RET/PTC rearrangement in benign and malignant thyroid diseases: a clinical standpoint

Abstract

Cytological examination of fine needle aspiration biopsy is the primary means for distinguishing benign from malignant nodules. However, as inconclusive cytology is very frequent, the introduction of molecular markers in the preoperative diagnosis of thyroid nodules has been proposed in recent years. In this article, we review the clinical implications of preoperative detection of rearrangements of the RET gene (RET/papillary thyroid carcinoma (PTC)) in thyroid nodules. The prevalence of RET/PTC in PTC depends on the histological subtypes, geographical factors, radiation exposure, and detection method. Initially, RET/PTC was considered an exclusive PTC hallmark and later it was also found sporadically in benign thyroid lesions. More recently, the very sensitive detection methods, interphase fluorescence in situ hybridization (FISH) and Southern blot on RT-PCR amplicons, demonstrated that the oligoclonal occurrence of RET rearrangement in benign thyroid lesions is not a rare event and suggested that it could be associated with a faster enlargement in benign nodules. For this reason, RET/PTC cannot be considered as an absolute marker of PTC, and its diagnostic application must be limited to assays able to distinguish between clonal and oligoclonal expression. Detection of RET/PTC by quantitative assays will be useful for diagnostic purposes in cytology specimens when a precise cutoff will be fixed in a clinical setting. Until that time, less sensitive RET/PTC detection methods and FISH analysis remain the most appropriate means to refine inconclusive cytology. Future studies with a long follow-up will further clarify the clinical significance of low level of RET rearrangements in benign nodules.

An update on molecular biology of thyroid cancers

“…RET/PTC, BRAF, NTRK, RAS and PAX8-PPAR␥ mutations have been frequently explored for diagnosis of thyroid cancer. Gene expression profiling and microRNA studies have identified a variety of potential molecular markers to help distinguish benign from malignant thyroid neoplasms especially for nodules that are classified as indeterminate for malignancy by FNAB [36,37,45,34,[90][91][92][93][109][110][111][112][113]178,[180][181][182]. The inability to exclude malignancy in these nodules may often lead to unnecessary surgery or two step surgical procedures.…”

Application of molecular biology of differentiated thyroid cancer for clinical prognostication

“…et al , Marotta et al 2011a) and biological significance of the mutation had been hampered by the application of different detection methods. The low percentage of tumours having RET rearrangements as driver mutational event represents a crucial limitation for clinical application of the mutation, both in the diagnostic and the prognostic setting.…”

“…The use of highly sensitive techniques also allowed the detection of non-clonal mutational events, namely the presence of RET rearrangements in a small proportion of tumour cells or even in a single cell. This paradoxically hampered the possible clinical application of the mutation as molecular marker, in both diagnostic and prognostic settings (Marotta et al 2011a). Indeed, several authors reported the presence of RET/PTC in benign thyroid diseases, including not only Hashimoto's thyroiditis (Wirtschafter et al 1997, Sheils et al 2000, Rhoden et al 2006) but also thyroid nodules revealing benign histology (Cinti et al 2000, Elisei et al 2001.…”

Phospho-Signaling at Oocyte Maturation and Fertilization: Set Up for Embryogenesis and Beyond Part I. Protein Kinases

“…Receptor tyrosine kinase are rearranged during transfection (RET) for activation and about 15 RET gene rearrangement was identified in papillary thyroid carcinoma (PTC) among which RET/PTC1 and RET/PTC3 are the most common type (Marotta et al 2011). RET was detected in mammalian (human) oocytes (Farhi et al 2010) and are expressed in embryos throughout the early development with an increase after the early blastocyst stage (Kawamura et al 2008).…”