Functional germline variants in DNA damage repair pathways are associated with altered survival in adults with glioma treated with temozolomide

doi:10.1101/2023.10.13.23296963

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[Preprint]. 2024 Oct 10:2023.10.13.23296963.

doi: 10.1101/2023.10.13.23296963.

Functional germline variants in DNA damage repair pathways are associated with altered survival in adults with glioma treated with temozolomide

Geno Guerra¹, George Wendt¹, Lucie McCoy¹, Helen M Hansen¹, Linda Kachuri^{2

3}, Annette M Molinaro^{1

4}, Terri Rice¹, Victoria Guan⁵, Lianne Capistrano⁵, Allison Hsieh⁵, Veruna Kalsi⁵, Jaimie Sallee⁵, Jennie W Taylor^{1

6}, Jennifer L Clarke^{1

6}, Eduardo Rodriguez Almaraz^{1

4}, John K Wiencke^{1

4}, Jeanette E Eckel-Passow⁷, Robert B Jenkins⁸, Margaret Wrensch¹, Stephen S Francis^{1

4

9}

Affiliations

¹ Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
² Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA.
³ Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA.
⁴ Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.
⁵ School of Pharmacy, University of California San Francisco, San Francisco, CA, USA.
⁶ Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
⁷ Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
⁸ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
⁹ Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.

PMID: 39417102
PMCID: PMC11482862
DOI: 10.1101/2023.10.13.23296963

Functional germline variants in DNA damage repair pathways are associated with altered survival in adults with glioma treated with temozolomide

Geno Guerra et al. medRxiv. 2024.

[Preprint]. 2024 Oct 10:2023.10.13.23296963.

doi: 10.1101/2023.10.13.23296963.

Authors

Affiliations

¹ Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
² Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA.
³ Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA.
⁴ Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.
⁵ School of Pharmacy, University of California San Francisco, San Francisco, CA, USA.
⁶ Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
⁷ Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
⁸ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
⁹ Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.

PMID: 39417102
PMCID: PMC11482862
DOI: 10.1101/2023.10.13.23296963

Update in

Functional germline variants in DNA damage repair pathways are associated with altered survival in adults with glioma treated with temozolomide.
Guerra G, Wendt G, McCoy L, Hansen HM, Kachuri L, Molinaro AM, Rice T, Guan V, Capistrano L, Hsieh A, Kalsi V, Sallee J, Taylor JW, Clarke JL, Almaraz ER, Wiencke JK, Eckel-Passow JE, Jenkins RB, Wrensch M, Francis SS. Guerra G, et al. Neuro Oncol. 2025 Jun 21;27(5):1385-1398. doi: 10.1093/neuonc/noae275. Neuro Oncol. 2025. PMID: 39745907

Abstract

Background: Temozolomide (TMZ) treatment has demonstrated, but 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 UCSF Adult Glioma Study 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 (HR=1.21, p=0.019) 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 chemo-sensitization.Genetically predicted elevated compared to normal brain expression of PNKP was associated with dramatically worse survival for TMZ-treated patients with IDH-mutant and 1p/19q non-codeleted gliomas (p=0.015). 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.

Keywords: DNA damage repair; glioma; pharmacogenomics; survival; temozolomide.

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Conflict of interest statement

Conflict of Interest The authors declare they have no competing interests.

Figures

**Figure 1:. Overview of study design.**
A visual outline of the sample set of glioma cases included, DNA damage repair genes selected, and pipeline overviews for both the individual SNP analyses and genetic transcript expression analyses.

**Figure 2:. Kaplan-Meier plots visualizing the survival times associated with germline polymorphisms in subtype-specific glioma patients treated with temozolomide.**
Plots demonstrate the survival trajectories related to different polymorphisms of cases treated with the drug temozolomide, for a specific glioma subtype, as indicated. The x-axes represent time measured in months post-diagnosis. Dashed vertical lines represent median survival times. Log rank p-values measuring significance of statistical differences between curves are as indicated in each plot. Included number of cases with genotype of interest are indicated in parentheses.

**Figure 3:. Genetically imputed DNA repair gene transcript level associations with subtype specific glioma survival, for patients who were treated with temozolomide.**
a) Nominal ACAT-O omnibus p-values for cases treated with temozolomide. Colors indicate glioma subtype tested. Shape indicates direction of effect for increasing expression. Results marked by a square indicate ACAT-O p-value <0.05 in the complementary no-TMZ group. b) Elevated genetically imputed transcript levels of the gene *TDG* using weights from the GTEx brain (caudate basal ganglia) show prognostic benefit to *IDH* wildtype glioma cases treated with TMZ. ‘Low’ is genetically imputed level of zero, ‘High’ is expression >0. c) Elevated imputed expression of *NEIL2* (using GTEx brain cortex weights) is associated with decreased survival for cases with *IDH* mutant 1p19q codeleted gliomas treated with TMZ. ‘Low’ is genetically imputed level of zero, ‘High’ is expression >0. d) Elevated imputed expression of the gene *PNKP* is associated with significantly decreased survival times in cases with *IDH* mutant 1p19q non-codeleted gliomas treated with TMZ. Using GTEx brain-substantia nigra weights. ‘Low’ represents the bottom 40% of expressors, ‘High’ represents the top 60%.

