MES transition of GBM cells. Additionally, microglia communicated with GBM cells through the interaction between the receptor ITGB2 on microglia and the ligand ICAM-1 on GBM cells, while an increased secretion of ICAM-1 was induced by the proinflammatory cytokine leukemia inhibitory factor (LIF). Further studies demonstrated that inhibition of cyclin-dependent kinase 7 substantially reduced the recruitment of SNW1 to the super-enhancer of LIF, resulting in transcriptional inhibition of LIF. We identified notoginsenoside R1 as a novel LIF inhibitor that exhibited synergistic effects in combination with temozolomide.</p><p><strong>Conclusions: </strong>Our research reveals that the epigenetic-mediated interaction of GBM cells with TAM drives the MES transition of GBM and provides a novel therapeutic avenue for patients with MES GBM.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11300025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140329967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jana Ivanidze, Se Jung Chang, Arsalan Haghdel, Joon Tae Kim, Arindam Roy Choudhury, Alan Wu, Rohan Ramakrishna, Theodore H Schwartz, Babacar Cisse, Philip Stieg, Leland Muller, Joseph R Osborne, Rajiv S Magge, Nicolas A Karakatsanis, Michelle Roytman, Eaton Lin, Susan C Pannullo, Joshua D Palmer, Jonathan P S Knisely
Background: Our purpose was to determine the utility of [68Ga]-DOTATATE PET/MRI in meningioma response assessment following radiosurgery.
Methods: Patients with meningioma prospectively underwent postoperative DOTATATE PET/MRI. Co-registered PET and gadolinium-enhanced T1-weighted MRI were employed for radiosurgery planning. Follow-up DOTATATE PET/MRI was performed at 6-12 months post-radiosurgery. Maximum absolute standardized uptake value (SUV) and SUV ratio (SUVRSSS) referencing superior sagittal sinus (SSS) blood pool were obtained. Size change was determined by Response Assessment in Neuro-Oncology (RANO) criteria. Association of SUVRSSS change magnitude and progression-free survival (PFS) was evaluated using Cox regression.
Results: Twenty-seven patients with 64 tumors (26% World Health Organization [WHO]-1, 41% WHO-2, 26% WHO-3, and 7% WHO-unknown) were prospectively followed post stereotactic radiosurgery (SRS) or stereotactic body radiotherapy (SBRT; mean dose: 30 Gy, modal dose 35 Gy, mean of 5 fractions). Post-irradiation SUV and SUVRSSS decreased by 37.4% and 44.4%, respectively (P < .0001). Size product decreased by 8.9%, thus failing to reach the 25% significance threshold as determined by RANO guidelines. Mean follow-up time was 26 months (range: 6-44). Overall mean PFS was 83% and 100%/100%/54% in WHO-1/-2/-3 subcohorts, respectively, at 34 months. At maximum follow-up (42-44 months), PFS was 100%/83%/54% in WHO-1/-2/-3 subcohorts, respectively. Cox regression analyses revealed a hazard ratio of 0.48 for 10-unit reduction in SUVRSSS in the SRS cohort.
Conclusions: DOTATATE PET SUV and SUVRSSS demonstrated marked, significant decrease post-radiosurgery. Lesion size decrease was statistically significant; however, it was not clinically significant by RANO criteria. DOTATATE PET/MR thus represents a promising imaging biomarker for response assessment in meningiomas treated with radiosurgery.
