Oncotarget

Research Papers:

CAD/POLD2 gene expression is associated with poor overall survival and chemoresistance in bladder urothelial carcinoma

Kevin B. Givechian _, Chad Garner, Hermes Garban, Shahrooz Rabizadeh and Patrick Soon-Shiong

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Oncotarget. 2018; 9:29743-29752. https://doi.org/10.18632/oncotarget.25701

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Abstract

Kevin B. Givechian1, Chad Garner1, Hermes Garban2, Shahrooz Rabizadeh1,2 and Patrick Soon-Shiong1,2

1NantOmics LLC, Culver City, CA 90232, USA

2NantBioscience, Inc. | NantWorks, Culver City, CA 90232, USA

Correspondence to:

Kevin B. Givechian, email: Kevin.Givechian@nantomics.com

Keywords: DNA repair; chemoresistance; pyrmidine synthesis; bladder carcinoma; survival

Received: April 11, 2018    Accepted: June 13, 2018    Published: July 03, 2018

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.


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