A Long-term Progression-free Survival with Glioblastoma Patient Harboring MSH6 Pathogenic Germline Mutation: A Case Report

A Long-term Progression-free Survival with Glioblastoma Patient Harboring MSH6 Pathogenic Germline Mutation: A Case Report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A Long-term Progression-free Survival with Glioblastoma Patient Harboring MSH6 Pathogenic Germline Mutation: A Case Report Yiqiang Zhou, Yanxiang Zhang, Tiantian Han, Yueshan Piao, Jie Tang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5741696/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Lynch syndrome (LS) is a cancer syndrome caused by germline mutations in DNA mismatch repair genes. Patients with Lynch syndrome have higher risk of brain tumors, predominantly high-grade gliomas. LS-related gliomas have poor overall survival. Case presentation We present a case of a31-year-old male patient with a frontal lesion by magnetic resonance imaging (MRI). The pathological diagnosis was isocitrate dehydrogenase (IDH) wildtype glioblastoma (WHO grade 4) with 30% Ki-67 proliferation index. After surgery, this patient received radiotherapy and temozolomide chemotherapy following Stupp protocol. During over 64 months follow up, no sign of tumor recurrence was found after surgery. Therefore, next-generation sequencing was suggested to this patient. The result revealed a heterozygous germline variation of c.3261dup in exon 5 of MSH6 gene which resulted in a truncated MSH6 protein (MSH6 p.F1088Lfs*5) with a tumor mutation burden of 327.36 Mut/Mb. Conclusion MMR deficiency may lead to TMZ resistance in glioma cells. However, this case had long-term benefits from standard radio- and chemo-therapy after surgery, probably due to the distinct molecular characteristics and tumor microenvironment. This finding provided insight to perform clinical studies to investigate the molecular characterization of Lynch associated glioma patients and the role of microglia in antitumor. Lynch syndrome glioblastoma long-term survive case report Figures Figure 1 Figure 2 Figure 3 Figure 4 Key Points 1. This report demonstrated the long-term recurrence free survival of a patient with glioblastoma carrying pathogenic germline mutation. 2. The long-term benefits of the Stupp regimen in this case indicated that Lynch associated glioblastoma was not initially resistant to TMZ treatment, and did not support the previous reports that MMR deficiency lead to TMZ resistance in glioma cells. 3. The results of tumor microenvironment analysis revealed the enrichment of CD68 + in microglia, might exert cytotoxic potential of microglial cells and result in antitumor actions. 4. This finding provided insight to perform clinical studies to investigate the molecular characterization of Lynch associated glioma patients and the role of microglia in antitumor. Background Lynch syndrome (LS) is an autosomal dominant disorder that arises from heterozygous or homozygous germline mutations in known DNA mismatch repair (MMR) genes, including MLH1, MSH2, MSH6, PMS2 or EPCAM [ 1 – 3 ]. There exists a correlation between LS and an increased lifetime risk of developing colorectal cancer as well as several other malignancies, including those that impact the biliary tract, brain (typically glioblastoma), endometrium, stomach, urinary tract, sebaceous adenomas, keratoacanthomas, and skin. The cumulative risk of developing brain tumors in patients with LS is estimated to be between 1% and 6%. Compared to MLH1 and MSH6 mutations, the risk is higher in subjects carrying pathogenic MSH2 mutations[ 4 ]. LS-related glioblastomas (GBMs) often exhibit unique molecular and histological characteristics, including higher tumor mutation burden (TMB) and microsatellite instability (MSI)[ 5 ]. Studies have reported that LS-related gliomas generally have worse prognosis and may be resistant to temozolomide (TMZ), with limited benefit from Stupp treatment[ 6 , 7 ]. Due to the distinct molecular landscape of the tumors, the treatment for LS-related GMBs should be personalized. In this case, we describe an isocitrate dehydrogenase (IDH) wildtype GBM patient with germline MSH6 mutation, who is surviving over 50 months with no sign of recurrence after surgery and standard radio- and chemo-therapy. Case Presentation A 31-year-old male patient suffered from intermittent headache, nausea, and vomit for 3 weeks. With progressive headache, he had unstable walking a week later. The magnetic resonance imaging (MRI) revealed a ring-enhancing (5.4×5.2×5.0 cm) lesion in the left frontal lobe, involving left corpus callosum, left frontal horn of lateral ventricle and basal ganglia region. Magnetic resonance spectroscopy (MRS) showed significantly increased Cho and decreased NAA and Cr. The margin of the lesion was isodensity in CT scan, and peritumoral edema was observed (Fig. 1 ). Additionally, he had a family history of cancer, both of his mother’s sisters suffered from breast cancer. A glioma was suspected pre-operatively, and the lesion was completely removed via trans-longitudinal fissure approach under left frontal craniotomy (May, 2020). Pathological Analysis Hematoxylin and eosin (HE) staining showed the widespread infiltration of tumor cells in the brain tissues. Nuclear atypia and pleomorphism could be observed. There were scattered large mononucleated and multinucleated giant tumor cells, as well as apparent mitotic figures. There were also areas with endothelial proliferation, lymphocyte infiltration and necrosis (Fig. 2 A-C). Immunohistochemistry (IHC) staining showed the expression of GFAP, Olio-2, Vimentin, p53, CD34, MGMT, EGFR and H3K27me3 in tumor cells. There was loss of nuclear staining of ATRX in glioma cells. Ki-67 proliferation index was about 30% (Fig. 2 D-I). No expression of CK, EMA, BRAFV600E, IDH1-R132H, EGFRvIII was detected. The pathological diagnosis was IDH1-R132H wild-type glioblastoma (WHO grade 4). IHC staining of CD4, CD8, CD68 and CD163 were performed, no significant expression of CD4 and CD8 were observed. In contrast, CD68 + microglia were abundant in the tumor tissue. Post-operative treatment and follow-up The patient received radiotherapy and temozolomide chemotherapy following the Stupp protocol. Routine MRI follow-up were performed every 6 months. During over 64 months follow up, no sign of tumor recurrence