{"title":"[Ga68] DOTATATE PET/MRI-guided radiosurgical treatment planning and response assessment in meningiomas.","authors":"Jana Ivanidze, Se Jung Chang, Arsalan Haghdel, Joon Tae Kim, Arindam Roy Choudhury, Alan Wu, Rohan Ramakrishna, Theodore H Schwartz, Babacar Cisse, Philip Stieg, Leland Muller, Joseph R Osborne, Rajiv S Magge, Nicolas A Karakatsanis, Michelle Roytman, Eaton Lin, Susan C Pannullo, Joshua D Palmer, Jonathan P S Knisely","doi":"10.1093/neuonc/noae067","DOIUrl":"10.1093/neuonc/noae067","url":null,"abstract":"<p><strong>Background: </strong>Our purpose was to determine the utility of [68Ga]-DOTATATE PET/MRI in meningioma response assessment following radiosurgery.</p><p><strong>Methods: </strong>Patients with meningioma prospectively underwent postoperative DOTATATE PET/MRI. Co-registered PET and gadolinium-enhanced T1-weighted MRI were employed for radiosurgery planning. Follow-up DOTATATE PET/MRI was performed at 6-12 months post-radiosurgery. Maximum absolute standardized uptake value (SUV) and SUV ratio (SUVRSSS) referencing superior sagittal sinus (SSS) blood pool were obtained. Size change was determined by Response Assessment in Neuro-Oncology (RANO) criteria. Association of SUVRSSS change magnitude and progression-free survival (PFS) was evaluated using Cox regression.</p><p><strong>Results: </strong>Twenty-seven patients with 64 tumors (26% World Health Organization [WHO]-1, 41% WHO-2, 26% WHO-3, and 7% WHO-unknown) were prospectively followed post stereotactic radiosurgery (SRS) or stereotactic body radiotherapy (SBRT; mean dose: 30 Gy, modal dose 35 Gy, mean of 5 fractions). Post-irradiation SUV and SUVRSSS decreased by 37.4% and 44.4%, respectively (P < .0001). Size product decreased by 8.9%, thus failing to reach the 25% significance threshold as determined by RANO guidelines. Mean follow-up time was 26 months (range: 6-44). Overall mean PFS was 83% and 100%/100%/54% in WHO-1/-2/-3 subcohorts, respectively, at 34 months. At maximum follow-up (42-44 months), PFS was 100%/83%/54% in WHO-1/-2/-3 subcohorts, respectively. Cox regression analyses revealed a hazard ratio of 0.48 for 10-unit reduction in SUVRSSS in the SRS cohort.</p><p><strong>Conclusions: </strong>DOTATATE PET SUV and SUVRSSS demonstrated marked, significant decrease post-radiosurgery. Lesion size decrease was statistically significant; however, it was not clinically significant by RANO criteria. DOTATATE PET/MR thus represents a promising imaging biomarker for response assessment in meningiomas treated with radiosurgery.</p><p><strong>Clinicaltrials.gov identifier: </strong>NCT04081701.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11300004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140326924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alice Ryba, Zeynep Özdemir, Nitzan Nissimov, Lisa Hönikl, Nicolas Neidert, Martin Jakobs, Darius Kalasauskas, Aleksandrs Krigers, Claudius Thomé, Christian F Freyschlag, Florian Ringel, Andreas Unterberg, Philip Dao Trong, Jürgen Beck, Dieter Henrik Heiland, Bernhard Meyer, Peter Vajkoczy, Julia Onken, Walter Stummer, Eric Suero Molina, Jens Gempt, Manfred Westphal, Ulrich Schüller, Malte Mohme
Background: H3 K27M-mutated gliomas were first described as a new grade 4 entity in the 2016 World Health Organization classification. Current studies have focused on its typical appearance in children and young adults, increasing the need to better understand the prognostic factors and impact of surgery on adults. Here, we report a multicentric study of this entity in adults.
Methods: We included molecularly confirmed H3 K27M-mutated glioma cases in patients ≥ 18 years diagnosed between 2016 and 2022. Clinical, radiological, and surgical features were analyzed. Univariate and multivariate analyses were performed to identify prognostic factors.
Results: Among 70 patients with a mean age of 36.1 years, the median overall survival (OS) was 13.6 ± 14 months. Gross-total resection was achieved in 14.3% of patients, whereas 30% had a subtotal resection and 54.3% a biopsy. Tumors located in telencephalon/diencephalon/myelencephalon were associated with a poorer OS, while a location in the mesencephalon/metencephalon showed a significantly longer OS (8.7 vs. 25.0 months, P = .007). Preoperative Karnofsky-Performance Score (KPS) ≤ 80 showed a reduced OS (4.2 vs. 18 months, P = .02). Furthermore, ATRX loss, found in 25.7%, was independently associated with an increased OS (31 vs. 8.3 months, P = .0029). Notably, patients undergoing resection showed no survival benefit over biopsy (12 vs. 11 months, P = .4006).
Conclusions: The present study describes surgical features of H3 K27M-mutated glioma in adulthood in a large multicentric study. Our data reveal that ATRX status, location and KPS significantly impact OS in H3 K27M-mutated glioma. Importantly, our dataset indicates that resection does not offer a survival advantage over biopsy.
