Expression of the RET proto-oncogene and the RET/PTC oncogenes in papillary thyroid carcinomas and its correlation to clinical manifestations

Abstract

Background Papillary thyroid carcinoma (PTC) is the commonest thyroid cancer. It has an excellent prognosis if the patients receive appropriate treatment. However, a subgroup of patients with PTC develop distant metastases and eventually die from the disease. There are considerable difficulties in identifying such patients before operation, and there is a need for better tools to do so. Genetic changes, such as expression of the oncogenic fusion proteins RET/PTC 1–5, have been described but their correlation with the clinical picture and prognosis is unclear. Methods Sixty-one PTCs (50 primary and 11 recurrent tumours) from 61 patients were selected and analysed for expression of the RET tyrosine kinase domain (RET-TK) and the oncogenes RET/PTC by reversed transcribed polymerase chain reaction, followed by restriction enzyme digestion and direct sequencing. This expression was then correlated with clinical features of lymph node metastasis, distant metastasis, poor differentiation, tall cell variant, extrathyroidal growth, previous external radiation, recurrent disease and death from disease. Results Thirty PTCs (49 per cent) showed expression of RET-TK. Thirteen of them appeared to express wild-type RET, as upstream exons were also expressed. Three were explained by RET/PTC expression: one RET/PTC1, one RET/PTC3 and one with a unique variant of RET/PTC3, previously only described in a patient with PTC from Chernobyl. Poor differentiation, but no other histopathological parameter, was significantly correlated with the expression of wild-type RET. Furthermore, in PTCs from 15 patients with a poor clinical outcome (death from disease or distant metastases) RET-TK expression was found significantly more often. Conclusion Half of the PTCs showed expression of RET-TK. Surprisingly, only three of them could be explained by known RET/PTC oncogenes. Probably, some of the PTCs express wild-type RET while others could be explained by new, or not yet identified, RET/PTC rearrangements. Regardless of the mechanism for RET-TK expression, this seems to be correlated with a poor prognosis. If this holds true in a larger sample, RET-TK expression could be used as an additional marker to identify patients with PTC who have a less favourable prognosis, and who may benefit from more extensive treatment.