Objective: RET fusion genes are known driver mutation in thyroid cancer and have been described mainly in pediatric thyroid carcinomas, in which they represent the most common genetic alteration. In large cohorts of adult patients, RET fusions have not yet been well characterized. The aims of this study were to identify RET fusion-positive thyroid tumors in a cohort of different types of thyroid carcinomas and to correlate them with clinical and histopathological features and to determine the prognostic significance of RET fusion genes based on long-term follow-up of patients with thyroid cancer harboring this mutation.
Methods: The cohort consisted of 1067 different thyroid cancer samples (fresh frozen tissues). Based on the detected mutation, samples were triaged. Samples positive for the BRAF, HRAS, KRAS, NRAS, RET or NTRK fusion gene mutation were excluded from the further RET fusion gene analyses. Samples were analyzed using Real-Time PCR (LC480, Roche) or using the FusionPlex Comprehensive Thyroid and Lung panel (ArcherDx) by next generation sequencing on MiSeq sequencer (Illumina).
Results: RET fusion genes were detected in 103/914 (11.3%) papillary thyroid carcinomas, from which 32/118 (27.1%) were from pediatric patients (7-20 years old) and 71/796 (8.9%) were from adult patients. A total of 17 types of RET fusions were found, including the following partner genes: CCDC6, NCOA4, PRKAR1A, SQSTM1, IKBKG, RASAL2, TPR, ACBD5, RUFY2, BBIP1, AFAP1L2, AKAP13, TRIM27, SPECC1L, FBXO41, GOLGA5, SSBP2. The RET fusion-positive carcinomas were associated with follicular growth pattern, multifocality, extrathyroidal invasion, lymph node and distant metastases. Lymph node metastases were found in almost all (93.8%) pediatric cases. On the other hand, most patients responded well to radioiodine treatment.
Conclusion: In summary, RET fusion gene were found only in papillary thyroid carcinomas. The frequency was approximately three times higher in pediatric patients than in adult patients. RET fusion-positive carcinomas correlated with aggressive tumor behavior. In conclusion, the genetic molecular testing of RET fusions is important not only for patients diagnosis and prognosis, but also for possible targeted therapy.
Supported by the Ministry of Health of the Czech Republic DRO (Institute of Endocrinology EU, 00023761) and AZV NU21-01-00448 grant.
21 May 2022 - 24 May 2022