Polymorphisms within base and nucleotide excision repair pathways and risk of differentiated thyroid carcinoma

Abstract

The thyrocytes are exposed to high levels of oxidative stress which could induce DNA damages. Base excision repair (BER) is one of the principal mechanisms of defense against oxidative DNA damage, however recent evidences suggest that also nucleotide excision repair (NER) could be involved. The aim of present work was to identify novel differentiated thyroid cancer (DTC) risk variants in BER and NER genes. For this purpose, the most strongly associated SNPs within NER and BER genes found in our previous GWAS on DTC were selected and replicated in an independent series of samples for a new case-control study. Although a positive signal was detected at the nominal level of 0.05 for rs7689099 (encoding for an aminoacid change proline to arginine at codon 117 within NEIL3), none of the considered SNPs (i.e. rs7990340 and rs690860 within RFC3, rs3744767 and rs1131636 within RPA1, rs16962916 and rs3136166 in ERCC4, and rs17739370 and rs7689099 in NEIL3) was associated with the risk of DTC when the correction of multiple testing was applied. In conclusion, a role of NER and BER pathways was evoked in the susceptibility to DTC. However, this seemed to be limited to few polymorphic genes and the overall effect size appeared weak.

Functional Polymorphisms in DNA Repair Genes Are Associated with Sporadic Colorectal Cancer Susceptibility and Clinical Outcome

“…Sequence variability in different DNA glycosylases have been proposed as susceptibility factors for different malignancies [46]. Specifically, NEIL3 SNPs were associated with the risk of glioma, prostate, and thyroid cancer [47,48,49], with rs7689099 being associated with a reduced risk of differentiated thyroid carcinoma and prostate cancer [47,49]. None of the other associated SNPs were found in linkage disequilibrium with rs7689099.…”

Lessons from Fukushima: Latest Findings of Thyroid Cancer After the Fukushima Nuclear Power Plant Accident

“…Applicable to the risk for radiation-related thyroid cancer, finding markers of susceptibility or resistance in order to understand why some individuals develop malignancy after exposure to a similar dose of radiation while the vast majority does not would be a substantial advance. Genetic association studies in sporadic thyroid cancer lead to the identification of four chromosomal loci with five single-nucleotide polymorphisms (SNPs) displaying the following most significant association signals: rs966423 ( DIRC3 ), rs2439302 ( NRG1 ), rs965513 ( PTCSC2/FOXE1 ), rs944289 ( PTCSC3 ), and rs116909374 ( MBIP1 ) ( 40–42 ), and an additional study, using an extremely large cohort, recently discovered six novel chromosomal regions whose effects are less pronounced ( 43 ). The strongest association signal was detected for rs965513 ( PTCSC2/FOXE1 ) located on chromosome 9q22.33.…”

Thyroid cancers of follicular origin in a genomic light: in-depth overview of common and unique molecular marker candidates

“…Applying a presumption that the DNA repair genes of base (BER) or nucleotide (NER) excision repair pathways might be involved in TC tumorigenesis, Cipollini et al , genotyped known SNPs in 450 case-control paired DTC samples from an Italian population [ 32 ]. The TT variant of base excision repair gene NEIL3 , which codes a DNA glycosylase, was associated with increased risk of DTC.…”