Involvement of DNA Base Excision Repair (BER) in Early Stages of Thyroid Carcinogenesis and Its Correlations with Clinical Features and Inflammatory Microenvironment

Introduction. Thyroid carcinoma of the follicular epithelium is the most frequent endocrine tumor and accounts for about 5% of thyroid nodules. Many aspects of the molecular pathogenesis of thyroid nodules remain to be elucidated, although the association between thyroid hormone metabolism, oxidative DNA damage, and the high rate of spontaneous mutations present in normal thyroid seem to underlie carcinogenesis. To test whether the Base Excision Repair system for oxidative DNA stress damage was involved in the early stages of thyroid carcinogenesis, we evaluated BER molecules in a series of euthyroid nodules in relation to clinical and inflammatory features. Material and Methods. Forty-one TIR3B euthyroid nodules and adjacent normal tissues were selected from patients undergone thyroid surgery at Unit of Surgical Oncology of SS Annunziata Hospital, Chieti. Informed consent was obtained from all patients. Gene and protein expression were evaluated by qRT-PCR and IHC respectively. All statistical analyses were performed using R statistical software. Significance was set at p< 0,05. Results and Discussions Patients medical records showed the presence of Ab- Anti-TPO and Anti-TG in 19 out of 41 cases, even if under the cut-off values; thus, we subdivided tissues into goiters without inflammatory features (NIG: n°22) and goiters with inflammatory features (IG: n°19). Positive significant gene expression variations were found in IG tissues for the coding and IL8 genes [p=0.05] as well as for HO-1 [p=0.01] involved in tissue adaptation to pro-inflammatory damage and MUTYH [p=0.04]. The transcription factor Jun/AP1 appears to be significantly more expressed in NIG tissues [p=0.02]. A significant positive correlation between the expression of ERBB2 and MUTYH was observed both in pathological and adjacent/relative normal tissues, with p=0.023 and p<0.001 respectively. OGG1 expression showed an inverse relationship with Anti-TPO [p=0.011] in pathological tissues, while in normal tissues it showed a direct relationship [p=0.008]. IHC protein expression revealed strong expression of OGG1 and AP1/Ref1 in the IG coinciding with the presence of a lymphocytic infiltrate in the tissue microenvironment. Conclusion. The present study provided the first evidence that BER may play a role in thyroid pathophysiology and that overexpression of OGG1 protein could be a marker of thyroid nodular disease in association with anti-TPO autoantibodies.