Abstract
The incidence of papillary thyroid cancer (PTC) in those areas exposed to fallout from the Chernobyl accident has increased dramatically, particularly in those under 19 at exposure. To determine whether there is a radiation signature, we studied the molecular pathology of post Chernobyl thyroid cancer using a variety of techniques on material supplied by the Chernobyl Tissue Bank (www.chernobyltissuebank.com). Ret rearrangement was studied by RT-PCR in 100 papillary cancers from patients aged under 15 at the time of the Chernobyl accident; 44% of these harboured ret rearrangements; the frequency in PTCs from children in England and Wales is 48%. There was no correlation with either age at exposure or latency. We found that the majority of PTCs (72%) harboured positive cells using FISH for ret rearrangement, and the maximum number of positive nuclei was 55%. Only 41% of cases were positive for ret on RT-PCR. Clustering of FISH positive nuclei was found in 31% of cases, suggesting subclonal growth. One case showed ret rearrangement as well as a chromosomal insertion ins (12;7)(q13;q11q22). The distribution of rearranged genes within the tumour studied by FISH suggests a distinct tumour heterogeneity in this case. Sampling of different areas of the tumour is therefore likely to account for differences between FISH and RT-PCR results. Expression analysis of 2400 genes was also performed 12 cases of PTC using Micromax cDNA array and compared with 9 PTCs from Belgium and France. Hierarchical clustering analysis on the 50% most expressed genes showed no differences between the 2 groups of tumours. Permutation analyses revealed differences in the expression of 10 genes; 5 of these related to lymphoid infiltration in the tumours, the other 5 showed small differences in expression, and are therefore likely to be of no biological significance. We have also compared the frequency of the common B-RAF mutation (T1796A) in a series of Ukrainian PTCs. 32 patients were aged over 30 and 35 cases aged under 16 at the time of diagnosis. 18 (58%) of the adult cases, but only 1 of the 35 cases aged under 16 harboured a B-RAF T1796A mutation. In the young cohort the overall frequency of RET rearrangement was 45.7%. Eight of the younger group of patients were born after 1st December 1986, and were therefore not exposed to radioiodine in fallout from Chernobyl, either in utero or as young children. None of the PTCs from these 8 patients were positive for B-RAF mutation. The frequency of RET rearrangement was 44% in the 27 cases exposed to radiation (median age 11.9, range 7.9-15.1) and 50% in the 8 not exposed (median age 13.8, range 7.9-15.7). Taken together, these results suggest that the different molecular biological profiles observed post Chernobyl are associated with the age of the patient at diagnosis with PTC, rather than being associated with a radiation aetiology.
