Introduction: BRAFV600E mutation is the most frequent alteration in papillary thyroid carcinoma (PTC). Although its relation to factors of poor prognosis was demonstrated in many studies the use of BRAF as a predictive marker in clinical treatment of PTC patients is controversial. The aim of our study was to analyze molecular consequences of BRAFV600E mutation in a transgenic mouse model performed for this purpose and to refer the obtained results to human PTCs.
Material and methods: Gene expression profiling was performed for the selected mouse samples obtained from the transgenic mouse model of BRAFV600E-induced PTC with the affymetrix platform and the data were referred to human thyroid dataset with particular emphasis on early steps of PTC carcinogenesis.
Results and conclusions: Most BRAF(+) mice developed malignant lesions (83%), of which 15% presented metastases to lungs or extrathyroidal invasion to muscles. These results confirm the initiating potential of the V600E mutation and its association with the aggressive PTC phenotype. Nevertheless 16% of BRAF(+) mice displayed non-malignant benign hyperplastic lesions or healthy thyroids. Gene signature obtained from the comparison of mouse non-malignant BRAF(+) to BRAF(−) thyroids enabled selection of 862 significantly deregulated genes, of which 532 were identified on the human HG-U133A microarray. We believe that the list of 532 genes represents the human signature of an early stage of BRAFV600E-derived PTC. On comparison of BRAF(+) PTCs to RET(+), RAS(+), or PTCs without BRAF and RET alterations and to healthy thyroids, 18 of the 532 genes displayed significantly deregulated expression in all comparisons. Seven out of 18 genes have not been previously reported to be related to BRAF mutation or thyroid carcinoma. Obtained results may be useful in development of new therapeutic strategies that would be able to overcome resistance to BRAF-targeted therapies.
Polish NSC grant no N N401 612440.
17 - 19 Feb 2016
European Society of Endocrinology