- Molecular signatures in thyroid carcinoma and in its potential precursor lesions
- Acquaviva, Giorgia <1985>
Subject
- MED/08 Anatomia patologica
Description
- Introduction. The molecular profile of Papillary Thyroid Carcinoma (PTC) has been throughly investigated. However, to date, there is no information regarding the BRAF molecular profile of the non-neoplastic tissue surrounding PTCs. Exploring this molecular signature may help to better understand thyroid tumorigenesis. Aims of this project are: i) to establish whether BRAF mutations are present in non-malignant tissue surrounding PTC and to characterize their activity; ii) to set up a RNA-based panel that may provide diagnostic, predictive and prognostic information on thyroid nodules/neoplasms. Material and Methods. We screened 30 PTCs and 100 non-malignant tissues surrounding the tumor using Next Generation Sequencing. The kinase activity of mutated proteins was evaluated measuring the activation of the MAPK pathway. The RNA-based panel was designed to detect fusion and dysregulated gene-expression, in a set of 44 fresh-frozen samples. Results. Ten (33.3%) PTCs were BRAF-WT and 20 BRAF-positive (66.6%). In 9 non-malignant tissues (9.0%) we identified “uncommon” BRAF mutations. The BRAF-S607F and BRAF-S607P had the same kinase activity of the BRAF-WT protein; the BRAF-A598T and BRAF-G593D proteins showed decreased activity. All “uncommon” BRAF mutations had a lower kinase activity if compared to BRAF-V600E or BRAF-K601E. The samples harboring the BRAF p.V600E mutation or RAS mutations had dysregulated expression of the BRAF-like or RAS-like genes, respectively. Unsupervised hierarchical analysis identified three major clusters: i) non-malignant tissue; ii) malignant tissue; iii) non-follicular thyroid cell derived cancers. Conclusion. Aim 1: non-malignant thyroid tissue may harbor “uncommon” BRAF mutations but without affecting the BRAF-kinase activity and therefore do not possess the tumorigenic potential necessary for the development of PTC. Aim 2: the RNA-based panel identifies three main profiles corresponding to: i) non-malignant tissue; ii) malignant tissue; iii) non-follicular thyroid cell derived cancers. This novel RNA based panel may be very useful to complement the preoperative evaluation of thyroid nodules.
Date
- 2019-04-12
Type
- Doctoral Thesis
- PeerReviewed
Format
- application/pdf
Identifier
urn:nbn:it:unibo-25287
Acquaviva, Giorgia (2019) Molecular signatures in thyroid carcinoma and in its potential precursor lesions, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Scienze biomediche e neuromotorie