could be observed on MRI (Fig. 3 ) Unlike the limited overall survival of most GBM patients, this patient has extraordinary prognosis. Therefore, we recommended him the next-generation sequencing (NGS) panel test to identify potential genetic alterations and also to confirm the pathology with molecular characteristics according to 2021 World Health Organization criteria. Molecular landscape NGS panel test revealed that IDH 1/2 mutation, promoter of O6-Methylguanine-DNA-methyltransferase ( pMGMT ) methylation, promoter of telomerase reverse transcriptase ( pTERT ) C228T and C250T mutation were not detected. EGFR and PDGFRA amplification, as well as chromosome 7 gain and 10 loss (+ 7/-10) were not identified in this patient. However, more than 390 somatic gene mutations were detected in this patient (Supplementary Table 1). Some of them are of clinical significance, such as ATRX c.4810-1G > T, NF1 (c.7441G > T, c.3574G > T, and c.2446C > T), PTEN (c.701G > A, c.517C > T), TP53 (c.455C > T, c.916C > T, c.742C > T) and ATM c.8921C > T. Furthermore, we identified a heterozygous germline variation in MSH6 gene (MSH6 p.F1088Lfs*5). According to the variant interpretation guidelines of the American College of Medical Genetics and Genomics (ACMG), this variation is confirmed to be a pathogenic mutation. The results comprehensively suggested that the tumor was an LS-related IDH wild-type GBM. Additionally, the patient’s mother and his 3-year-old son were detected with the same mutation in MSH6 gene (Fig. 4 A and B). IHC staining showed loss of MSH6 protein expression in the tumor tissue (Fig. 4 C-F). The patient and his mother received gastroscopy and enteroscopy, no gastroenteric tumor was discovered. The patient’s mother has no sign of breast cancer or other LS-related tumors. Importantly, both of the patient’s two aunts (mother’s older and younger sisters) suffered breast cancers. This patient had typical characteristics of high TMB, with a TMB of 327.36 Mut/Mb. Microsatellite instability (MSI) testing using NGS showed microsatellite-stable (MSS) in this patient. No hotspot mutation of POLE gene was discovered. Discussion This case presented a LS-related IDH wild-type GBM patient with long term survival (LTS). Patients with LS have a quadrupled chance of developing brain tumors, primarily high-grade gliomas[ 8 ]. There was 56% of the LS-related brain tumor patients being diagnosed as GBM[ 4 ]. Therkildsen et al. reported that 14% (41/288) LS patients developed primary brain tumors at a median age of 41.5 years. Among the 41 LS patients with brain tumors, 68% had mutations in MSH2 , 15% in MSH6 , 15% in MLH1 and 2% in PMS2 . Our patient was detected to be with germline MSH6 mutation (MSH6 p.F1088Lfs*5). MMR gene mutation has been reported in 4.7% of IDH -mutant astrocytoma, and 2.1% of IDH-wild-type glioblastoma. In recurrent gliomas, about 19.35% of IDH -mutant astrocytoma has MMR gene mutation, and which is 14.75% in IDH -wildtype glioblastomas[ 9 ]. No significant difference of progression-free survival (PFS) or overall survival (OS) was observed between MMR-mutant group and MMR-wildtype group in IDH-wildtype glioblastoma patients[ 9 ]. Gliomas in LS patients often harbor additional mutations, including TP53 and ATRX alterations, contributing to the oncogenic landscape of these tumors[ 10 ]. This patient was detected with TP53 and ATRX mutation, which is rare that ATRX alteration usually happens in IDH mutant gliomas[ 11 ]. TMB is a critical predictive biomarker in evaluating the genomic instability of solid tumors, and is usually associated with high MSI[ 12 ]. This patient exhibited super-high TMB (327.36 Muts/Mb), may resulting from the deficiency of MMR system, which allows for the accumulation of numerous gene mutations. It has been reported that LS-related gliomas have significantly higher TMB in comparison with non-LS counterparts[ 13 ], suggesting a distinct molecular profile in LS-related gliomas that may affect treatment response and prognosis. A high TMB in cancers is generally associated with better response to immunotherapy and improved OS[ 14 – 16 ]. Due to the super-high TMB, this patient may benefit from immune checkpoint inhibitors (ICIs), such as pembrolizumab or nivolumab. If the tumor recurs in the future, ICIs should be recommended. LS-associated GBM exhibits heterogeneity in clinicopathologic and molecular genetic features, as well as a suppressive tumor immune microenvironment, CD8 + T cells and CD163 + macrophages were abundant in each GBM tissue[ 7 ]. However, we analyzed the expression of CD4, CD8, CD68 and CD163 in the tumor tissues using IHC. The abundant signals of CD68 + were observed in infiltrated microglial, while no significant CD4 + and CD8 + cells were found. It is interesting that CD68 + microglial may exert pro-inflammatory immune function in specific situations, such as during CD8 lymphocyte depletion or depletion, which may be an immune compensation mechanism. TMZ, an alkylating agent, is the standard chemotherapy for treating gliomas, yet its efficacy in LS-related gliomas should be concerned. The efficacy of TMZ and other alkylating agents are depending on the function of mismatch repair cycle. It has been reported that knockout of MMR genes in patient-derived glioma cells showed resistance to TMZ treatment, but not to lomustine (CCNU, a bifunctional alkylating agent)[ 17 ]. The lower sensitivity to TMZ in LS-related gliomas may be attribute to the presence of high TMB that can produce a more complex mutational landscape, making glioma cells more adaptable and less predictable in their response to chemotherapy. Moreover, mutations in DNA repair pathways, particularly those involving MMR mechanisms, can diminish the cytotoxic effects of TMZ, which relies on inducing DNA damage to exert its therapeutic benefits[ 18 , 19 ]. Due to lacking to NGS panel test result after surgery, this patient accepted standard radio- and chemotherapy following Stupp protocol. Therefore, it is extremely important to know the landscape of genomic alteration for glioma patients. The unique genetic and molecular profile of LS-related gliomas must be considered when formulating treatment plans, potentially leading to the exploration of alternative therapeutic options for patients exhibiting resistance to standard therapies. Somatic ataxia