Friday, April 18, 2014

Thyroidectomies from Patients with a History of Therapeutic Radiation During Childhood and Adolescence Yield Unique Mutational Profiles

           Since the 1950’s it has been observed that radiation in childhood is a risk factor for thyroid carcinoma, however, radiation may also be related to benign nodular hyperplasias. There are two scenarios of exposure to radiation that have been studied in relation to thyroid cancer; nuclear fallout, such as the nuclear accident in Chernobyl,  and therapeutic radiation. Most research has been base on the radiation exposure due to nuclear fall out, however exposure due to therapeutic radiation of the head and neck, is more common. Because of the observation that radiation was creating a great risk for cancer, the therapeutic radiation treatments are now only used in response to morbidity and mortality cases. Unfortunately,  due to the long lag time between exposure and thyroid disease onset, the children from the 1950s and 60s are only recently being treated for thyroid disease.
In recent studies, rat thyrocytes subjected to radiation were found to have clonal DNA damage.  In a new study conductedby Adel Assaad, Laura Voeghtly and Jennifer L. Hunt, differences in genetic alterations were observed between the radiation-induced and sporadic papillary carcinoma and follicular derived carcinomas. The most commonly studied mutations in papillary carcinomas have been the ras gene mutations and, RET/PTC translocations, and BRAF mutations. However, after studying the Chernobyl patients with papillary carcinoma, it was observed that the  radiation-induced tumors had higher mutational rates for ras gene mutations and the RET/PTC translocations, while the BRAF mutations were uncommon. In another study, BRAF mutation frequencies were also found to be low in tumors of patients with history of therapeutic radiation in childhood. This lead to the idea that BRAF mutations are generally uncommon in radiation induced tumors. Investigators, however, took into account the findings that the translocations alone were likely insufficient to induce carcinomas and that there are likely other genetic and molecular events leading to the malignant transformation. Tumor suppressor gene mutations are likely the missing link, however tumor suppressor gene genotype has not been well studied in radiation-induced tumors of either of the two exposure scenarios.  
PCR was also performed  for 18 different genetic  loci, identified from the comparative study of the rats, using thyroids from patients with a history of radiation (30 cases: 3 chronic lymphocytic thyroiditis, 11 benign hyperplastic nodules, 7 follicular adenomas, 2 follicular carcinomas, 7 papillary thyroid carcinomas), patients who had recent therapeutic external beam radiation for laryngeal carcinoma (12 cases), and patients who had no radiation and underwent thyroidectomy with laryngectomy for laryngeal carcinoma (15 cases). The reasons for the use of therapeutic radiation treatment are listed in Table 3. After a semiquantative capillary electrophoresis analysis was performed, the frequency of allelic losses from each group was calculated. The frequency of allelic loss from non-radiated patients was 2.3%, while the frequency of allelic loss of patients radiated as children was 39%.  The frequency of allelic loss was also high in patients with benign nodular diseases who were subjected to radiation as a child.

                  It was clear that the growing thyroid of children is at greater risk than that of adults for carcinomas due to radiation exposure. Even if the transformation is not malignant, radiation could cause other problems with the thyroid such as hyperthyroidism, thyroiditis, autoimmune thyroiditis, and hyperplastic changes. The development of these problems is caused by the propagation of the mutation abnormalities as the thyroid matures.