{"title":"Insights from a multicenter study on adult H3 K27M-mutated glioma: Surgical resection's limited influence on overall survival, ATRX as molecular prognosticator.","authors":"Alice Ryba, Zeynep Özdemir, Nitzan Nissimov, Lisa Hönikl, Nicolas Neidert, Martin Jakobs, Darius Kalasauskas, Aleksandrs Krigers, Claudius Thomé, Christian F Freyschlag, Florian Ringel, Andreas Unterberg, Philip Dao Trong, Jürgen Beck, Dieter Henrik Heiland, Bernhard Meyer, Peter Vajkoczy, Julia Onken, Walter Stummer, Eric Suero Molina, Jens Gempt, Manfred Westphal, Ulrich Schüller, Malte Mohme","doi":"10.1093/neuonc/noae061","DOIUrl":"10.1093/neuonc/noae061","url":null,"abstract":"<p><strong>Background: </strong>H3 K27M-mutated gliomas were first described as a new grade 4 entity in the 2016 World Health Organization classification. Current studies have focused on its typical appearance in children and young adults, increasing the need to better understand the prognostic factors and impact of surgery on adults. Here, we report a multicentric study of this entity in adults.</p><p><strong>Methods: </strong>We included molecularly confirmed H3 K27M-mutated glioma cases in patients ≥ 18 years diagnosed between 2016 and 2022. Clinical, radiological, and surgical features were analyzed. Univariate and multivariate analyses were performed to identify prognostic factors.</p><p><strong>Results: </strong>Among 70 patients with a mean age of 36.1 years, the median overall survival (OS) was 13.6 ± 14 months. Gross-total resection was achieved in 14.3% of patients, whereas 30% had a subtotal resection and 54.3% a biopsy. Tumors located in telencephalon/diencephalon/myelencephalon were associated with a poorer OS, while a location in the mesencephalon/metencephalon showed a significantly longer OS (8.7 vs. 25.0 months, P = .007). Preoperative Karnofsky-Performance Score (KPS) ≤ 80 showed a reduced OS (4.2 vs. 18 months, P = .02). Furthermore, ATRX loss, found in 25.7%, was independently associated with an increased OS (31 vs. 8.3 months, P = .0029). Notably, patients undergoing resection showed no survival benefit over biopsy (12 vs. 11 months, P = .4006).</p><p><strong>Conclusions: </strong>The present study describes surgical features of H3 K27M-mutated glioma in adulthood in a large multicentric study. Our data reveal that ATRX status, location and KPS significantly impact OS in H3 K27M-mutated glioma. Importantly, our dataset indicates that resection does not offer a survival advantage over biopsy.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11300017/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140175777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lourdes Sainero-Alcolado, Tomas Sjöberg Bexelius, Giuseppe Santopolo, Ye Yuan, Judit Liaño-Pons, Marie Arsenian-Henriksson
Neuroblastoma (NB), an heterogenous pediatric tumor of the sympathetic nervous system, is the most common and deadly extracranial solid malignancy diagnosed in infants. Numerous efforts have been invested in understanding its origin and in development of novel curative targeted therapies. Here, we summarize the recent advances in the identification of the cell of origin and the genetic alterations occurring during development contributing to NB. We discuss current treatment regimens, present and future directions for identification of novel therapeutic metabolic targets, differentiation agents, as well as personalized combinatory therapies as potential approaches for improving survival and quality of life of children with NB.
神经母细胞瘤(NB)是小儿交感神经系统的一种异质性肿瘤,是婴儿中最常见、最致命的颅外实体瘤。人们在了解其起源和开发新型治疗性靶向疗法方面投入了大量精力。在此,我们总结了最近在确定起源细胞和导致 NB 的发育过程中发生的基因改变方面取得的进展。我们将讨论目前的治疗方案、新型治疗代谢靶点的目前和未来鉴定方向、分化药物以及个性化联合疗法,作为改善 NB 患儿生存和生活质量的潜在方法。
{"title":"Defining Neuroblastoma: from origin to precision medicine.","authors":"Lourdes Sainero-Alcolado, Tomas Sjöberg Bexelius, Giuseppe Santopolo, Ye Yuan, Judit Liaño-Pons, Marie Arsenian-Henriksson","doi":"10.1093/neuonc/noae152","DOIUrl":"https://doi.org/10.1093/neuonc/noae152","url":null,"abstract":"<p><p>Neuroblastoma (NB), an heterogenous pediatric tumor of the sympathetic nervous system, is the most common and deadly extracranial solid malignancy diagnosed in infants. Numerous efforts have been invested in understanding its origin and in development of novel curative targeted therapies. Here, we summarize the recent advances in the identification of the cell of origin and the genetic alterations occurring during development contributing to NB. We discuss current treatment regimens, present and future directions for identification of novel therapeutic metabolic targets, differentiation agents, as well as personalized combinatory therapies as potential approaches for improving survival and quality of life of children with NB.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Minyoung Oh, Hyungwoo Cho, Ji Eun Park, Ho Sung Kim, Heounjeong Go, Chan-Sik Park, Sang-Wook Lee, Sang Woo Song, Young-Hoon Kim, Young Hyun Cho, Seok Ho Hong, Jeong Hoon Kim, Dong Yun Lee, Jin-Sook Ryu, Dok Hyun Yoon, Jae Seung Kim
Background: The role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in the prognostication and response evaluation of primary central nervous system lymphoma (PCNSL) remains inadequately defined.