telangiectasia mutated ( ATM ) gene mutation was detected in this patient (c.8921C > T). ATM plays a critical role in the repair of DNA double-strand breaks (DSB)[ 20 ]. Germ-line mutations of ATM lead to the autosomal recessive ataxia telangiectasia (A-T) syndrome, which increases cancer susceptibility[ 21 ]. Somatic mutations of ATM can be detected in many types of cancers, mostly in hematologic malignancies[ 22 ]. It has been reported that ATM mutations exist in less than 5% of glioblastoma and about 1% of medulloblastomas[ 23 ]. Studies revealed that ATM inhibition enhances the efficacy of radiation in primary brainstem glioma models and pediatric high-grade glioma[ 24 , 25 ]. Similarly, ATM mutations improve radio-sensitivity in IDH wild-type high grade gliomas[ 26 ]. Conclusion In summary, we report a case of long-term survived (> 50 months) IDH -wildtype glioblastoma patient with germline MSH6 gene mutation, who is diagnosed as a LS-related glioblastoma. MMR deficiency may lead to TMZ resistance in glioma cells. However, this case had long-term benefits from standard radio- and chemo-therapy after surgery. This case demonstrates distinct molecular characteristics and tumor microenvironment. These results indicated the importance of comprehensive molecular profile in the diagnosis and guild individual treatment for glioma patients. Due to the limited efficacy of TMZ for LS-related glioblastoma with high TMB, the use of ICIs or combining lomustine with PARP inhibitors could potentially enhance chemosensitivity and improve prognosis when the tumor recurs. Abbreviations Lynch Syndrome (LS) Muts Homolog 6 (MSH6) Isocitrate Dehydrogenase (IDH) World Health Organization (WHO) Glioblastomas (GBMs) Mismatch Repair (MMR) Tumor Mutation Burden (TMB) Microsatellite Instability (MSI) Magnetic Resonance Imaging (MRI) Magnetic Resonance Spectroscopy (MRS) Hematoxylin And Eosin (HE) Immunohistochemistry (IHC) Glial Fibrillary Acidic Protein (GFAP) O6-Methylguanine-DNA Methyltransferase (MGMT) Epidermal Growth Factor Receptor (EGFR) The Alpha-Thalassemia Mental Retardation X-Linked (ATRX) Next-Generation Sequencing (NGS) Promoter of O6-Methylguanine-DNA-Methyltransferase (pMGMT) Promoter of Telomerase Reverse Transcriptase (pTERT) Microsatellite-Stable (MSS) Long Term Survival (LTS) Progression-Free Survival (PFS) Overall Survival (OS) Ataxia Telangiectasia Mutated (ATM) Declarations Ethics approval and consent to participate This study was conducted under the approval of the Ethics Committee of Xuanwu Hospital, Capital Medical University. Patients informed consent for the publication has been obtained. Consent for publication Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal. Availability of data and materials Not applicable. Competing Interests: No conflict of interests to be disclosed. Funding None Authors’ contribution All authors have read and approved the manuscript. Data curation: YZ, TH, and YP. Investigation: YZ. Methodology: YZ. Project administration: YP and JT. Supervision: YP and JT. Writing – original draft: YZ. Writing– review & editing: YP and JT. Acknowledgments None References Moreira L, Balaguer F, Lindor N, de la Chapelle A, Hampel H, Aaltonen LA, et al. Identification of Lynch syndrome among patients with colorectal cancer. JAMA. 2012;308 15:1555-65; doi: 10.1001/jama.2012.13088. Lynch HT, Snyder CL, Shaw TG, Heinen CD, Hitchins MP. 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N Engl J Med. 2014;371 23:2189-99; doi: 10.1056/NEJMoa1406498. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348 6230:124-8; doi: 10.1126/science.aaa1348. Touat M, Li YY, Boynton AN, Spurr LF, Iorgulescu JB, Bohrson CL, et al. Mechanisms and therapeutic implications of hypermutation in gliomas. Nature. 2020;580 7804:517-23; doi: 10.1038/s41586-020-2209-9. Heinen CD. Translating mismatch repair mechanism into cancer care. Curr Drug Targets. 2014;15 1:53-64; doi: 10.2174/1389450114666140106100128. Alnahhas I, Rayi A, Ong S, Giglio P, Puduvalli V. Management of gliomas in patients with Lynch syndrome. Neuro Oncol. 2021;23 1:167-8; doi: 10.1093/neuonc/noaa227. Bednarski JJ, Sleckman BP. Integrated signaling in developing lymphocytes: the role of DNA damage responses. Cell Cycle. 2012;11 22:4129-34; doi: 10.4161/cc.22021. Li A, Swift M. Mutations at the ataxia-telangiectasia locus and clinical phenotypes of A-T patients. Am J Med Genet. 2000;92 3:170-7; doi: 10.1002/(sici)1096-8628(20000529)92:33.0.co;2-#. Boultwood J. Ataxia telangiectasia gene mutations in leukaemia and lymphoma. J Clin Pathol. 2001;54 7:512-6; doi: 10.1136/jcp.54.7.512. Choi M, Kipps T, Kurzrock R. ATM Mutations in Cancer: Therapeutic Implications. Mol Cancer Ther. 2016;15 8:1781-91; doi: 10.1158/1535-7163.MCT-15-0945. Deland K, Starr BF, Mercer JS, Byemerwa J, Crabtree DM, Williams NT, et al. Tumor genotype dictates radiosensitization after Atm deletion in primary brainstem glioma models. J Clin Invest. 2021;131 1; doi: 10.1172/JCI142158. Xie J, Kuriakose T, Bianski B, Twarog N, Savage E, Xu K, et al. ATM inhibition enhances the efficacy of radiation across distinct molecular subgroups of pediatric high-grade glioma. Neuro Oncol. 2023;25 10:1828-41; doi: 10.1093/neuonc/noad064. Kim N, Kim SH, Kang SG, Moon JH, Cho J, Suh CO, et al. ATM mutations improve radio-sensitivity in wild-type isocitrate dehydrogenase-associated high-grade glioma: retrospective analysis using next-generation sequencing data. Radiat Oncol. 