Geno Guerra, George Wendt, Lucie McCoy, Helen M Hansen, Linda Kachuri, Annette M Molinaro, Terri Rice, Victoria Guan, Lianne Capistrano, Allison Hsieh, Veruna Kalsi, Jaimie Sallee, Jennie W Taylor, Jennifer L Clarke, Eduardo Rodriguez Almaraz, John K Wiencke, Jeanette E Eckel-Passow, Robert B Jenkins, Margaret Wrensch, Stephen S Francis
{"title":"DNA损伤修复途径中的功能性种系变异与替莫唑胺治疗的成年胶质瘤患者的生存改变有关。","authors":"Geno Guerra, George Wendt, Lucie McCoy, Helen M Hansen, Linda Kachuri, Annette M Molinaro, Terri Rice, Victoria Guan, Lianne Capistrano, Allison Hsieh, Veruna Kalsi, Jaimie Sallee, Jennie W Taylor, Jennifer L Clarke, Eduardo Rodriguez Almaraz, John K Wiencke, Jeanette E Eckel-Passow, Robert B Jenkins, Margaret Wrensch, Stephen S Francis","doi":"10.1093/neuonc/noae275","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Temozolomide (TMZ) treatment has demonstrated a variable impact on glioma prognosis. This study examines associations of survival with DNA repair gene germline polymorphisms among glioma patients who did and did not have TMZ treatment. Identifying genetic markers which sensitize tumor cells to TMZ could personalize therapy and improve outcomes.</p><p><strong>Methods: </strong>We evaluated TMZ-related survival associations of pathogenic germline SNPs and genetically predicted transcript levels within 34 DNA repair genes among 1504 glioma patients from the University of California San Francisco Adult Glioma Study (UCSF AGS) and Mayo Clinic, whose diagnoses spanned pre- and post-TMZ eras within the major known glioma prognostic molecular subtypes.</p><p><strong>Results: </strong>Among those who received TMZ, 5 SNPs were associated with overall survival, but not in those who did not receive TMZ. Only rs2308321-G, in MGMT, was associated with decreased survival (hazard ratio = 1.21, P = .019) for all glioma subtypes. Rs73191162-T (near UNG), rs13076508-C (near PARP3), rs7840433-A (near NEIL2), and rs3130618-A (near MSH5) were only associated with survival and TMZ treatment for certain subtypes, suggesting subtype-specific germline chemosensitization. Genetically predicted elevated expression of PNKP, compared to normal brain expression, was associated with markedly poor survival in TMZ-treated patients with isocitrate dehydrogenase (IDH)-mutant and 1p/19q non-codeleted gliomas (P = .015), with a median difference of over 70 months in overall survival times. Similarly, NEIL2 and TDG expressions were associated with altered TMZ-related survival only among certain subtypes.</p><p><strong>Conclusions: </strong>Functional germline alterations within DNA repair genes were associated with TMZ sensitivity, measured by overall survival among adults with glioma. These variants should be evaluated in prospective analyses and functional studies.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1385-1398"},"PeriodicalIF":16.4000,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12187373/pdf/","citationCount":"0","resultStr":"{\"title\":\"Functional germline variants in DNA damage repair pathways are associated with altered survival in adults with glioma treated with temozolomide.\",\"authors\":\"Geno Guerra, George Wendt, Lucie McCoy, Helen M Hansen, Linda Kachuri, Annette M Molinaro, Terri Rice, Victoria Guan, Lianne Capistrano, Allison Hsieh, Veruna Kalsi, Jaimie Sallee, Jennie W Taylor, Jennifer L Clarke, Eduardo Rodriguez Almaraz, John K Wiencke, Jeanette E Eckel-Passow, Robert B Jenkins, Margaret Wrensch, Stephen S Francis\",\"doi\":\"10.1093/neuonc/noae275\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Temozolomide (TMZ) treatment has demonstrated a variable impact on glioma prognosis. This study examines associations of survival with DNA repair gene germline polymorphisms among glioma patients who did and did not have TMZ treatment. Identifying genetic markers which sensitize tumor cells to TMZ could personalize therapy and improve outcomes.</p><p><strong>Methods: </strong>We evaluated TMZ-related survival associations of pathogenic germline SNPs and genetically predicted transcript levels within 34 DNA repair genes among 1504 glioma patients from the University of California San Francisco Adult Glioma Study (UCSF AGS) and Mayo Clinic, whose diagnoses spanned pre- and post-TMZ eras within the major known glioma prognostic molecular subtypes.