Medullary thyroid carcinoma (MTC) is responsible for 13.4% of the total deaths attributable to thyroid cancer in human beings and research on MTC over the last 40 years has identified the RET proto-oncogene as a very relevant component of development of both sporadic and hereditary MTC.
The ability to predict the risk of MEN2 and medullary thyroid carcinoma (MTC) by genetic RET proto-oncogene analysis has provided an essential tool in identifying patients in whom thyroid cancer can be prevented by prophylactic thyroidectomy but emphasizes the need for clear policy guidelines.
We analyzed the methylation pattern of 17 gene promoters in nine thyroid cancer cell lines and in 38 primary thyroid carcinomas (13 papillary thyroid carcinoma [PTC], 10 follicular thyroid carcinoma [FTC], 9 undifferentiated thyroid carcinoma [UTC], 6 medullary thyroid carcinoma [MTC]), 12 goiters, and 10 follicular adenomas (FA) by methylation- specific polymerase chain reaction (PCR).
We evaluated the best tagging SNPs from our previous PTC study and additionally included SNPs in or near FOXE1 and NKX2-1 genes, known susceptibility loci for thyroid cancer.
This study demonstrates that all thyroid carcinomas harboring activating RET rearrangements exhibit a well-differentiated phenotype, that of papillary carcinoma, and indicates that the subset of RET/PTC-positive papillary carcinomas do not progress to more aggressive, less differentiated tumor phenotypes.
In contrast, the significance of somatic RET mutations in sporadic MTC is unknown. p53 seems to play a crucial role in the dedifferentiation process of thyroid carcinoma.
Although the mechanisms of cellular injury and repair resulting from ionizing radiation are well described, the genomics of radiation-induced tumours are still relatively poorly understood, with some exceptions, such as RET rearrangement in thyroid carcinomas following iodine-131 exposure and MYC amplification in cutaneous angiosarcoma following chest wall irradiation for breast cancer.
Potentially druggable kinase fusions involving ALK, ROS, RET, NTRK and FGFR gene families were detected in bladder carcinoma (3.3%), glioblastoma (4.4%), head and neck cancer (1.0%), low-grade glioma (1.5%), lung adenocarcinoma (1.6%), lung squamous cell carcinoma (2.3%) and thyroid carcinoma (8.7%), suggesting a potential for application of kinase inhibitors across tumor types.
RET, a transmembrane receptor tyrosine kinase and a receptor for the glial cell-derived neurotrophic factor family ligands, was one of the first oncogenes to be identified, and has been shown to be an oncogene in thyroid cancer and pheochromocytoma.
Further, we found that the frequency of FRET-SE between four pairs of genes that form rearrangements in thyroid cancer was 5% for RET and CCDC6, 4% for RET and NCOA4, 2% for BRAF and AKAP9, and 2% for NTRK1 and TPR.
ZD 6474 has shown promising activity in preclinical models against RET kinase, and its contemporary inhibition of vascular endothelial growth factor and epidermal growth factor pathways renders it a very attractive drug for clinical trials in thyroid cancer.
Somatic mutations in RET exons 12 and 15 in sporadic medullary thyroid carcinomas: different spectrum of mutations in sporadic type from hereditary type.
In few papillary thyroid carcinomas (PTC) and oxyphilic thyroid carcinoma, the clinical impact of the 15 known RET hybrid oncogene variants (RET/PTC 1 to 12, 1L, 3r2, 3r3) is subject to controversial discussions.
Common somatic mutations in BRAF, rearranged in transformation/papillary thyroid carcinomas (RET/PTC) and neurotrophin receptor-tyrosine kinase (NTRK) also do not account for the gender disparity in thyroid cancer.
To assess the therapeutic potential of AL3810 in treating thyroid cancer involving RET gene fusion, we showed that AL3810 (1-10 μmol/L) dose-dependently inhibited the proliferation of RET-driven Baf3 cell line Baf3-CCDC6-RET, and the auto-phosphorylation of RET in these cells.
Because RET/PTC rearrangements are unique to thyroid carcinomas, our findings support the clinical evaluation of sorafenib for patients with PTC and the identification of patients most likely to respond to sorafenib treatment.