Methods: We conducted a retrospective analysis of 268 consecutive newly diagnosed patients with PCNSL between 2006 and 2020. Of these patients, 105 and 110 patients were included to evaluate the prognostic value of baseline and post-treatment 18F-FDG-PET/CT scans, respectively. Tumor uptake was considered positive when it exceeded that of the contralateral brain upon visual assessment. Quantitative analysis of baseline 18F-FDG-PET/CT included measurement of the maximal standardized uptake value (SUVmax), total metabolic tumor volume (TMTV), and total lesion glycolysis (TLG).
Results: The median age of the 268 patients was 62 years (range: 17-85), with 55% being male. The median progression-free survival (PFS) was 24.5 months (95% confidence interval [CI], 19.9-29.1), and the median overall survival (OS) was 34.5 months (95% CI, 22.9-46.1). The average SUVmax was 15.3 ± 5.7 and the mean TMTV and TLG were 12.6 ± 13.9 cm3 and 135.0 ± 152.7 g, respectively. Patients with a baseline TMTV ≥17.0 cm3 had significantly shorter OS (12.5 vs. 74.0 months, p=0.011). Post-treatment metabolic response by 18F-FDG-PET/CT significantly predicted PFS (median: 10.5 vs. 46.0 months, p=0.001) and OS (median: 21.0 vs. 62.0 months, p=0.002), whereas anatomic response by contrast-enhanced MRI showed no statistically significant differences in PFS (p=0.130) or OS (p=0.540).
Conclusion: Baseline TMTV and post-treatment metabolic response, as assessed by 18F-FDG-PET/CT, are significant prognostic factors in patients with PCNSL.
{"title":"Enhancing Prognostication and Treatment Response Evaluation in Primary CNS Lymphoma with 18F-FDG PET/CT.","authors":"Minyoung Oh, Hyungwoo Cho, Ji Eun Park, Ho Sung Kim, Heounjeong Go, Chan-Sik Park, Sang-Wook Lee, Sang Woo Song, Young-Hoon Kim, Young Hyun Cho, Seok Ho Hong, Jeong Hoon Kim, Dong Yun Lee, Jin-Sook Ryu, Dok Hyun Yoon, Jae Seung Kim","doi":"10.1093/neuonc/noae146","DOIUrl":"https://doi.org/10.1093/neuonc/noae146","url":null,"abstract":"<p><strong>Background: </strong>The role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in the prognostication and response evaluation of primary central nervous system lymphoma (PCNSL) remains inadequately defined.</p><p><strong>Methods: </strong>We conducted a retrospective analysis of 268 consecutive newly diagnosed patients with PCNSL between 2006 and 2020. Of these patients, 105 and 110 patients were included to evaluate the prognostic value of baseline and post-treatment 18F-FDG-PET/CT scans, respectively. Tumor uptake was considered positive when it exceeded that of the contralateral brain upon visual assessment. Quantitative analysis of baseline 18F-FDG-PET/CT included measurement of the maximal standardized uptake value (SUVmax), total metabolic tumor volume (TMTV), and total lesion glycolysis (TLG).</p><p><strong>Results: </strong>The median age of the 268 patients was 62 years (range: 17-85), with 55% being male. The median progression-free survival (PFS) was 24.5 months (95% confidence interval [CI], 19.9-29.1), and the median overall survival (OS) was 34.5 months (95% CI, 22.9-46.1). The average SUVmax was 15.3 ± 5.7 and the mean TMTV and TLG were 12.6 ± 13.9 cm3 and 135.0 ± 152.7 g, respectively. Patients with a baseline TMTV ≥17.0 cm3 had significantly shorter OS (12.5 vs. 74.0 months, p=0.011). Post-treatment metabolic response by 18F-FDG-PET/CT significantly predicted PFS (median: 10.5 vs. 46.0 months, p=0.001) and OS (median: 21.0 vs. 62.0 months, p=0.002), whereas anatomic response by contrast-enhanced MRI showed no statistically significant differences in PFS (p=0.130) or OS (p=0.540).</p><p><strong>Conclusion: </strong>Baseline TMTV and post-treatment metabolic response, as assessed by 18F-FDG-PET/CT, are significant prognostic factors in patients with PCNSL.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vinton W T Cheng, Richard Heywood, Rasheed Zakaria, Rebecca Burger, Kieran Zucker, Siddarth Kannan, Muhammad Alifian Remifta Putra, Amanda Fitzpatrick, Gary Doherty, Paul Sanghera, Michael D Jenkinson, Carlo Palmieri
Background: Recent studies have challenged the notion that patients with brain metastasis (BM) or leptomeningeal metastasis (LM) should be excluded from systemic therapy clinical trials. This scoping study summarises the BM/LM clinical studies published between 2010 and 2023.
