RET/PTC and PAX8/PPARγ chromosomal rearrangements in post‐Chernobyl thyroid cancer and their association with iodine‐131 radiation dose and other characteristics

Abstract

Background Childhood exposure to I-131 from the 1986 Chernobyl accident led to a sharp increase in papillary thyroid carcinoma (PTC) incidence in regions surrounding the reactor. Data concerning the association between genetic mutations in PTCs and individual radiation doses are limited. Methods We performed mutational analysis of 62 PTCs diagnosed in a Ukrainian cohort of patients who were <18 y.o. in 1986 and received 0.008-8.6 Gy of I-131 to the thyroid and explored associations between mutation types and I-131 dose and other characteristics. Results RET/PTC rearrangements were most common (35%), followed by BRAF (15%) and RAS (8%) point mutations. Two tumors carrying PAX8/PPARγ rearrangement were identified. We found a significant negative association with I-131 dose for BRAF and RAS point mutations and a significant concave association with I-131 dose, with an inflection point at 1.6 Gy and odds ratio 2.1, based on a linear-quadratic model for RET/PTC and PAX8/PPARγ rearrangements. The trends with dose were significantly different between tumors with point mutations and rearrangements. Compared to point mutations, rearrangements were associated with residence in the relatively iodine deficient Zhytomyr region, younger age at exposure or surgery, and male gender. Conclusions Our results provide the first demonstration of PAX8/PPARγ rearrangements in post-Chernobyl tumors and show different associations for point mutations and chromosomal rearrangements with I-131 dose and other factors. These data support the relationship between chromosomal rearrangements, but not point mutations, and I-131 exposure and point to a possible role of iodine deficiency in generation of RET/PTC rearrangements in these patients.

Oncogenic rearrangements driving ionizing radiation–associated human cancer

“…This lends further support to the notion that this particular pathway plays a major role in thyroid carcinogenesis (1,3). An important exception to this paradigm is represented by the two samples that featured PPARG rearrangements (CREB3L2-PPARG, PAX8-PPARG), confirming the previous observations of Leeman-Neill and colleagues (20). These samples were from follicular rather than classic-variant PTCs, which supports previous studies that correlate PPARG genetic lesions with this particular morphological PTC subtype (1).…”

“…It would be interesting to learn whether these features are applicable to the other radiation-associated gene rearrangements identified by Ricarte-Filho and coworkers. Moreover, since post-Chernobyl carcinomas occurred in young patients and in geographic areas with reduced iodine supply (19,20), it would also be interesting to determine whether age and iodine concentration influence thyrocyte chromatin organization. In this context, it is plausible that, due to gene proximity, radiation exposure promotes the formation of thyroid cancer-driving gene fusion events.…”

Genetic alterations of differentiated thyroid carcinoma in iodine‐rich and iodine‐deficient countries

“…Another study from Italy, however, did not find a statistical difference in the BRAF V600E mutation rate of PTCs between iodine‐rich and iodine‐deficient areas 20. The prevalence of RAS codon 61 mutations in FTCs was reported to be five times higher in the iodine‐deficient country of Hungary than in iodine‐rich Canada 28, and a possible relationship of iodine deficiency and generation of RET/PTC rearrangements has been suggested 29. However, Bartolone et al.…”

Radiation exposure and thyroid cancer: a review

“…RET/PTC3 rearrangement was the most frequently observed rearrangement in aggressive PTC that occurred in young children soon after the Chernobyl accident, and RET/PTC1 rearrangement was more frequently observed in classical PTC that occurred later after the accident. Other RET/PTC rearrangements have been found in Chernobyl thyroid cancers that may differ either by the partner gene or by the breakpoint site (34)(35)(36)(37)(38)(39)(40). In a series of 26 papillary thyroid cancers that occurred in highly contaminated children in Ukraine, kinase fusion oncogenes resulting from intra-chromosomal rearrangements that activate the mitogen-activated kinase pathway (MAP kinase pathway) were found in 23 (including RET/PTC, BRAF, and TRK rearrangements), and BRAF (n = 2) and TSHR (n = 1) gene point mutations were found in only 3 tumors (36).…”