2020;15 1:184; doi: 10.1186/s13014-020-01619-y. Supplementary Files SupplementaryTable1.xlsx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5741696","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":406268294,"identity":"220a32e0-ea51-4083-a6a9-cfae644ae662","order_by":0,"name":"Yiqiang Zhou","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+0lEQVRIiWNgGAWjYDACCRBhwMADJBkfMDAcIE0LswEJWiCATYIoLfKzm49J8xRYy/DPbr9Wzdt2R05+dgPj44pfuLUwzjmWJs1jkM4jcedM2c2Zbc+MDe4cYDY824dbC7NEjhlQy2Eehhs5aTc+bjucuEEigU2ysQe3FjaYFnmgloJEoJb5Mwho4YFpMbiRfowBZEvDDaCWhh+4tUhIpCVbzgH6xfBGDrPkzH+HgX452GzY2IBbi/yM5IM33vyxtpe7kf7wM8+Zw8AQaz74sOEPbi0gwMTDwAxyowHUYsYGBsY2/FoYf4C1sD+AagERBGwZBaNgFIyCEQUA69lTo9R58OoAAAAASUVORK5CYII=","orcid":"","institution":"Department of Neurosurgery, Xuanwu Hospital, Capital Medical University","correspondingAuthor":true,"prefix":"","firstName":"Yiqiang","middleName":"","lastName":"Zhou","suffix":""},{"id":406268295,"identity":"c4cc5b09-492c-4aff-aaac-3076914ceb68","order_by":1,"name":"Yanxiang Zhang","email":"","orcid":"","institution":"State Key Laboratory of Neurology and Oncology Drug Development, Jiangsu Simcere Diagnostics Co., Ltd.","correspondingAuthor":false,"prefix":"","firstName":"Yanxiang","middleName":"","lastName":"Zhang","suffix":""},{"id":406268296,"identity":"29d06525-79a6-47e0-881e-14f1006dbf0c","order_by":2,"name":"Tiantian Han","email":"","orcid":"","institution":"State Key Laboratory of Neurology and Oncology Drug Development, Jiangsu Simcere Diagnostics Co., Ltd.","correspondingAuthor":false,"prefix":"","firstName":"Tiantian","middleName":"","lastName":"Han","suffix":""},{"id":406268297,"identity":"710d5b46-5a30-4c37-aff7-6721a9798644","order_by":3,"name":"Yueshan Piao","email":"","orcid":"","institution":"Department of Pathology, Xuanwu Hospital, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yueshan","middleName":"","lastName":"Piao","suffix":""},{"id":406268298,"identity":"11c01fa1-0d93-4db1-96c9-2006d22ae3ce","order_by":4,"name":"Jie Tang","email":"","orcid":"","institution":"Department of Neurosurgery, Xuanwu Hospital, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"Tang","suffix":""}],"badges":[],"createdAt":"2024-12-31 11:33:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5741696/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5741696/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":75311973,"identity":"ff4f40f0-a327-481f-8196-49dcc6bf3430","added_by":"auto","created_at":"2025-02-03 09:10:44","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":72623,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePre-operative MRI and CT scan.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) T1-weighted MRI showed a lesion in left frontal lobe, involving left corpus callosum, left frontal horn of lateral ventricle and basal ganglia region.\u003c/p\u003e\n\u003cp\u003e(B and C) The lesion was mixed intense on T2-weighted and flair image, peritumoral edema was observed.\u003c/p\u003e\n\u003cp\u003e(D) Elevated signal was observed on DWI image in the enhancing component.\u003c/p\u003e\n\u003cp\u003e(E and F) Axial and coronal T1-weighted images with enhancement.\u003c/p\u003e\n\u003cp\u003e(G) MRS showed significantly increased Cho and decreased NAA and Cr.\u003c/p\u003e\n\u003cp\u003e(H) CT scan showed the margin of the lesion was isodensity.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5741696/v1/43f6bff6975a8ac6ffe1d3f3.jpg"},{"id":75312830,"identity":"f3a94422-54f6-4d72-9030-fdc5fa3c2b6f","added_by":"auto","created_at":"2025-02-03 09:18:44","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":151129,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eHistopathological features.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A-C) H\u0026amp;E staining showed nuclear atypia and pleomorphism, scattered large mononucleated and multinucleated giant tumor cells, as well as apparent mitotic figures. The endothelial proliferation, lymphocyte infiltration and necrosis could be observed.\u003c/p\u003e\n\u003cp\u003e(D) IHC staining showed the expression of GFAP in GBM.\u003c/p\u003e\n\u003cp\u003e(E and F) Partial expression of Olig-2 and p53.\u003c/p\u003e\n\u003cp\u003e(G) Loss of nuclear staining of ATRX in glioma cells.\u003c/p\u003e\n\u003cp\u003e(H) Ki67 proliferation index was about 30%.\u003c/p\u003e\n\u003cp\u003e(I) Positive expression of CD68 in microglia.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5741696/v1/24999eb47e28b6ae20c6fac1.jpg"},{"id":75311978,"identity":"138afebb-7849-4616-b804-8fa3e832298b","added_by":"auto","created_at":"2025-02-03 09:10:44","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":112608,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePost-operative MRI.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A-H) MRI scan in December, 2023. Perfusion-weighted imaging (PWI) was performed. No sigh of tumor recurrence was revealed.\u003c/p\u003e\n\u003cp\u003e(I-P) MRI scan in April, 2024. No obvious change was observed.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5741696/v1/51cef7cab2b786494a59c422.jpg"},{"id":75312829,"identity":"c6978781-d1e3-4251-9737-c06c17da8fe6","added_by":"auto","created_at":"2025-02-03 09:18:44","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":129455,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eMSH6\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003emutation and loss of MSH6 protein expression.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Pedigree of the family and sequencing analysis of \u003cem\u003eMSH6 p.F1088Lfs*5 \u003c/em\u003e(\u003cem\u003ec.3261dup\u003c/em\u003e) mutation .\u003c/p\u003e\n\u003cp\u003e(B) Family member (II:2, III:2, IV:1) with the heterozygous \u003cem\u003eMSH6 p.F1088Lfs*5 \u003c/em\u003e(\u003cem\u003ec.3261dup\u003c/em\u003e) allele. Family member (II:1) with wild-type allele of \u003cem\u003eMSH6\u003c/em\u003e.\u003c/p\u003e\n\u003cp\u003e(C) Loss of MSH6 protein expression in tumor tissue.\u003c/p\u003e\n\u003cp\u003e(D-F) IHC staining of MSH2, MLH1 and PMS2 protein in tumor tissue.\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5741696/v1/5b39ba610f93f71724c7f215.jpg"},{"id":78094151,"identity":"8b0ff013-d0e3-47af-a355-493226576a78","added_by":"auto","created_at":"2025-03-09 21:47:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":962956,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5741696/v1/93a9898c-5e5d-4e5e-8079-a242b5128d44.pdf"},{"id":75311985,"identity":"300bcfc9-ba78-4484-9194-34070638d265","added_by":"auto","created_at":"2025-02-03 09:10:44","extension":"xlsx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":73975,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5741696/v1/b2dc047a022e0990ccaf5854.xlsx"}],"financialInterests":"","formattedTitle":"A Long-term Progression-free Survival with Glioblastoma Patient Harboring MSH6 Pathogenic Germline Mutation: A Case Report","fulltext":[{"header":"Key Points","content":"\u003cp\u003e1. This report demonstrated the long-term recurrence free survival of a patient with glioblastoma carrying pathogenic germline mutation.