Methods: MEDLINE, CINAHL, CAB Abstracts, PsycINFO, Cochrane Library, HINARI, International Pharmaceutical Abstracts, PubMed, Scopus, Web of Science, and EMBASE electronic databases were searched on 21 June 2021. An updated search was performed on 21 February 2023. Eligible studies should involve investigation of a therapeutic intervention in solid tumour patients with BM and/or LM and a reported patient outcome. Extracted study-level data, included study type, publication date, geographical location, number of BM/LM patients in study, primary tumour type and type of therapeutic intervention.
Results: 4921 unique studies were eligible for analysis. The key finding is that BM/LM clinical research is expanding globally, both observational studies and clinical trials. Despite the shift over time towards a higher proportion of systemic therapy trials, the majority still do not include patients with symptomatic disease and lack reporting of BM/LM specific endpoints. Globally, there has been a trend to more international collaboration in BM/LM clinical studies.
Conclusions: This analysis of the BM/LM literature charts the evolving landscape of studies involving this previously excluded population. Given the increasing clinical research activity, particularly involving late-stage systemic therapy trials, it is imperative that due consideration is given to the intracranial activity of new investigational agents. Wider adoption of standardised reporting of intracranial-specific endpoints will facilitate evaluation of relative intracranial efficacy.
{"title":"BMScope: A scoping review to chart the evolving clinical study landscape in brain and leptomeningeal metastasis.","authors":"Vinton W T Cheng, Richard Heywood, Rasheed Zakaria, Rebecca Burger, Kieran Zucker, Siddarth Kannan, Muhammad Alifian Remifta Putra, Amanda Fitzpatrick, Gary Doherty, Paul Sanghera, Michael D Jenkinson, Carlo Palmieri","doi":"10.1093/neuonc/noae140","DOIUrl":"https://doi.org/10.1093/neuonc/noae140","url":null,"abstract":"<p><strong>Background: </strong>Recent studies have challenged the notion that patients with brain metastasis (BM) or leptomeningeal metastasis (LM) should be excluded from systemic therapy clinical trials. This scoping study summarises the BM/LM clinical studies published between 2010 and 2023.</p><p><strong>Methods: </strong>MEDLINE, CINAHL, CAB Abstracts, PsycINFO, Cochrane Library, HINARI, International Pharmaceutical Abstracts, PubMed, Scopus, Web of Science, and EMBASE electronic databases were searched on 21 June 2021. An updated search was performed on 21 February 2023. Eligible studies should involve investigation of a therapeutic intervention in solid tumour patients with BM and/or LM and a reported patient outcome. Extracted study-level data, included study type, publication date, geographical location, number of BM/LM patients in study, primary tumour type and type of therapeutic intervention.</p><p><strong>Results: </strong>4921 unique studies were eligible for analysis. The key finding is that BM/LM clinical research is expanding globally, both observational studies and clinical trials. Despite the shift over time towards a higher proportion of systemic therapy trials, the majority still do not include patients with symptomatic disease and lack reporting of BM/LM specific endpoints. Globally, there has been a trend to more international collaboration in BM/LM clinical studies.</p><p><strong>Conclusions: </strong>This analysis of the BM/LM literature charts the evolving landscape of studies involving this previously excluded population. Given the increasing clinical research activity, particularly involving late-stage systemic therapy trials, it is imperative that due consideration is given to the intracranial activity of new investigational agents. Wider adoption of standardised reporting of intracranial-specific endpoints will facilitate evaluation of relative intracranial efficacy.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141879211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shaista Chaudhary, Ujjal Das, Shaima Jabbar, Omkaram Gangisetty, Bénédicte Rousseau, Simon Hanft, Dipak K Sarkar
Background: Pituitary neuroendocrine tumors, PitNETs, are often aggressive and precipitate in distant metastases that are refractory to current therapies. However, the molecular mechanism in PitNETs' aggressiveness is not well understood. Developmental pluripotency-associated 4 (DPPA4) is known as a stem cell regulatory gene and overexpressed in certain cancers, but its function in the context of PitNETs' aggressiveness is not known.
