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. 2025 Jun 21;27(5):1385-1398.
doi: 10.1093/neuonc/noae275.

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

Geno Guerra  1 , George Wendt  1 , Lucie McCoy  1 , Helen M Hansen  1 , Linda Kachuri  2   3 , Annette M Molinaro  4   1 , Terri Rice  1 , Victoria Guan  5 , Lianne Capistrano  5 , Allison Hsieh  5 , Veruna Kalsi  5 , Jaimie Sallee  5 , Jennie W Taylor  6   1 , Jennifer L Clarke  6   1 , Eduardo Rodriguez Almaraz  4   1 , John K Wiencke  4   1 , Jeanette E Eckel-Passow  7 , Robert B Jenkins  8 , Margaret Wrensch  1 , Stephen S Francis  9   4   1
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Functional germline variants in DNA damage repair pathways are associated with altered survival in adults with glioma treated with temozolomide

Geno Guerra et al. Neuro Oncol. .

Abstract

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.

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

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