Richard Drexler, Thomas Sauvigny, Ulrich Schüller, Alicia Eckhardt, Cecile L Maire, Robin Khatri, Fabian Hausmann, Sonja Hänzelmann, Tobias B Huber, Stefan Bonn, Helena Bode, Katrin Lamszus, Manfred Westphal, Lasse Dührsen, Franz L Ricklefs
{"title":"表观遗传学分析显示IDH野生型胶质母细胞瘤中5-ALA荧光的缺乏与EGFR扩增之间存在强烈的相关性。","authors":"Richard Drexler, Thomas Sauvigny, Ulrich Schüller, Alicia Eckhardt, Cecile L Maire, Robin Khatri, Fabian Hausmann, Sonja Hänzelmann, Tobias B Huber, Stefan Bonn, Helena Bode, Katrin Lamszus, Manfred Westphal, Lasse Dührsen, Franz L Ricklefs","doi":"10.1093/nop/npad025","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>5-aminolevulinic acid (5-ALA) fluorescence-guided resection increases the percentage of complete CNS tumor resections and improves the progression-free survival of <i>IDH</i>-wildtype glioblastoma patients. A small subset of <i>IDH</i>-wildtype glioblastoma shows no 5-ALA fluorescence. An explanation for these cases is missing. In this study, we used DNA methylation profiling to further characterize non-fluorescent glioblastomas.</p><p><strong>Methods: </strong>Patients with newly diagnosed and recurrent <i>IDH</i>-wildtype glioblastoma that underwent surgery were analyzed. The intensity of intraoperative 5-ALA fluorescence was categorized as non-visible or visible. DNA was extracted from tumors and genome-wide DNA methylation patterns were analyzed using Illumina EPIC (850k) arrays. Furthermore, 5-ALA intensity was measured by flow cytometry on human gliomasphere lines (BT112 and BT145).</p><p><strong>Results: </strong>Of 74 included patients, 12 (16.2%) patients had a non-fluorescent glioblastoma, which were compared to 62 glioblastomas with 5-ALA fluorescence. Clinical characteristics were equally distributed between both groups. We did not find significant differences between DNA methylation subclasses and 5-ALA fluorescence (<i>P</i> = .24). The distribution of cells of the tumor microenvironment was not significantly different between the non-fluorescent and fluorescent tumors. Copy number variations in <i>EGFR and</i> simultaneous EGFRvIII expression were strongly associated with 5-ALA fluorescence since all non-fluorescent glioblastomas were <i>EGFR</i>-amplified (<i>P</i> < .01). This finding was also demonstrated in recurrent tumors. Similarly, <i>EGFR</i>-amplified glioblastoma cell lines showed no 5-ALA fluorescence after 24 h of incubation.</p><p><strong>Conclusions: </strong>Our study demonstrates an association between non-fluorescent <i>IDH</i>-wildtype glioblastomas and <i>EGFR</i> gene amplification which should be taken into consideration for recurrent surgery and future studies investigating <i>EGFR</i>-amplified gliomas.</p>","PeriodicalId":19234,"journal":{"name":"Neuro-oncology practice","volume":null,"pages":null},"PeriodicalIF":2.4000,"publicationDate":"2023-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10502788/pdf/","citationCount":"0","resultStr":"{\"title\":\"Epigenetic profiling reveals a strong association between lack of 5-ALA fluorescence and <i>EGFR</i> amplification in <i>IDH</i>-wildtype glioblastoma.\",\"authors\":\"Richard Drexler, Thomas Sauvigny, Ulrich Schüller, Alicia Eckhardt, Cecile L Maire, Robin Khatri, Fabian Hausmann, Sonja Hänzelmann, Tobias B Huber, Stefan Bonn, Helena Bode, Katrin Lamszus, Manfred Westphal, Lasse Dührsen, Franz L Ricklefs\",\"doi\":\"10.1093/nop/npad025\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>5-aminolevulinic acid (5-ALA) fluorescence-guided resection increases the percentage of complete CNS tumor resections and improves the progression-free survival of <i>IDH</i>-wildtype glioblastoma patients. A small subset of <i>IDH</i>-wildtype glioblastoma shows no 5-ALA fluorescence. An explanation for these cases is missing. In this study, we used DNA methylation profiling to further characterize non-fluorescent glioblastomas.</p><p><strong>Methods: </strong>Patients with newly diagnosed and recurrent <i>IDH</i>-wildtype glioblastoma that underwent surgery were analyzed. The intensity of intraoperative 5-ALA fluorescence was categorized as non-visible or visible. DNA was extracted from tumors and genome-wide DNA methylation patterns were analyzed using Illumina EPIC (850k) arrays. Furthermore, 5-ALA intensity was measured by flow cytometry on human gliomasphere lines (BT112 and BT145).