\u003c/p\u003e\u003cp\u003e2. The long-term benefits of the Stupp regimen in this case indicated that Lynch associated glioblastoma was not initially resistant to TMZ treatment, and did not support the previous reports that MMR deficiency lead to TMZ resistance in glioma cells.\u003c/p\u003e\u003cp\u003e3. The results of tumor microenvironment analysis revealed the enrichment of CD68\u0026thinsp;+\u0026thinsp;in microglia, might exert cytotoxic potential of microglial cells and result in antitumor actions.\u003c/p\u003e\u003cp\u003e4. This finding provided insight to perform clinical studies to investigate the molecular characterization of Lynch associated glioma patients and the role of microglia in antitumor.\u003c/p\u003e"},{"header":"Background","content":"\u003cp\u003eLynch syndrome (LS) is an autosomal dominant disorder that arises from heterozygous or homozygous germline mutations in known DNA mismatch repair (MMR) genes, including \u003cem\u003eMLH1, MSH2, MSH6, PMS2 or EPCAM\u003c/em\u003e [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. There exists a correlation between LS and an increased lifetime risk of developing colorectal cancer as well as several other malignancies, including those that impact the biliary tract, brain (typically glioblastoma), endometrium, stomach, urinary tract, sebaceous adenomas, keratoacanthomas, and skin. The cumulative risk of developing brain tumors in patients with LS is estimated to be between 1% and 6%. Compared to \u003cem\u003eMLH1\u003c/em\u003e and \u003cem\u003eMSH6\u003c/em\u003e mutations, the risk is higher in subjects carrying pathogenic \u003cem\u003eMSH2\u003c/em\u003e mutations[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. LS-related glioblastomas (GBMs) often exhibit unique molecular and histological characteristics, including higher tumor mutation burden (TMB) and microsatellite instability (MSI)[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eStudies have reported that LS-related gliomas generally have worse prognosis and may be resistant to temozolomide (TMZ), with limited benefit from Stupp treatment[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Due to the distinct molecular landscape of the tumors, the treatment for LS-related GMBs should be personalized. In this case, we describe an \u003cem\u003eisocitrate dehydrogenase (IDH)\u003c/em\u003e wildtype GBM patient with germline \u003cem\u003eMSH6\u003c/em\u003e mutation, who is surviving over 50 months with no sign of recurrence after surgery and standard radio- and chemo-therapy.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 31-year-old male patient suffered from intermittent headache, nausea, and vomit for 3 weeks. With progressive headache, he had unstable walking a week later. The magnetic resonance imaging (MRI) revealed a ring-enhancing (5.4\u0026times;5.2\u0026times;5.0 cm) lesion in the left frontal lobe, involving left corpus callosum, left frontal horn of lateral ventricle and basal ganglia region. Magnetic resonance spectroscopy (MRS) showed significantly increased Cho and decreased NAA and Cr. The margin of the lesion was isodensity in CT scan, and peritumoral edema was observed (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Additionally, he had a family history of cancer, both of his mother\u0026rsquo;s sisters suffered from breast cancer. A glioma was suspected pre-operatively, and the lesion was completely removed via trans-longitudinal fissure approach under left frontal craniotomy (May, 2020).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePathological Analysis\u003c/p\u003e \u003cp\u003eHematoxylin and eosin (HE) staining showed the widespread infiltration of tumor cells in the brain tissues. Nuclear atypia and pleomorphism could be observed. There were scattered large mononucleated and multinucleated giant tumor cells, as well as apparent mitotic figures. There were also areas with endothelial proliferation, lymphocyte infiltration and necrosis (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA-C). Immunohistochemistry (IHC) staining showed the expression of GFAP, Olio-2, Vimentin, p53, CD34, MGMT, EGFR and H3K27me3 in tumor cells. There was loss of nuclear staining of ATRX in glioma cells. Ki-67 proliferation index was about 30% (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD-I). No expression of CK, EMA, BRAFV600E, IDH1-R132H, EGFRvIII was detected. The pathological diagnosis was IDH1-R132H wild-type glioblastoma (WHO grade 4). IHC staining of CD4, CD8, CD68 and CD163 were performed, no significant expression of CD4 and CD8 were observed. In contrast, CD68\u0026thinsp;+\u0026thinsp;microglia were abundant in the tumor tissue.\u003c/p\u003e \u003cp\u003ePost-operative treatment and follow-up\u003c/p\u003e \u003cp\u003eThe patient received radiotherapy and temozolomide chemotherapy following the Stupp protocol. Routine MRI follow-up were performed every 6 months. During over 64 months follow up, no sign of tumor recurrence could be observed on MRI (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) Unlike the limited overall survival of most GBM patients, this patient has extraordinary prognosis. Therefore, we recommended him the next-generation sequencing (NGS) panel test to identify potential genetic alterations and also to confirm the pathology with molecular characteristics according to 2021 World Health Organization criteria.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eMolecular landscape\u003c/p\u003e \u003cp\u003eNGS panel test revealed that \u003cem\u003eIDH 1/2\u003c/em\u003e mutation, promoter of \u003cem\u003eO6-Methylguanine-DNA-methyltransferase\u003c/em\u003e (\u003cem\u003epMGMT\u003c/em\u003e) methylation, promoter of \u003cem\u003etelomerase reverse transcriptase\u003c/em\u003e (\u003cem\u003epTERT\u003c/em\u003e) C228T and C250T mutation were not detected. \u003cem\u003eEGFR\u003c/em\u003e and \u003cem\u003ePDGFRA\u003c/em\u003e amplification, as well as chromosome 7 gain and 10 loss (+\u0026thinsp;7/-10) were not identified in this patient.\u003c/p\u003e \u003cp\u003eHowever, more than 390 somatic gene mutations were detected in this patient (Supplementary Table\u0026nbsp;1). Some of them are of clinical significance, such as \u003cem\u003eATRX\u003c/em\u003e c.4810-1G\u0026thinsp;\u0026gt;\u0026thinsp;T, \u003cem\u003eNF1\u003c/em\u003e (c.7441G\u0026thinsp;\u0026gt;\u0026thinsp;T, c.3574G\u0026thinsp;\u0026gt;\u0026thinsp;T, and c.2446C\u0026thinsp;\u0026gt;\u0026thinsp;T), \u003cem\u003ePTEN\u003c/em\u003e (c.701G\u0026thinsp;\u0026gt;\u0026thinsp;A, c.517C\u0026thinsp;\u0026gt;\u0026thinsp;T), \u003cem\u003eTP53\u003c/em\u003e (c.455C\u0026thinsp;\u0026gt;\u0026thinsp;T, c.916C\u0026thinsp;\u0026gt;\u0026thinsp;T, c.742C\u0026thinsp;\u0026gt;\u0026thinsp;T) and \u003cem\u003eATM\u003c/em\u003e c.8921C\u0026thinsp;\u0026gt;\u0026thinsp;T.