A Role for RAD51-interacting POLQ SNPs in Papillary Thyroid Carcinogenesis
*Jianliang Man, *Timothy Murtha, *Reju Korah, Tobias Carling
Yale, New Haven, CT
Introduction. Chromosomal translocations and fusion genes are commonly found in papillary thyroid carcinoma (PTC), suggesting a role for inaccurate repair of double-strand breaks (DSB) in PTC tumorigenesis. DNA polymerase theta (POLQ), a unique error-prone polymerase interacts with RAD51 recombinase to mediate DSB repair in mammalian cells. We hypothesized that single-nucleotide polymorphisms (SNP) of POLQ in RAD51 interaction domains may increase the risk for papillary thyroid tumorigenesis.
Methods. A cohort of 121 histologically confirmed fresh-frozen PTC specimens were identified. Genomic DNA was extracted, and SNPs within exons 17 and 29 of the POLQ gene were identified using a combination of Sanger method and next-generation sequencing. Allele frequencies were compared to population data from 1000 Genomes. Demographics and clinical characteristics were obtained from electronic medical records and associations were determined using Chi-square and Mann-Whitney tests.
Results. Two SNPs were significantly enriched within our PTC cohort when compared to population data: rs3218649 (16.4%, p<0.001) and rs1381057 (9%, p=0.005). One SNP, rs3218651, was found at significantly lower frequency (-13%, p<0.001). The amino acid changes caused by rs3218649 (T982R) and rs3218651 (H1201R) are in the central domain of POLQ carrying RAD51 interaction sites. While the presence of rs3218649 correlated with an increase in frame-shift mutations (p=0.04), tumors with rs1381057 were on average 0.5 cm larger (Mann-Whitney p=0.016).
Conclusion. POLQ SNPs in RAD51 interaction domains have altered allele frequencies in our PTC cohort compared to the general population, suggesting that genetic variations in POLQ may contribute to PTC tumorigenesis, potentially by influencing POLQ-RAD51 interactions. Further studies are needed to elucidate the impact of POLQ SNPs on the clinical behavior of PTC.
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