Insights into the impact of base-excision–repair genes on immunotherapy response in solid tumors.

Abstract

e14548 Background: Base-excision repair (BER) is the primary pathway that removes ubiquitous single-base lesions from oxidative and alkylation stress, preserving genome integrity and preventing error-prone repair. When BER is disrupted, accumulation of DNA damage can heighten tumor immunogenicity—through increased mutational consequences and activation of cytosolic DNA–sensing pathways—creating a biologic context favorable to immune checkpoint blockade. We therefore asked whether BER gene alterations correlate with improved clinical outcomes to ICI across solid tumors. Methods: We pooled five published ICI cohorts with genomic/clinical annotation—DFCI Metastatic Melanoma (Science 2015); DFCI Clear-Cell Renal Cell Carcinoma (Science 2018/2019); MSK Melanoma (NEJM 2014); UCLA Metastatic Melanoma (Cell 2016); and MSK Immunotherapy/TMB (Nature Genetics 2019)—yielding 1,908 patients treated with anti-PD-1/PD-L1, anti-CTLA-4, or combination therapy across renal cell carcinoma, melanoma, non-small cell lung cancer, colorectal cancer, cancer of unknown primary, bladder cancer, breast cancer, glioma, esophagogastric cancer, non-melanoma skin cancer, and head & neck cancer. Data were retrieved via cBioPortal. Patients were classified as BER-altered if they harbored ≥1 qualifying event in MUTYH, PARP1, or NTHL1 (loss-of-function or pathogenic/likely-pathogenic missense; deep deletions; amplifications excluded); comparator: triple-wildtype. OS from ICI initiation was compared by Kaplan–Meier/log-rank; Cox models adjusted for age, tumor type, ICI class, and sex. Subg roup analyses focused on melanoma, NSCLC, and CRC. Results: 78 patients were BER-altered, OF WHICH melanoma (53%), NSCLC (10%), and CRC (10%. Overall, BER-altered patients had longer OS than unaltered patients (mOS 32.4 vs 18.0 months; log-rank p = 0.0139). At the gene level, PARP1 alterations were associated with superior OS (median 32.4 vs 18.0 months; p = 0.0278). MUTYH alterations showed a favourable trend but did not reach statistical significance (mOS 49.3 vs 18.0 months; p = 0.299), and NTHL1 alterations were uncommon and showed similar survival to unaltered cases (mOS 20.1 vs 18.0 months; p = 0.870) By tumor type, NSCLC showed a favorable association (p = 0.0389), whereas melanoma was neutral (p = 0.561). Tumor mutational burden (exploratory): the BER-altered group had higher TMB than the unaltered group (median 21.7 vs 5.9 nonsynonymous mutations/Mb; p < 0.001). Co-mutations (BER-altered): the most common co-mutations were KMT2D, GRIN2A, PTPRT, BRAF, MUC16, and TERT. Conclusions: Alterations in MUTYH/PARP1/NTHL1—particularly PARP1—identify a subset of ICI-treated patients with improved OS, with the clearest effect in NSCLC and neutrality in melanoma.These findings support prospective validation and consideration of BER status, alongside genomic context such as TMB, in immunotherapy stratification.