\u003c/p\u003e \u003cp\u003eFurthermore, we identified a heterozygous germline variation in \u003cem\u003eMSH6\u003c/em\u003e gene (MSH6 p.F1088Lfs*5). According to the variant interpretation guidelines of the American College of Medical Genetics and Genomics (ACMG), this variation is confirmed to be a pathogenic mutation. The results comprehensively suggested that the tumor was an LS-related IDH wild-type GBM. Additionally, the patient\u0026rsquo;s mother and his 3-year-old son were detected with the same mutation in \u003cem\u003eMSH6\u003c/em\u003e gene (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA and B). IHC staining showed loss of MSH6 protein expression in the tumor tissue (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC-F). The patient and his mother received gastroscopy and enteroscopy, no gastroenteric tumor was discovered. The patient\u0026rsquo;s mother has no sign of breast cancer or other LS-related tumors. Importantly, both of the patient\u0026rsquo;s two aunts (mother\u0026rsquo;s older and younger sisters) suffered breast cancers.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThis patient had typical characteristics of high TMB, with a TMB of 327.36 Mut/Mb. Microsatellite instability (MSI) testing using NGS showed microsatellite-stable (MSS) in this patient. No hotspot mutation of POLE gene was discovered.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis case presented a LS-related \u003cem\u003eIDH\u003c/em\u003e wild-type GBM patient with long term survival (LTS). Patients with LS have a quadrupled chance of developing brain tumors, primarily high-grade gliomas[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. There was 56% of the LS-related brain tumor patients being diagnosed as GBM[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Therkildsen et al. reported that 14% (41/288) LS patients developed primary brain tumors at a median age of 41.5 years. Among the 41 LS patients with brain tumors, 68% had mutations in \u003cem\u003eMSH2\u003c/em\u003e, 15% in \u003cem\u003eMSH6\u003c/em\u003e, 15% in \u003cem\u003eMLH1\u003c/em\u003e and 2% in \u003cem\u003ePMS2\u003c/em\u003e. Our patient was detected to be with germline \u003cem\u003eMSH6\u003c/em\u003e mutation (MSH6 p.F1088Lfs*5).\u003c/p\u003e \u003cp\u003eMMR gene mutation has been reported in 4.7% of \u003cem\u003eIDH\u003c/em\u003e-mutant astrocytoma, and 2.1% of IDH-wild-type glioblastoma. In recurrent gliomas, about 19.35% of \u003cem\u003eIDH\u003c/em\u003e-mutant astrocytoma has MMR gene mutation, and which is 14.75% in \u003cem\u003eIDH\u003c/em\u003e-wildtype glioblastomas[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. No significant difference of progression-free survival (PFS) or overall survival (OS) was observed between MMR-mutant group and MMR-wildtype group in IDH-wildtype glioblastoma patients[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Gliomas in LS patients often harbor additional mutations, including \u003cem\u003eTP53\u003c/em\u003e and \u003cem\u003eATRX\u003c/em\u003e alterations, contributing to the oncogenic landscape of these tumors[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This patient was detected with \u003cem\u003eTP53\u003c/em\u003e and \u003cem\u003eATRX\u003c/em\u003e mutation, which is rare that \u003cem\u003eATRX\u003c/em\u003e alteration usually happens in \u003cem\u003eIDH\u003c/em\u003e mutant gliomas[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTMB is a critical predictive biomarker in evaluating the genomic instability of solid tumors, and is usually associated with high MSI[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. This patient exhibited super-high TMB (327.36 Muts/Mb), may resulting from the deficiency of MMR system, which allows for the accumulation of numerous gene mutations. It has been reported that LS-related gliomas have significantly higher TMB in comparison with non-LS counterparts[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], suggesting a distinct molecular profile in LS-related gliomas that may affect treatment response and prognosis. A high TMB in cancers is generally associated with better response to immunotherapy and improved OS[\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Due to the super-high TMB, this patient may benefit from immune checkpoint inhibitors (ICIs), such as pembrolizumab or nivolumab. If the tumor recurs in the future, ICIs should be recommended. LS-associated GBM exhibits heterogeneity in clinicopathologic and molecular genetic features, as well as a suppressive tumor immune microenvironment, CD8\u0026thinsp;+\u0026thinsp;T cells and CD163\u0026thinsp;+\u0026thinsp;macrophages were abundant in each GBM tissue[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, we analyzed the expression of CD4, CD8, CD68 and CD163 in the tumor tissues using IHC. The abundant signals of CD68\u0026thinsp;+\u0026thinsp;were observed in infiltrated microglial, while no significant CD4\u0026thinsp;+\u0026thinsp;and CD8\u0026thinsp;+\u0026thinsp;cells were found. It is interesting that CD68\u0026thinsp;+\u0026thinsp;microglial may exert pro-inflammatory immune function in specific situations, such as during CD8 lymphocyte depletion or depletion, which may be an immune compensation mechanism.