Methods: We employed both rat and human models of PitNETs. In the rat pituitary tumor model (RPT), we used prenatal-alcohol-exposed (PAE) female Fischer rats which developed aggressive PitNETs following estrogen treatment, while in the human pituitary tumor (HPT) model, we used aggressively proliferative cells from pituitary tumors of patients undergone surgery. Various molecular, cellular, and epigenetic techniques were used to determine the role of DPPA4 in PitNETs' aggressiveness.
Results: We show that DPPA4 is overexpressed in association with increased cell stemness factors in aggressive PitNETs of PAE rats and of human patients. Gene-editing experiments demonstrate that DPPA4 increases the expression of cell stemness and tumor aggressiveness genes and promotes proliferation, colonization, migration, and tumorigenic potential of PitNET cells. ChIP assays and receptor antagonism studies reveal that DPPA4 binds to canonical WINTs promoters and increases directly or indirectly the Wnt/β-catenin control of cell stemness, tumor growth, and aggressiveness of PitNETs. Epigenetic studies show involvement of histone methyltransferase in alcohol activation of DPPA4.
Conclusions: These findings support a role of DPPA4 in tumor stemness and aggressiveness and provide a preclinical rationale for modulating this stemness regulator for the treatment of PitNETs.
{"title":"DPPA4 increases aggressiveness of pituitary neuroendocrine tumors by enhancing cell stemness.","authors":"Shaista Chaudhary, Ujjal Das, Shaima Jabbar, Omkaram Gangisetty, Bénédicte Rousseau, Simon Hanft, Dipak K Sarkar","doi":"10.1093/neuonc/noae148","DOIUrl":"https://doi.org/10.1093/neuonc/noae148","url":null,"abstract":"<p><strong>Background: </strong>Pituitary neuroendocrine tumors, PitNETs, are often aggressive and precipitate in distant metastases that are refractory to current therapies. However, the molecular mechanism in PitNETs' aggressiveness is not well understood. Developmental pluripotency-associated 4 (DPPA4) is known as a stem cell regulatory gene and overexpressed in certain cancers, but its function in the context of PitNETs' aggressiveness is not known.</p><p><strong>Methods: </strong>We employed both rat and human models of PitNETs. In the rat pituitary tumor model (RPT), we used prenatal-alcohol-exposed (PAE) female Fischer rats which developed aggressive PitNETs following estrogen treatment, while in the human pituitary tumor (HPT) model, we used aggressively proliferative cells from pituitary tumors of patients undergone surgery. Various molecular, cellular, and epigenetic techniques were used to determine the role of DPPA4 in PitNETs' aggressiveness.</p><p><strong>Results: </strong>We show that DPPA4 is overexpressed in association with increased cell stemness factors in aggressive PitNETs of PAE rats and of human patients. Gene-editing experiments demonstrate that DPPA4 increases the expression of cell stemness and tumor aggressiveness genes and promotes proliferation, colonization, migration, and tumorigenic potential of PitNET cells. ChIP assays and receptor antagonism studies reveal that DPPA4 binds to canonical WINTs promoters and increases directly or indirectly the Wnt/β-catenin control of cell stemness, tumor growth, and aggressiveness of PitNETs. Epigenetic studies show involvement of histone methyltransferase in alcohol activation of DPPA4.</p><p><strong>Conclusions: </strong>These findings support a role of DPPA4 in tumor stemness and aggressiveness and provide a preclinical rationale for modulating this stemness regulator for the treatment of PitNETs.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141879212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nathan K Leclair, Abrar Choudury, William C Chen, Stephen T Magill, Kathleen McCortney, Craig M Horbinski, Zhenhong Chen, Ezequiel Goldschmidt, Charlotte D Eaton, Ketan R Bulsara, Wenya Linda Bi, Akash J Patel, Felix Sahm, David Raleigh, Olga Anczukow
Background: Advances in our understanding of the molecular biology of meningiomas have led to significant gains in the ability to predict patient prognosis and tumor recurrence and to identify novel targets for therapeutic design. Specifically, classification of meningiomas based on DNA methylation has greatly improved our ability to risk stratify patients, however new questions have arisen in terms of the underlying impact these DNA methylation signatures have on meningioma biology.
