Molecular determination of benign and malignant thyroid tumors

Abstract

Recent molecular studies have revolutionized our understanding of the pathogenesis of thyroid tumors and particular advances have been made in three areas. First, toxic thyroid nodules, which originate from constitutive activation of thyroid-stimulating hormone receptor/Gs α signaling and represent the dominant cause of thyrotoxicosis in regions with iodine deficiency. Second, papillary thyroid cancer, the most frequent thyroid malignancy, which is characterized by a common fingerprint of constitutive mitogen-activated protein kinase activation. Importantly, this is caused by distinct genetic alterations in radiation-induced (RET/PTC, NTRK and AKAP9/BRAF rearrangements) and sporadic tumors (BRAF and RAS point mutation) and, recently, there exciting in vitro have emerged explaining the structural basis for this. These findings suggest a scenario in which the fate of a thyroid tumor is determined by the specific genetic defect at the beginning. Third, application of microarray analysis in nodular pathologies in which the oncogenic pathway is less clear, notably follicular neoplasia, has led to the identification of a number of promising genetic markers (TFF-3, Gal-3, PLAB, CCND2 and PCKD2) for the diagnostic distinction of follicular adenoma and carcinoma. In addition to the diagnostic perspective, the identification of molecular fingerprints of thyroid tumors opens novel avenues for an improved therapeutic approach; for example, selective antagonism of cell signaling in treatment-refractory thyroid cancer.

Keywords::

• thyroid nodules
• thyroid cancer
• clonality
• somatic mutation
• TSH receptor
• RET/PTC rearrangement
• RAS
• BRAF
• PAX8/PPARγ rearrangement

Acknowledgements

I am grateful to Stefan Karger, Kerstin Krause, Cornelia Engelhardt, Monika Gutknecht and Beate Jessnitzer for their enthusiasm and dedication in the study of molecular aspects of nodular thyroid disease. I would like to thank Markus Eszlinger for his advice on the discussion of microarray analysis of thyroid tumors. The author is a fellow of the Emmy Noether Program of the Deutsche Forschungsgemeinschaft (DFG FU 356/1–2).