\u003c/p\u003e \u003cp\u003eTMZ, an alkylating agent, is the standard chemotherapy for treating gliomas, yet its efficacy in LS-related gliomas should be concerned. The efficacy of TMZ and other alkylating agents are depending on the function of mismatch repair cycle. It has been reported that knockout of MMR genes in patient-derived glioma cells showed resistance to TMZ treatment, but not to lomustine (CCNU, a bifunctional alkylating agent)[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The lower sensitivity to TMZ in LS-related gliomas may be attribute to the presence of high TMB that can produce a more complex mutational landscape, making glioma cells more adaptable and less predictable in their response to chemotherapy. Moreover, mutations in DNA repair pathways, particularly those involving MMR mechanisms, can diminish the cytotoxic effects of TMZ, which relies on inducing DNA damage to exert its therapeutic benefits[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Due to lacking to NGS panel test result after surgery, this patient accepted standard radio- and chemotherapy following Stupp protocol. Therefore, it is extremely important to know the landscape of genomic alteration for glioma patients. The unique genetic and molecular profile of LS-related gliomas must be considered when formulating treatment plans, potentially leading to the exploration of alternative therapeutic options for patients exhibiting resistance to standard therapies.\u003c/p\u003e \u003cp\u003eSomatic ataxia telangiectasia mutated (\u003cem\u003eATM\u003c/em\u003e) gene mutation was detected in this patient (c.8921C\u0026thinsp;\u0026gt;\u0026thinsp;T). ATM plays a critical role in the repair of DNA double-strand breaks (DSB)[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Germ-line mutations of \u003cem\u003eATM\u003c/em\u003e lead to the autosomal recessive ataxia telangiectasia (A-T) syndrome, which increases cancer susceptibility[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Somatic mutations of \u003cem\u003eATM\u003c/em\u003e can be detected in many types of cancers, mostly in hematologic malignancies[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. It has been reported that \u003cem\u003eATM\u003c/em\u003e mutations exist in less than 5% of glioblastoma and about 1% of medulloblastomas[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Studies revealed that ATM inhibition enhances the efficacy of radiation in primary brainstem glioma models and pediatric high-grade glioma[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Similarly, \u003cem\u003eATM\u003c/em\u003e mutations improve radio-sensitivity in IDH wild-type high grade gliomas[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, we report a case of long-term survived (\u0026gt;\u0026thinsp;50 months) \u003cem\u003eIDH\u003c/em\u003e-wildtype glioblastoma patient with germline \u003cem\u003eMSH6\u003c/em\u003e gene mutation, who is diagnosed as a LS-related glioblastoma. MMR deficiency may lead to TMZ resistance in glioma cells. However, this case had long-term benefits from standard radio- and chemo-therapy after surgery. This case demonstrates distinct molecular characteristics and tumor microenvironment. These results indicated the importance of comprehensive molecular profile in the diagnosis and guild individual treatment for glioma patients. Due to the limited efficacy of TMZ for LS-related glioblastoma with high TMB, the use of ICIs or combining lomustine with PARP inhibitors could potentially enhance chemosensitivity and improve prognosis when the tumor recurs.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eLynch Syndrome (LS)\u003c/p\u003e\n\u003cp\u003eMuts Homolog 6 (MSH6)\u003c/p\u003e\n\u003cp\u003eIsocitrate Dehydrogenase (IDH)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWorld Health Organization (WHO)\u003c/p\u003e\n\u003cp\u003eGlioblastomas (GBMs)\u003c/p\u003e\n\u003cp\u003eMismatch Repair (MMR)\u003c/p\u003e\n\u003cp\u003eTumor Mutation Burden (TMB)\u003c/p\u003e\n\u003cp\u003eMicrosatellite Instability (MSI)\u003c/p\u003e\n\u003cp\u003eMagnetic Resonance Imaging (MRI)\u003c/p\u003e\n\u003cp\u003eMagnetic Resonance Spectroscopy (MRS)\u003c/p\u003e\n\u003cp\u003eHematoxylin And Eosin (HE)\u003c/p\u003e\n\u003cp\u003eImmunohistochemistry (IHC)\u003c/p\u003e\n\u003cp\u003eGlial Fibrillary Acidic Protein (GFAP)\u003c/p\u003e\n\u003cp\u003eO6-Methylguanine-DNA Methyltransferase (MGMT)\u003c/p\u003e\n\u003cp\u003eEpidermal Growth Factor Receptor (EGFR)\u003c/p\u003e\n\u003cp\u003eThe Alpha-Thalassemia Mental Retardation X-Linked (ATRX)\u003c/p\u003e\n\u003cp\u003eNext-Generation Sequencing (NGS)\u003c/p\u003e\n\u003cp\u003ePromoter of O6-Methylguanine-DNA-Methyltransferase (pMGMT)\u003c/p\u003e\n\u003cp\u003ePromoter of Telomerase Reverse Transcriptase (pTERT)\u003c/p\u003e\n\u003cp\u003eMicrosatellite-Stable (MSS)\u003c/p\u003e\n\u003cp\u003eLong Term Survival (LTS)\u003c/p\u003e\n\u003cp\u003eProgression-Free Survival (PFS)\u003c/p\u003e\n\u003cp\u003eOverall Survival (OS)\u003c/p\u003e\n\u003cp\u003eAtaxia Telangiectasia Mutated (ATM)\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted under the approval of the Ethics Committee of Xuanwu Hospital, Capital Medical University. Patients informed consent for the publication has been obtained.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo conflict of interests to be disclosed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors have read and approved the manuscript. Data curation: YZ, TH, and YP. Investigation: YZ. Methodology: YZ. Project administration: YP and JT. Supervision: YP and JT. Writing – original draft: YZ. Writing– review \u0026amp; editing: YP and JT.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMoreira L, Balaguer F, Lindor N, de la Chapelle A, Hampel H, Aaltonen LA, et al. Identification of Lynch syndrome among patients with colorectal cancer. JAMA. 2012;308 15:1555-65; doi: 10.1001/jama.2012.13088.\u003c/li\u003e\n\u003cli\u003eLynch HT, Snyder CL, Shaw TG, Heinen CD, Hitchins MP. Milestones of Lynch syndrome: 1895-2015. Nat Rev Cancer. 2015;15 3:181-94; doi: 10.1038/nrc3878.\u003c/li\u003e\n\u003cli\u003eSinicrope FA. Lynch Syndrome-Associated Colorectal Cancer. 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Neurosurgery. 2010;67 3:811-7; discussion 7; doi: 10.1227/01.NEU.0000375513.12925.5C.\u003c/li\u003e\n\u003cli\u003eYao ZG, Hua F, Yin ZH, Xue YJ, Hou YH, Nie YC, et al. Characteristics of glioblastomas and immune microenvironment in a Chinese family with Lynch syndrome and concurrent porokeratosis. Front Oncol. 2023;13:1194232; doi: 10.3389/fonc.2023.1194232.\u003c/li\u003e\n\u003cli\u003eVasen HF, Stormorken A, Menko FH, Nagengast FM, Kleibeuker JH, Griffioen G, et al. MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families. J Clin Oncol. 2001;19 20:4074-80; doi: 10.1200/JCO.2001.19.20.4074.