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References

1. Ostrom QT, Price M, Neff C, et al. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2015–2019. Neuro-Oncol. 2022;24(Supplement_5):v1–v95. doi: 10.1093/neuonc/noac202 - DOI - PMC - PubMed
1. Eckel-Passow JE, Lachance DH, Molinaro AM, et al. Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors. N Engl J Med. 2015;372(26):2499–2508. doi: 10.1056/NEJMoa1407279 - DOI - PMC - PubMed
1. Molinaro AM, Taylor JW, Wiencke JK, Wrensch MR. Genetic and molecular epidemiology of adult diffuse glioma. Nat Rev Neurol. 2019;15(7):405–417. doi: 10.1038/s41582-019-0220-2 - DOI - PMC - PubMed
1. Stupp R, Mason WP, Van Den Bent MJ, et al. Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. N Engl J Med. 2005;352(10):987–996. doi: 10.1056/NEJMoa043330 - DOI - PubMed
1. Singh N, Miner A, Hennis L, Mittal S. Mechanisms of temozolomide resistance in glioblastoma - a comprehensive review. Cancer Drug Resist. Published online 2020. doi: 10.20517/cdr.2020.79 - DOI - PMC - PubMed

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[1] Ostrom QT, Price M, Neff C, et al. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2015–2019. Neuro-Oncol. 2022;24(Supplement_5):v1–v95. doi: 10.1093/neuonc/noac202 - DOI - PMC - PubMed

[2] Ostrom QT, Price M, Neff C, et al. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2015–2019. Neuro-Oncol. 2022;24(Supplement_5):v1–v95. doi: 10.1093/neuonc/noac202 - DOI - PMC - PubMed

[3] Eckel-Passow JE, Lachance DH, Molinaro AM, et al. Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors. N Engl J Med. 2015;372(26):2499–2508. doi: 10.1056/NEJMoa1407279 - DOI - PMC - PubMed

[4] Eckel-Passow JE, Lachance DH, Molinaro AM, et al. Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors. N Engl J Med. 2015;372(26):2499–2508. doi: 10.1056/NEJMoa1407279 - DOI - PMC - PubMed

[5] Molinaro AM, Taylor JW, Wiencke JK, Wrensch MR. Genetic and molecular epidemiology of adult diffuse glioma. Nat Rev Neurol. 2019;15(7):405–417. doi: 10.1038/s41582-019-0220-2 - DOI - PMC - PubMed

[6] Molinaro AM, Taylor JW, Wiencke JK, Wrensch MR. Genetic and molecular epidemiology of adult diffuse glioma. Nat Rev Neurol. 2019;15(7):405–417. doi: 10.1038/s41582-019-0220-2 - DOI - PMC - PubMed

[7] Stupp R, Mason WP, Van Den Bent MJ, et al. Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. N Engl J Med. 2005;352(10):987–996. doi: 10.1056/NEJMoa043330 - DOI - PubMed

[8] Stupp R, Mason WP, Van Den Bent MJ, et al. Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. N Engl J Med. 2005;352(10):987–996. doi: 10.1056/NEJMoa043330 - DOI - PubMed

[9] Singh N, Miner A, Hennis L, Mittal S. Mechanisms of temozolomide resistance in glioblastoma - a comprehensive review. Cancer Drug Resist. Published online 2020. doi: 10.20517/cdr.2020.79 - DOI - PMC - PubMed

[10] Singh N, Miner A, Hennis L, Mittal S. Mechanisms of temozolomide resistance in glioblastoma - a comprehensive review. Cancer Drug Resist. Published online 2020. doi: 10.20517/cdr.2020.79 - DOI - PMC - PubMed

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This is a preprint.

Functional germline variants in DNA damage repair pathways are associated with altered survival in adults with glioma treated with temozolomide

Affiliations

Functional germline variants in DNA damage repair pathways are associated with altered survival in adults with glioma treated with temozolomide

Authors

Affiliations

Update in

Abstract

Conflict of interest statement

Figures

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LinkOut - more resources

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This is a preprint.

Update in

Abstract

Conflict of interest statement

Figures

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References

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Research Materials