Methods: This study utilizes RNA-seq data from 486 meningioma samples corresponding to three meningioma DNA methylation groups (Merlin-intact, Immune-enriched, and Hypermitotic), followed by in vitro experiments utilizing human meningioma cell lines.
Results: We identify alterations in RNA splicing between meningioma DNA methylation groups including individual splicing events that correlate with Hypermitotic meningiomas and predict tumor recurrence and overall patient prognosis and compile a set of splicing events that can accurately predict DNA methylation classification based on RNA-seq data. Furthermore, we validate these events using RT-PCR in patient samples and meningioma cell lines. Additionally, we identify alterations in RNA binding proteins and splicing factors that lie upstream of RNA splicing events, including upregulation of SRSF1 in Hypermitotic meningiomas which we show drives alternative RNA splicing changes. Finally, we design splice switching antisense oligonucleotides to target RNA splicing changes in NASP and MFF observed in Hypermitotic meningiomas, providing a rationale for RNA-based therapeutic design.
Conclusions: RNA splicing is an important driver of meningioma phenotypes that can be useful in prognosticating patients and as a potential exploit for therapeutic vulnerabilities.
{"title":"RNA splicing as a biomarker and phenotypic driver of meningioma DNA methylation groups.","authors":"Nathan K Leclair, Abrar Choudury, William C Chen, Stephen T Magill, Kathleen McCortney, Craig M Horbinski, Zhenhong Chen, Ezequiel Goldschmidt, Charlotte D Eaton, Ketan R Bulsara, Wenya Linda Bi, Akash J Patel, Felix Sahm, David Raleigh, Olga Anczukow","doi":"10.1093/neuonc/noae150","DOIUrl":"https://doi.org/10.1093/neuonc/noae150","url":null,"abstract":"<p><strong>Background: </strong>Advances in our understanding of the molecular biology of meningiomas have led to significant gains in the ability to predict patient prognosis and tumor recurrence and to identify novel targets for therapeutic design. Specifically, classification of meningiomas based on DNA methylation has greatly improved our ability to risk stratify patients, however new questions have arisen in terms of the underlying impact these DNA methylation signatures have on meningioma biology.</p><p><strong>Methods: </strong>This study utilizes RNA-seq data from 486 meningioma samples corresponding to three meningioma DNA methylation groups (Merlin-intact, Immune-enriched, and Hypermitotic), followed by in vitro experiments utilizing human meningioma cell lines.</p><p><strong>Results: </strong>We identify alterations in RNA splicing between meningioma DNA methylation groups including individual splicing events that correlate with Hypermitotic meningiomas and predict tumor recurrence and overall patient prognosis and compile a set of splicing events that can accurately predict DNA methylation classification based on RNA-seq data. Furthermore, we validate these events using RT-PCR in patient samples and meningioma cell lines. Additionally, we identify alterations in RNA binding proteins and splicing factors that lie upstream of RNA splicing events, including upregulation of SRSF1 in Hypermitotic meningiomas which we show drives alternative RNA splicing changes. Finally, we design splice switching antisense oligonucleotides to target RNA splicing changes in NASP and MFF observed in Hypermitotic meningiomas, providing a rationale for RNA-based therapeutic design.</p><p><strong>Conclusions: </strong>RNA splicing is an important driver of meningioma phenotypes that can be useful in prognosticating patients and as a potential exploit for therapeutic vulnerabilities.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141879215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Grégory Thomson, Mathilde Filser, Léa Guerrini-Rousseau, Arnault Tauziede-Espariat, Christine Bourneix, Marion Gauthier-Villars, Fatoumata Simaga, Kévin Beccaria, Cécile Faure-Conter, Aurélien Maureille, Hélène Zattara-Cannoni, Nicolas Andre, Natacha Entz-Werle, Laurence Brugieres, Ludovic Mansuy, Philippe Denizeau, Sophie Julia, Olivier Ingster, Sophie Lejeune, Afane Brahimi, Isabelle Coupier, Valérie Bonadona, Olivier Delattre, Julien Masliah-Planchon, Franck Bourdeaut
Background: Rhabdoid tumors (RT) are aggressive, rare tumors predominantly affecting young children, characterized by bi-allelic SMARCB1 gene inactivation. While most SMARCB1 alterations are acquired de novo, a third of cases exhibit germline alterations, defining Rhabdoid Tumors Predisposition Syndrome (RTPS1). With increased sensitivity of next-generation sequencing (NGS), mosaicisms in genes linked to genetic diseases are more detectable. This study focuses on exploring SMARCB1 germline alterations, notably mosaicism in blood samples of children with RT and in parents, using a custom NGS panel.
