Overexpression of human DNA polymerase theta is a biomarker of aggressive and DNA repair-deficient papillary thyroid cancers

Background: DNA Polymerase theta (POLQ) is an Enzyme that repairs double-strand DNA breaks. POLQ is overexpressed in several Cancer types, and increased expression is associated with a poor prognosis. Ablating POLQ function in vitro increases drug sensitivity to agents that cause double-strand DNA breaks, including chemotherapies and ionizing radiation. POLQ's role in thyroid Cancer remains poorly understood.

Methods: Expression of POLQ and Other genes of interest were analyzed in 513 papillary thyroid cancers (505 primary tumors and 8 metastatic lesions) and 59 normal thyroid samples available in the Cancer Genome Atlas. The Cancer Genome Atlas RNA and DNA Sequencing data were queried with the Xena platform. The Recombination Proficiency Score was calculated to assess DNA repair efficiency. Other signaling events associated with thyroid tumorigenesis and clinical outcomes were analyzed. Univariate and multivariate analyses were performed. Treatment with the POLQ inhibitors ART558 and Novobiocin tested the effect of POLQ inhibition on in vitro thyroid Cancer growth.

Results: POLQ expression was increased in papillary thyroid cancers compared to normal thyroid tissue (P < .05). POLQ expression levels were inversely correlated with Recombination Proficiency Score levels (P < .05). POLQ expression was highest in tall cell papillary thyroid cancers and in metastases. Higher POLQ expression was also associated with dedifferentiation, BRaf signaling, and shorter progression-free intervals (P < .05). Treatment with POLQ inhibitors decreased in vitro thyroid Cancer growth (P < .05).

Conclusion: These findings suggest that increased POLQ expression could serve as a valuable clinical marker and a potential therapeutic target in the treatment of thyroid Cancer.