Prognostic significance of RET and NTRK1 rearrangements in sporadic papillary thyroid carcinoma

Abstract Background The genetic background of papillary thyroid carcinoma (PTC) has been elucidated by the identification of somatic translocations of the tyrosine kinases RET and NTRK1. Expression of RET/PTC chimeras has been demonstrated in 10–25 per cent of sporadic PTCs while rearrangements of NTRK1 were detected less frequently. Based upon the limited data available, some investigators have hypothesized that RET/PTC activation is preferentially associated with slow growing tumours of low malignancy in elderly patients, while other studies support the contrary. Methods Tumour tissues from 115 patients with sporadic PTC were harvested at operation and snap frozen. Following RNA extraction, expression analysis of the RET proto-oncogene as well as the NTRK1 gene was performed by multiplex reverse transcriptase–polymerase chain reaction. Samples with suspected rearrangements of the genes were further analysed for expression of the hybrid messenger RNAs RET/PTC1 to RET/PTC4, and for known NTRK1 chimeras. Clinical data of all patients were documented in an extensive database of thyroid carcinomas maintained by this research group. Results Twenty-one (18 per cent) of 115 tumour samples revealed somatic rearrangements of RET while translocations of the NTRK1 gene were demonstrated in 2 per cent of all samples analysed to date. The mean age of all patients was 52 (range 14–86, median 54) years and that of patients positive for RET rearrangements was 49 (range 14–82, median 49) years. Nine of 21 RET-rearranged tumours showed aggressive behaviour with locally invasive tumour growth and infiltration of adjacent structures such as muscles, vessels and trachea. Tumour samples without detectable RET translocations were associated with organ-exceeding tumour growth in only 20 per cent of cases. Conclusion These data represent one of the most comprehensive studies on gene translocations and their clinical significance in PTC. In accordance with international publications, an incidence of 2 per cent of NTRK1 rearrangements and 18 per cent of RET translocations is reported, which is in contrast to other national reports of low rearrangement rates. Somatic translocations were associated with tumours demonstrating aggressive behaviour in almost half of patients with PTC in all age groups, indicating a prognostic role of oncogenic RET/PTC activation.