Methods: A cohort of 280 children and 140 parents with germline analysis was studied. Germline DNA from 111 children with RT and 32 parents were re-analyzed with a custom NGS panel with 1,500X average depth targeting the SMARCB1 gene to identify intragenic variants not detected with conventional low-sensitivity methods. Follow-up data was obtained for 77 patients.
Results: Nine previously undetected mosaicism cases were identified, totaling 17/280 patients with a mosaic variant (6.1%) in the cohort, with variant allele frequencies between 0.9% and 33%, thus highlighting the prior underestimation of its prevalence. Follow-up data showed that 4 out of 7 survivors with mosaic variants developed distinct novel tumors, two sharing SMARCB1 alterations with the initial tumor, emphasizing the potential clinical impact of SMARCB1 mosaicism.
Conclusions: The hitherto underestimated rate of SMARCB1 mosaicism in RT underscores the need for optimized genetic counseling and oncological monitoring. The findings have significant medical implications, considering the dire prognosis of RT.
{"title":"Post-zygotic mosaicism of SMARCB1 variants in patients with rhabdoid tumors: a not so rare condition exposing to successive tumors.","authors":"Grégory Thomson, Mathilde Filser, Léa Guerrini-Rousseau, Arnault Tauziede-Espariat, Christine Bourneix, Marion Gauthier-Villars, Fatoumata Simaga, Kévin Beccaria, Cécile Faure-Conter, Aurélien Maureille, Hélène Zattara-Cannoni, Nicolas Andre, Natacha Entz-Werle, Laurence Brugieres, Ludovic Mansuy, Philippe Denizeau, Sophie Julia, Olivier Ingster, Sophie Lejeune, Afane Brahimi, Isabelle Coupier, Valérie Bonadona, Olivier Delattre, Julien Masliah-Planchon, Franck Bourdeaut","doi":"10.1093/neuonc/noae122","DOIUrl":"https://doi.org/10.1093/neuonc/noae122","url":null,"abstract":"<p><strong>Background: </strong>Rhabdoid tumors (RT) are aggressive, rare tumors predominantly affecting young children, characterized by bi-allelic SMARCB1 gene inactivation. While most SMARCB1 alterations are acquired de novo, a third of cases exhibit germline alterations, defining Rhabdoid Tumors Predisposition Syndrome (RTPS1). With increased sensitivity of next-generation sequencing (NGS), mosaicisms in genes linked to genetic diseases are more detectable. This study focuses on exploring SMARCB1 germline alterations, notably mosaicism in blood samples of children with RT and in parents, using a custom NGS panel.</p><p><strong>Methods: </strong>A cohort of 280 children and 140 parents with germline analysis was studied. Germline DNA from 111 children with RT and 32 parents were re-analyzed with a custom NGS panel with 1,500X average depth targeting the SMARCB1 gene to identify intragenic variants not detected with conventional low-sensitivity methods. Follow-up data was obtained for 77 patients.</p><p><strong>Results: </strong>Nine previously undetected mosaicism cases were identified, totaling 17/280 patients with a mosaic variant (6.1%) in the cohort, with variant allele frequencies between 0.9% and 33%, thus highlighting the prior underestimation of its prevalence. Follow-up data showed that 4 out of 7 survivors with mosaic variants developed distinct novel tumors, two sharing SMARCB1 alterations with the initial tumor, emphasizing the potential clinical impact of SMARCB1 mosaicism.</p><p><strong>Conclusions: </strong>The hitherto underestimated rate of SMARCB1 mosaicism in RT underscores the need for optimized genetic counseling and oncological monitoring. The findings have significant medical implications, considering the dire prognosis of RT.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141879214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}