Abstract
Somatic mutations in DNA repair genes have been clinically associated with chemosensitivity, although few studies have interrogated the nucleotide synthesis pathways that supply DNA repair processes. Previous work suggests that bladder urothelial carcinoma is uniquely enriched for mutations in nucleotide excision repair genes, and that these mutations are associated with response to platinum-based therapy and favorable survival. Conversely, the de novo pyrimidine synthesis pathway has recently emerged as a putative clinical target. This anabolic process is thought to supply DNA repair processes such as nucleotide excision repair; that is, DNA repair enzymes may require a sufficient nucleotide supply available to reverse the intended genotoxic damage of systemic chemotherapy in rapidly proliferating cancer cells. Therefore, we explored the prognostic complementarity between de novo pyrimidine synthesis and nucleotide excision repair expression in a total of 570 bladder urothelial carcinoma patients. Ultimately, we show that the de novo pyrimidine synthesis gene CAD is associated with poor survival (P = 0.008) and is co-altered with the nucleotide excision repair gene POLD2. High expression of POLD2 was also associated with poor overall survival (P = 0.019) and was significantly correlated with CAD expression in pre-treatment patient tumor samples (P = 2.44e-4). Expression of each gene was associated with cisplatin-based therapy resistance, and accordingly, CADhighPOLD2high patients were associated with worse survival than CADhighPOLD2low and CADlowPOLD2high patients. Together, these biomarkers could help elucidate mechanisms of chemoresistance to further personalize therapeutic strategies in bladder urothelial carcinoma.
Highlights
The implications of DNA repair gene alterations have recently emerged to help better stratify urothelial cancer patients by predicted response to systemic chemotherapy [1,2,3]
Of the three genes in the de novo pyrimidine synthesis (PS) pathway, only carbamoylphosphate synthetase 2 (CAD) was associated with poor survival in the discovery set (P = 0.008; hazard ratio for risk group (HR) = 1.44, 95% confidence interval (CI): 1.06 – 1.95; Table 1)
The prognostic significance of CAD was confirmed in the validation set (P = 0.017; HR = 2.42, 95% CI: 1.14 – 5.11; Table 1)
Summary
The implications of DNA repair gene alterations have recently emerged to help better stratify urothelial cancer patients by predicted response to systemic chemotherapy [1,2,3]. In regards to chemotherapy response, recent work has highlighted the ability of cancer cells to exploit the adaptive nature of the de novo pyrimidine synthesis (PS) pathway for their own malignant benefit [5]. This pathway was found to be inducible by chemotherapy in triple-negative breast cancer, wherein targeting the pathway in a combination therapy rendered cancer cells sensitive to chemotherapy [5]. Despite the malignant implication of CAD during aspartate diversion, the prevalence of DNA repair alterations during chemotherapy treatment, and the activation of de novo NAD+ synthesis for DNA repair during tumor progression (all of which were observed in bladder cancer) [2,3,4,5,6,7,8], the de novo PS pathway has not yet been clinically explored in bladder urothelial carcinoma (BLCA)
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