RET/PTC rearrangements in thyroid nodules: Studies in irradiated and not irradiated, malignant and benign thyroid lesions in children and adults

Rearrangements of the RET proto-oncogene may occur in both naturally occurr ing and radiation-induced papillary thyroid carcinomas. Conflicting results on the frequency and type of RET/PTC rearrangements have been reported in relation to age, radiation exposure, and histological tumor variant. We designed the present study to evaluate in a single laboratory, using the same methodologies, the pattern of RET/PTC activation in thyroid tumors fr om different groups of patients (exposed or not exposed to radiation, child ren or adults, with benign or malignant tumors) in relationship to the abov e mentioned variables. We studied 154 patients with benign nodules (n = 65) or papillary thyroid c ancer (n = 89). In the last group, 25 were Belarus children exposed to the post-Chernobyl radioactive fallout, 17 were Italian adults exposed to exter nal radiotherapy for benign diseases, and 47 were Italian subjects (25 chil dren and 22 adults) with no history of radiation exposure. Among patients w ith benign thyroid nodules, 21 were Belarus subjects (18 children and 3 adu lts) exposed to the post-Chernobyl radioactive fallout, 8 were Italian adul ts exposed to external radiation on the head and neck, and 36 were Italian adults with naturally occurring benign nodules. The overall frequency of RET/PTC rearrangements in papillary thyroid cancer was 55%. The highest frequency was found in post-Chernobyl children and wa s significantly higher (P = 0.02) than that found in Italian children not e xposed to radiation, but not significantly higher than that found in adults exposed to external radiation. No difference of RET/PTC rearrangements was found between samples from irradiated (external x-ray) or not irradiated a dult patients, as well as between children and adults with naturally occurr ing, not irradiated, thyroid cancer. When analyzing the type of RET/PTC rearrangement (RET/PTC1 or RET/PTC3), no major difference was apparent. In addition, eight cases with an unknown RE T/PTC rearrangement and three cases with the concomitant expression of RET/ PTC1 and RET/PTC3 were found. No significant correlation was observed betwe en the frequency and/or the type of RET/PTC rearrangement and clinical-epid emiological features of the patients such as age at diagnosis, age at expos ure, histological variant, gender and tumor-node-metastasis (TNM) categorie s. RET/PTC rearrangements were also found in 52.4% of post-Chernobyl benign no dules, in 37.5% of benign nodules exposed to external radiation and in 13.9 % of naturally occurring nodules (P = 0.005, between benign post-Chernobyl nodules and naturally occurring nodules). The relative frequency of RET/PTC 1 and RET/PTC3 in rearranged benign tumors showed no major difference. In conclusion, our results indicate that the presence of RET/PTC rearrangem ents in thyroid tumors is not restricted to the malignant phenotype, is not higher in radiation-induced tumors compared with those naturally occurring , is not different after exposure to radioiodine or external radiation, and is not dependent from young age. Other factors, probably influenced by eth nic or genetic background, may act independently from or in cooperation wit h radiation, to trigger the DNA damage leading to RET proto-oncogene activa tion.