Polymerase theta expression is correlated with proliferative capacity but not with DNA repair deficiency status in...

Polymerase theta (POLθ) inhibitors were developed to overcome resistance to PARP inhibitor treatment in homologous recombination (HR) deficient cancer. Biomarkers identifying PARP inhibitor-resistant cancer cases that specifically rely on POLθ activity for cancer cell survival will help to identify the sensitive patient population. From the TCGA RNAseq data, we determined POLθ expression levels, and from whole-exome and whole-genome sequencing data, we determined the number of POLθ-associated mutational signatures in solid tumors with various HR deficiency status. We found that POLθ expression levels did not differ significantly between HR-proficient and HR-deficient cancers. However, POLθ expression correlated strongly with proliferation-associated gene expression signatures and was predominantly observed in the S and G2/M phases of the cell cycle. POLθ-associated mutational signatures are correlated with POLθ expression levels only in BRCA2-deficient cancers. POLθ expression level and POLθ-associated mutational signatures may be indicative of POLθ inhibitor sensitivity in BRCA2-deficient tumors, but are unlikely to be informative in other cancers.