Functional germline variants in DNA damage repair pathways are associated with altered survival in adults with glioma treated with temozolomide
Authors: Guerra Geno , Wendt George , McCoy Lucie , Hansen Helen M. , Kachuri Linda , Molinaro Annette M. , Rice Terri , Guan Victoria , Capistrano Lianne , Hsieh Allison , Kalsi Veruna , Sallee Jaimie , Taylor Jennie W. , Clarke Jennifer L. , Rodriguez Almaraz Eduardo , Wiencke John K. , Eckel-Passow Jeanette E. , Jenkins Robert B. , Wrensch Margaret , Francis Stephen S. 
Published: October 2023

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, inMGMT, was associated with decreased survival (HR=1.21, p=0.019) for all glioma subtypes. Rs73191162-T (nearUNG), rs13076508-C (nearPARP3), rs7840433-A (nearNEIL2), and rs3130618-A (nearMSH5) 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 ofPNKPwas associated with dramatically worse survival for TMZ-treated patients withIDH-mutant and 1p/19q non-codeleted gliomas (p=0.015). Similarly,NEIL2andTDGexpressions 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.

Key points

We observed SNPs associated with glioma survival, specific to cases receiving TMZ

AnMGMTvariant may reduce glioma survival indirectly through myelosuppression

Decreased geneticPNKPexpression in the brain may sensitize cells to TMZ

Importance of the study

The introduction of temozolomide (TMZ) as a part of standard-of-care in the treatment of gliomas marked the last notable increase in patient survival. However, the effectiveness of TMZ is not universal, and can result in serious complications. The mechanism of action behind the drug is the introduction of damaging methyl groups across the tumor genome and leveraging of DNA damage repair (DDR) mechanisms to signal programmed cell death. Previous literature has identified that defects in DDR mechanisms can alter TMZ sensitivity. Using a unique dataset that spans the pre- and post-TMZ eras, we demonstrate that germline variation in DDR-related genes may have significant impact on overall survival for patients treated with TMZ, with no effects observed in the pre-TMZ era. This suggests that germline variants in these DDR genes could be used to personalize TMZ therapy to improve patient survival.