Abstract 1943P
Background
The DNA polymerases family (DNA-pol) is a crucial determinant of DNA repair, resulting in cancer progression and prognosis. Cancer cells exhibit a heightened basal level of activation of some responses to DNA breaks, accumulating DNA-pol as repair proteins, thereby increasing DNA mutations. Based on this, we speculated DNA-pol family to be associated with the response to immunotherapy. Therefore, we aimed to investigate the potential of DNA-pol as an immunotherapy response biomarker.
Methods
We carried out this study with a pan-cancer analysis of DNA-pol gene dysregulation in 15 kinds of cancer (6366 samples).
Results
We defined a distinct signature score of DNA-pol genes upregulated in cancer (DNA-pol-up) and linked to worse prognosis (HR=1.2, P<0.05). We found this DNA-pol-up transcriptional program dysregulation led to immune and inflammation biological processes enrichment and was correlated with the upstream regulator activation of TERT signaling (activation z-score=3.603 with FDR<0.05, correlation Rho=0.18 with P<0.001) in ingenuity pathway analysis and linked to immunologically active tumors by recruiting CD8+ T cells. Besides, this DNA-pol-up signature score was elevated in TERT-overexpressed CD8+ T cells, higher in MSI-H cancer (P<0.001), also positively associated with neoepitope peptides (Rho=0.18, P<0.001), tumor burden mutation (TMB, Rho=0.54, P<0.001), cancer stemness score (Rho=0.78, P<0.001), and tumor purity (Rho=0.29, P<0.001). Cancers that activate this program carried distinct genomic profiles, such as PIK3CA, KRAS, and TP53 mutations. Finally, this signature score was an independent predictor of the good response of PD-1 blockade (OR=2.52, P<0.05, kappa=0.21) and outperformed previously-proposed biomarkers, such as cytolytic activity (OR=2.70, P<0.05, kappa value=0), TMB (OR=0.9, P>0.05, kappa value=0), MSI (OR=0.91, P>0.05, kappa value=0). In a clinical trial dataset, this signature could stratify the responded patients from the non-responded (P=0.005, AUC=0.62).
Conclusions
Our findings identify a distinct transcriptional pattern of DNA-pol genes in operation across cancers that highlighted the impact of DNA-pol family genes on immunotherapy response for the first time.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Xinyu Bi and Zhiwen Luo.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.