26 April 2006 marks the 20th anniversary of the Chernobyl accident. On this occasion, the World Health Organization (WHO), within the UN Chernobyl Forum initiative, convened an Expert Group to evaluate the health impacts of Chernobyl. This paper summarises the findings relating to cancer. A dramatic increase in the incidence of thyroid cancer has been observed among those exposed to radioactive iodines in childhood and adolescence in the most contaminated territories. Iodine deficiency may have increased the risk of developing thyroid cancer following exposure to radioactive iodines, while prolonged stable iodine supplementation in the years after exposure may reduce this risk. Although increases in rates of other cancers have been reported, much of these increases appear to be due to other factors, including improvements in registration, reporting and diagnosis. Studies are few, however, and have methodological limitations. Further, because most radiation-related solid cancers continue to occur decades after exposure and because only 20 years have passed since the accident, it is too early to evaluate the full radiological impact of the accident. Apart from the large increase in thyroid cancer incidence in young people, there are at present no clearly demonstrated radiation-related increases in cancer risk. This should not, however, be interpreted to mean that no increase has in fact occurred: based on the experience of other populations exposed to ionising radiation, a small increase in the relative risk of cancer is expected, even at the low to moderate doses received. Although it is expected that epidemiological studies will have difficulty identifying such a risk, it may nevertheless translate into a substantial number of radiation-related cancer cases in the future, given the very large number of individuals exposed.

The BRAF gene has been shown to be a major target for mutations in papillary thyroid carcinoma (PTC) (36-69%), which forms almost all of the over 2000 cases of thyroid carcinoma that have occurred in Chernobyl. BRAF is activated by point mutation, and were it to occur at a high frequency in Chernobyl-related tumors, it would challenge the dominant role of double-strand breaks in radiation-induced PTC. In a previous study, we detected the BRAF V600E mutation in 46% (23 of 50) of sporadic adult PTC. Using the same methodology, we have analyzed 34 post-Chernobyl PTC and detected RET/PTC rearrangements in 14 (41%) and BRAF mutations (V600E) in four (12%). These two alterations did not coexist in any PTCs. The mean age at exposure of patients with PTC showing BRAF mutation was higher than that of patients with tumors without BRAF mutation irrespective of their RET status. We have also analyzed 17 sporadic cases of childhood PTC and found that only one (6%) harbored the BRAF V600E mutation. We conclude that the frequency of BRAF mutations is significantly lower (P = 0.0008) in post-Chernobyl PTC than in adult sporadic PTC, whereas no significant difference was found between post-Chernobyl and sporadic childhood PTCs.

The nuclear disaster that occurred in Chernobyl in 1986 offered the unique opportunity to study the molecular genetics of one human tumor type, papillary carcinoma of the thyroid gland, associated with a specific etiology. We have analyzed RET rearrangements in post-Chernobyl papillary thyroid carcinomas (n = 29), follicular thyroid adenomas (n = 2), and follicular thyroid carcinoma (n = 1) by interphase fluorescence in situ hybridization (FISH) analysis on paraffin-embedded tissue sections. Paraffin sections were microdissected before use to ensure that only tumor was present. Cell nuclei were scored for the presence of a split FISH signal (separated red and green signal) in addition to an overlapping signal. Only cells with either two overlapping signals or one split and one overlapping signal were counted to ensure that only complete cell nuclei had been scored. In total, 23 of 32 cases (72%) showed RET rearrangements diagnosed by FISH interphase analysis. In all cases, the tumors were composed of a mixture of cells with and without ret rearrangement on FISH. In some cases, this distribution was clearly nonrandom because clustering of rearranged cells was detected within the same tumor nodule. Accordingly, only 31% of the cases positive for rearrangement on FISH also scored positive using RT-PCR. These findings suggest that because RET/PTC rearrangements are not present in a majority of tumor cells, either a fraction of post-Chernobyl papillary thyroid tumors are of multiclonal origin, or ret rearrangement is a later, subclonal event.

Cell lines are crucial to elucidate mechanisms of tumorigenesis and serve as tools for cancer treatment screenings. Therefore, careful validation of whether these models have conserved properties of in vivo tumors is highly important. Thyrocyte-derived tumors are very interesting for cancer biology studies because from one cell type, at least five histologically characterized different benign and malignant tumor types can arise. To investigate whether thyroid tumorderived cell lines are representative in vitro models, characteristics of eight of those cell lines were investigated with microarrays, differentiation markers, and karyotyping. Our results indicate that these cell lines derived from differentiated and undifferentiated tumor types have evolved in vitro into similar phenotypes with gene expression profiles the closest to in vivo undifferentiated tumors. Accordingly, the absence of expression of most thyrocyte-specific genes, the nonresponsiveness to thyrotropin, as well as their large number of chromosomal abnormalities, suggest that these cell lines have acquired characteristics of fully dedifferentiated cells. They represent the outcome of an adaptation and evolution in vitro, which questions the reliability of these cell lines as models for differentiated tumors. However, they may represent useful models for undifferentiated cancers, and by their comparison with differentiated cells, can help to define the genes involved in the differentiation/dedifferentiation process. The use of any cell line as a model for a cancer therefore requires prior careful and thorough validation for the investigated property. [Cancer Res 2007;67(17):8113-20]