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Updated: Jun 10, 2025
Evaluating In Vitro DNA Damage Using Comet Assay
Published on: October 11, 2017
Functional germline variants in DNA damage repair pathways are associated with altered survival in adults with glioma
Geno Guerra1, George Wendt1, Lucie McCoy1
1Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
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.