</p><p><strong>Results: </strong>Of 74 included patients, 12 (16.2%) patients had a non-fluorescent glioblastoma, which were compared to 62 glioblastomas with 5-ALA fluorescence. Clinical characteristics were equally distributed between both groups. We did not find significant differences between DNA methylation subclasses and 5-ALA fluorescence (<i>P</i> = .24). The distribution of cells of the tumor microenvironment was not significantly different between the non-fluorescent and fluorescent tumors. Copy number variations in <i>EGFR and</i> simultaneous EGFRvIII expression were strongly associated with 5-ALA fluorescence since all non-fluorescent glioblastomas were <i>EGFR</i>-amplified (<i>P</i> < .01). This finding was also demonstrated in recurrent tumors. Similarly, <i>EGFR</i>-amplified glioblastoma cell lines showed no 5-ALA fluorescence after 24 h of incubation.</p><p><strong>Conclusions: </strong>Our study demonstrates an association between non-fluorescent <i>IDH</i>-wildtype glioblastomas and <i>EGFR</i> gene amplification which should be taken into consideration for recurrent surgery and future studies investigating <i>EGFR</i>-amplified gliomas.</p>\",\"PeriodicalId\":19234,\"journal\":{\"name\":\"Neuro-oncology practice\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.4000,\"publicationDate\":\"2023-05-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10502788/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neuro-oncology practice\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1093/nop/npad025\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/10/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q2\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuro-oncology practice","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1093/nop/npad025","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/10/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Epigenetic profiling reveals a strong association between lack of 5-ALA fluorescence and EGFR amplification in IDH-wildtype glioblastoma.
Background: 5-aminolevulinic acid (5-ALA) fluorescence-guided resection increases the percentage of complete CNS tumor resections and improves the progression-free survival of IDH-wildtype glioblastoma patients. A small subset of IDH-wildtype glioblastoma shows no 5-ALA fluorescence. An explanation for these cases is missing. In this study, we used DNA methylation profiling to further characterize non-fluorescent glioblastomas.
Methods: Patients with newly diagnosed and recurrent IDH-wildtype glioblastoma that underwent surgery were analyzed. The intensity of intraoperative 5-ALA fluorescence was categorized as non-visible or visible. DNA was extracted from tumors and genome-wide DNA methylation patterns were analyzed using Illumina EPIC (850k) arrays. Furthermore, 5-ALA intensity was measured by flow cytometry on human gliomasphere lines (BT112 and BT145).
Results: Of 74 included patients, 12 (16.2%) patients had a non-fluorescent glioblastoma, which were compared to 62 glioblastomas with 5-ALA fluorescence. Clinical characteristics were equally distributed between both groups. We did not find significant differences between DNA methylation subclasses and 5-ALA fluorescence (P = .24). The distribution of cells of the tumor microenvironment was not significantly different between the non-fluorescent and fluorescent tumors. Copy number variations in EGFR and simultaneous EGFRvIII expression were strongly associated with 5-ALA fluorescence since all non-fluorescent glioblastomas were EGFR-amplified (P < .01). This finding was also demonstrated in recurrent tumors. Similarly, EGFR-amplified glioblastoma cell lines showed no 5-ALA fluorescence after 24 h of incubation.
Conclusions: Our study demonstrates an association between non-fluorescent IDH-wildtype glioblastomas and EGFR gene amplification which should be taken into consideration for recurrent surgery and future studies investigating EGFR-amplified gliomas.
期刊介绍：
Neuro-Oncology Practice focuses on the clinical aspects of the subspecialty for practicing clinicians and healthcare specialists from a variety of disciplines including physicians, nurses, physical/occupational therapists, neuropsychologists, and palliative care specialists, who have focused their careers on clinical patient care and who want to apply the latest treatment advances to their practice. These include: Applying new trial results to improve standards of patient care Translating scientific advances such as tumor molecular profiling and advanced imaging into clinical treatment decision making and personalized brain tumor therapies Raising awareness of basic, translational and clinical research in areas of symptom management, survivorship, neurocognitive function, end of life issues and caregiving
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