Polymorphisms of DNA damage response genes in radiation-related and sporadic papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) etiologically occurs as a radiation-induced or sporadic malignancy. Genetic factors contributing to the susceptibility to either form remain unknown. In this retrospective case-control study, we evaluated possible associations between single-nucleotide polymorphisms (SNPs) in the candidate DNA damage response genes (ATM, XRCC1, TP53, XRCC3, MTF1) and risk of radiation-induced and sporadic PTC. A total of 255 PTC cases (123 Chernobyl radiation-induced and 132 sporadic, all in Caucasians) and 596 healthy controls (198 residents of Chernobyl areas and 398 subjects without history of radiation exposure, all Caucasians) were genotyped. The risk of PTC and SNPs interactions with radiation exposure were assessed by logistic regressions. The ATM G5557A and XRCC1 Arg399Gln polymorphisms, regardless of radiation exposure, associated with a decreased risk of PTC according to the multiplicative and dominant models of inheritance (odds ratio (OR) = 0.69, 95% confidence interval (CI) 0.45-0.86 and OR = 0.70, 95% CI 0.59-0.93 respectively). The ATM IVS22-77 T > C and TP53 Arg72Pro SNPs interacted with radiation (P = 0.04 and P = 0.01 respectively). ATM IVS22-77 associated with the increased risk of sporadic PTC (OR = 1.84, 95% CI 1.10-3.24) whereas TP53 Arg72Pro correlated with the higher risk of radiogenic PTC (OR = 1.80, 95% CI 1.06-2.36). In the analyses of ATM/TP53 (rs1801516/rs664677/rs609429/rs1042522) combinations, the GG/TC/CG/GC genotype strongly associated with radiation-induced PTC (OR = 2.10, 95% CI 1.17-3.78). The GG/CC/GG/GG genotype displayed a significantly increased risk for sporadic PTC (OR = 3.32, 95% CI 1.57-6.99). The results indicate that polymorphisms of DNA damage response genes may be potential risk modifiers of ionizing radiation-induced or sporadic PTCs.

TP53 codon 72 polymorphism in radiation-associated human papillary thyroid cancer.

The study investigated an association between the germline polymorphism at TP53 codon 72 and the development of papillary thyroid cancer (PTC) following exposure to radiation from the Chernobyl accident. TP53 genotype was examined in 48 pediatric/adolescent (age at diagnosis <18 years) and 68 adult post-Chernobyl patient with PTC, 53 adult patients with sporadic PTC and 313 healthy individuals from Russian-Ukrainian population. In addition, we evaluated loss of heterozygosity for TP53 and the allele expression ratio. The genotype of the patients was correlated with clinicopathological data. Arg TP53 homozygotes were found to be significantly underrepresented among adults with post-Chernobyl PTC, but not in children and adolescents when compared with sporadic PTC cases and the general population. In the tumors, cell transformation did not lead to allelic loss or biased TP53 allele expression in heterozygous individuals. None of TP53 genotypes specifically associated with tumor stage and morphology, however there were particular correlations with lymph node status in certain age groups of radiation-associated cases not seen in sporadic PTCs. The findings suggest TP53 allele combinations other than Arg/Arg may contribute to the risk of development of PTC in individuals exposed to radiation during their late childhood, adolescence or in young adulthood.

Large deletions in mitochondrial DNA in radiation-associated human thyroid tumors.

Paired DNA samples of tumor and normal thyroid tissue from adult patients possibly exposed to radioactive Chernobyl fallout [11 cases of papillary thyroid carcinoma (PTC) and 6 follicular adenomas] and from control samples (9 PTC occurring in Japanese patients) were examined for the relative mitochondrial DNA (mtDNA) content, prevalence and level of common deletion (CD), and large-scale deletions in mtDNA. Elevated relative mtDNA content as estimated by real-time PCR was found in tumor tissue in most cases, but no significant correlation with the level of radioiodine contamination of patients' residency nor with clinicopathological data were found. CD was detected in every DNA specimen from all types of tissue regardless of the presence of oxyphillic cell changes. Elevated level of the CD was predominantly found in tumor tissue of the radiation-associated group but not in sporadic PTC. No correlation was noted with clinicopathological parameters, radioiodine contamination, and relative mtDNA content. The quantity of large-scale deletions in mtDNA was elevated in most tumor tissues, especially in the radiation-associated group and tended to correlate with the level of radiopollutant in PTC. In contrast to sporadic PTC, highly significant-positive correlation between the presence of large scale mtDNA deletions and relative mtDNA content was found in radiation-associated tumors (P = 0.001 and P = 0.019 in PTC and follicular adenoma, respectively). Normal tissue displayed the inverse tendency. No association with level of the CD was found in either group of cases. Concordant increase of both relative mtDNA content and number of mtDNA deletions was detected more often in radiation-associated PTC than in sporadic PTC. Thus, simultaneous determination of the number of large-scale mtDNA deletions and relative mtDNA content may be useful to elucidate molecular distinctive features of radiation-associated thyroid tumors.