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, 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 , was associated with decreased survival (HR=1.21, p=0.019) for all glioma subtypes. Rs73191162-T (near ), rs13076508-C (near ), rs7840433-A (near ), and rs3130618-A (near ) 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 was associated with dramatically worse survival for TMZ-treated patients with -mutant and 1p/19q non-codeleted gliomas (p=0.015). Similarly, and 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.