\u003c/li\u003e\n\u003cli\u003eRichardson TE, Yokoda RT, Rashidipour O, Vij M, Snuderl M, Brem S, et al. Mismatch repair protein mutations in isocitrate dehydrogenase (IDH)-mutant astrocytoma and IDH-wild-type glioblastoma. Neurooncol Adv. 2023;5 1:vdad085; doi: 10.1093/noajnl/vdad085.\u003c/li\u003e\n\u003cli\u003eSuwala AK, Stichel D, Schrimpf D, Kloor M, Wefers AK, Reinhardt A, et al. Primary mismatch repair deficient IDH-mutant astrocytoma (PMMRDIA) is a distinct type with a poor prognosis. Acta Neuropathol. 2021;141 1:85-100; doi: 10.1007/s00401-020-02243-6.\u003c/li\u003e\n\u003cli\u003eAguilera P, Lopez-Contreras AJ. ATRX, a guardian of chromatin. Trends Genet. 2023;39 6:505-19; doi: 10.1016/j.tig.2023.02.009.\u003c/li\u003e\n\u003cli\u003eSha D, Jin Z, Budczies J, Kluck K, Stenzinger A, Sinicrope FA. Tumor Mutational Burden as a Predictive Biomarker in Solid Tumors. Cancer Discov. 2020;10 12:1808-25; doi: 10.1158/2159-8290.CD-20-0522.\u003c/li\u003e\n\u003cli\u003eYang C, Austin F, Richard H, Idowu M, Williamson V, Sabato F, et al. Lynch syndrome-associated ultra-hypermutated pediatric glioblastoma mimicking a constitutional mismatch repair deficiency syndrome. Cold Spring Harb Mol Case Stud. 2019;5 5; doi: 10.1101/mcs.a003863.\u003c/li\u003e\n\u003cli\u003eYarchoan M, Hopkins A, Jaffee EM. Tumor Mutational Burden and Response Rate to PD-1 Inhibition. N Engl J Med. 2017;377 25:2500-1; doi: 10.1056/NEJMc1713444.\u003c/li\u003e\n\u003cli\u003eSnyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371 23:2189-99; doi: 10.1056/NEJMoa1406498.\u003c/li\u003e\n\u003cli\u003eRizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348 6230:124-8; doi: 10.1126/science.aaa1348.\u003c/li\u003e\n\u003cli\u003eTouat M, Li YY, Boynton AN, Spurr LF, Iorgulescu JB, Bohrson CL, et al. Mechanisms and therapeutic implications of hypermutation in gliomas. Nature. 2020;580 7804:517-23; doi: 10.1038/s41586-020-2209-9.\u003c/li\u003e\n\u003cli\u003eHeinen CD. Translating mismatch repair mechanism into cancer care. Curr Drug Targets. 2014;15 1:53-64; doi: 10.2174/1389450114666140106100128.\u003c/li\u003e\n\u003cli\u003eAlnahhas I, Rayi A, Ong S, Giglio P, Puduvalli V. Management of gliomas in patients with Lynch syndrome. Neuro Oncol. 2021;23 1:167-8; doi: 10.1093/neuonc/noaa227.\u003c/li\u003e\n\u003cli\u003eBednarski JJ, Sleckman BP. Integrated signaling in developing lymphocytes: the role of DNA damage responses. Cell Cycle. 2012;11 22:4129-34; doi: 10.4161/cc.22021.\u003c/li\u003e\n\u003cli\u003eLi A, Swift M. Mutations at the ataxia-telangiectasia locus and clinical phenotypes of A-T patients. Am J Med Genet. 2000;92 3:170-7; doi: 10.1002/(sici)1096-8628(20000529)92:3\u0026lt;170::aid-ajmg3\u0026gt;3.0.co;2-#.\u003c/li\u003e\n\u003cli\u003eBoultwood J. Ataxia telangiectasia gene mutations in leukaemia and lymphoma. J Clin Pathol. 2001;54 7:512-6; doi: 10.1136/jcp.54.7.512.\u003c/li\u003e\n\u003cli\u003eChoi M, Kipps T, Kurzrock R. ATM Mutations in Cancer: Therapeutic Implications. Mol Cancer Ther. 2016;15 8:1781-91; doi: 10.1158/1535-7163.MCT-15-0945.\u003c/li\u003e\n\u003cli\u003eDeland K, Starr BF, Mercer JS, Byemerwa J, Crabtree DM, Williams NT, et al. Tumor genotype dictates radiosensitization after Atm deletion in primary brainstem glioma models. J Clin Invest. 2021;131 1; doi: 10.1172/JCI142158.\u003c/li\u003e\n\u003cli\u003eXie J, Kuriakose T, Bianski B, Twarog N, Savage E, Xu K, et al. ATM inhibition enhances the efficacy of radiation across distinct molecular subgroups of pediatric high-grade glioma. Neuro Oncol. 2023;25 10:1828-41; doi: 10.1093/neuonc/noad064.\u003c/li\u003e\n\u003cli\u003eKim N, Kim SH, Kang SG, Moon JH, Cho J, Suh CO, et al. ATM mutations improve radio-sensitivity in wild-type isocitrate dehydrogenase-associated high-grade glioma: retrospective analysis using next-generation sequencing data. Radiat Oncol. 2020;15 1:184; doi: 10.1186/s13014-020-01619-y.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Lynch syndrome, glioblastoma, long-term survive, case report","lastPublishedDoi":"10.21203/rs.3.rs-5741696/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5741696/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e Lynch syndrome (LS) is a cancer syndrome caused by germline mutations in DNA mismatch repair genes. Patients with Lynch syndrome have higher risk of brain tumors, predominantly high-grade gliomas. LS-related gliomas have poor overall survival.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation\u003c/strong\u003e We present a case of a31-year-old male patient with a frontal lesion by magnetic resonance imaging (MRI). The pathological diagnosis was \u003cem\u003eisocitrate dehydrogenase (IDH)\u003c/em\u003ewildtype glioblastoma (WHO grade 4) with 30% Ki-67 proliferation index. After surgery, this patient received radiotherapy and temozolomide chemotherapy following Stupp protocol. During over 64 months follow up, no sign of tumor recurrence was found after surgery. Therefore, next-generation sequencing was suggested to this patient. The result revealed a heterozygous germline variation of c.3261dup in exon 5 of \u003cem\u003eMSH6\u003c/em\u003e gene which resulted in a truncated MSH6 protein (MSH6 p.F1088Lfs*5) with a tumor mutation burden of 327.36 Mut/Mb.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e MMR deficiency may lead to TMZ resistance in glioma cells. However, this case had long-term benefits from standard radio- and chemo-therapy after surgery, probably due to the distinct molecular characteristics and tumor microenvironment. This finding provided insight to perform clinical studies to investigate the molecular characterization of Lynch associated glioma patients and the role of microglia in antitumor.\u003c/p\u003e","manuscriptTitle":"A Long-term Progression-free Survival with Glioblastoma Patient Harboring MSH6 Pathogenic Germline Mutation: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-03 09:10:39","doi":"10.21203/rs.3.rs-5741696/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"eff54704-f3ce-43f1-8a23-7fb189af56a9","owner":[],"postedDate":"February 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-03-09T21:39:01+00:00","versionOfRecord":[],"versionCreatedAt":"2025-02-03 09:10:39","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5741696","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5741696","identity":"rs-5741696","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}