</p><p><strong>Results: </strong>Among those who received TMZ, 5 SNPs were associated with overall survival, but not in those who did not receive TMZ. Only rs2308321-G, in MGMT, was associated with decreased survival (hazard ratio = 1.21, P = .019) for all glioma subtypes. Rs73191162-T (near UNG), rs13076508-C (near PARP3), rs7840433-A (near NEIL2), and rs3130618-A (near MSH5) were only associated with survival and TMZ treatment for certain subtypes, suggesting subtype-specific germline chemosensitization. Genetically predicted elevated expression of PNKP, compared to normal brain expression, was associated with markedly poor survival in TMZ-treated patients with isocitrate dehydrogenase (IDH)-mutant and 1p/19q non-codeleted gliomas (P = .015), with a median difference of over 70 months in overall survival times. Similarly, NEIL2 and TDG expressions were associated with altered TMZ-related survival only among certain subtypes.</p><p><strong>Conclusions: </strong>Functional germline alterations within DNA repair genes were associated with TMZ sensitivity, measured by overall survival among adults with glioma. These variants should be evaluated in prospective analyses and functional studies.</p>\",\"PeriodicalId\":19377,\"journal\":{\"name\":\"Neuro-oncology\",\"volume\":\" \",\"pages\":\"1385-1398\"},\"PeriodicalIF\":16.4000,\"publicationDate\":\"2025-06-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12187373/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neuro-oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1093/neuonc/noae275\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuro-oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/neuonc/noae275","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Functional germline variants in DNA damage repair pathways are associated with altered survival in adults with glioma treated with temozolomide.
Background: Temozolomide (TMZ) treatment has demonstrated a variable impact on glioma prognosis. This study examines associations of survival with DNA repair gene germline polymorphisms among glioma patients who did and did not have TMZ treatment. Identifying genetic markers which sensitize tumor cells to TMZ could personalize therapy and improve outcomes.
Methods: We evaluated TMZ-related survival associations of pathogenic germline SNPs and genetically predicted transcript levels within 34 DNA repair genes among 1504 glioma patients from the University of California San Francisco Adult Glioma Study (UCSF AGS) and Mayo Clinic, whose diagnoses spanned pre- and post-TMZ eras within the major known glioma prognostic molecular subtypes.
Results: Among those who received TMZ, 5 SNPs were associated with overall survival, but not in those who did not receive TMZ. Only rs2308321-G, in MGMT, was associated with decreased survival (hazard ratio = 1.21, P = .019) for all glioma subtypes. Rs73191162-T (near UNG), rs13076508-C (near PARP3), rs7840433-A (near NEIL2), and rs3130618-A (near MSH5) were only associated with survival and TMZ treatment for certain subtypes, suggesting subtype-specific germline chemosensitization. Genetically predicted elevated expression of PNKP, compared to normal brain expression, was associated with markedly poor survival in TMZ-treated patients with isocitrate dehydrogenase (IDH)-mutant and 1p/19q non-codeleted gliomas (P = .015), with a median difference of over 70 months in overall survival times. Similarly, NEIL2 and TDG expressions were associated with altered TMZ-related survival only among certain subtypes.
Conclusions: Functional germline alterations within DNA repair genes were associated with TMZ sensitivity, measured by overall survival among adults with glioma. These variants should be evaluated in prospective analyses and functional studies.
期刊介绍：
Neuro-Oncology, the official journal of the Society for Neuro-Oncology, has been published monthly since January 2010. Affiliated with the Japan Society for Neuro-Oncology and the European Association of Neuro-Oncology, it is a global leader in the field.
The journal is committed to swiftly disseminating high-quality information across all areas of neuro-oncology. It features peer-reviewed articles, reviews, symposia on various topics, abstracts from annual meetings, and updates from neuro-oncology societies worldwide.
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