Differences in the transcriptome of medullary thyroid cancer regarding the status and type of RET gene mutations

Malgorzata Oczko-Wojciechowska,Agnieszka Pawlaczek,Monika Kowal,Tomasz Stokowy,Dagmara Rusinek,Tomasz Tyszkiewicz,Agnieszka Czarniecka,Tomasz Gawlik,Barbara Nikiel,Barbara Jarzab,Sylwia Szpak-Ulczok,Bartosz Wojtas,Malgorzata Kowalska,Jolanta Krajewska,Ewa Chmielik,Michal Jarzab,Dariusz Lange,Malgorzata Wiench,Michal Swierniak

doi:10.1038/srep42074

Abstract

Medullary thyroid cancer (MTC) can be caused by germline mutations of the RET proto-oncogene or occurs as a sporadic form. It is well known that RET mutations affecting the cysteine-rich region of the protein (MEN2A-like mutations) are correlated with different phenotypes than those in the kinase domain (MEN2B-like mutations). Our aim was to analyse the whole-gene expression profile of MTC with regard to the type of RET gene mutation and the cancer genetic background (hereditary vs sporadic). We studied 86 MTC samples. We demonstrated that there were no distinct differences in the gene expression profiles of hereditary and sporadic MTCs. This suggests a homogeneous nature of MTC. We also noticed that the site of the RET gene mutation slightly influenced the gene expression profile of MTC. We found a significant association between the localization of RET mutations and the expression of three genes: NNAT (suggested to be a tumour suppressor gene), CDC14B (involved in cell cycle control) and NTRK3 (tyrosine receptor kinase that undergoes rearrangement in papillary thyroid cancer). This study suggests that these genes are significantly deregulated in tumours with MEN2A-like and MEN2B-like mutations; however, further investigations are necessary to demonstrate any clinical impact of these findings.

Highlights

Cases[7,8], familial medullary thyroid cancer (FMTC) (OMIM 155240), arising in up to 57% of all hereditary cases, and MEN2B (OMIM 162300), in approximately 5% of all hereditary MTCs9
In the absence of a ligand, the RET protein is a single unphosphorylated tyrosine kinase receptor, but in cancer cells, single point mutations in the RET proto-oncogene lead to the autophosphorylation of tyrosine residues, which induces the constitutive activation of the RET receptor and a permanent gain-of-function[12,13]
Differences in the gene expression profiles are usually observed when tumour tissue is compared to the corresponding normal tissue or between tumours of different genetic backgrounds

Summary

Introduction

Cases[7,8], familial medullary thyroid cancer (FMTC) (OMIM 155240), arising in up to 57% of all hereditary cases, and MEN2B (OMIM 162300), in approximately 5% of all hereditary MTCs9. The second RET protein domain is a hydrophobic region located within the cell membrane, and the third one is an intracellular tyrosine kinase domain (TK), which contains two tyrosine residues (TK1 and TK2) Mutations in this domain (mainly in codon 918 of the TK2 domain) lead to the autophosphorylation of the protein and activate the RET receptor without dimerization, but there is a distinct difference in the transforming activity among those mutations. As MEN2B-like mutations are considered the major somatic events in sporadic cancer, o a paradoxical discrepancy occurs between the possibly more aggressive clinical course of somatic RET 918-induced cancer and the generally better prognoses in all sporadic cancers It would, be valuable to compare gene expression profiles between hereditary and sporadic MTC and between sporadic MTC caused by MEN2B-like mutations in RET exon 16 and MEN2A-like mutations in codons 10–11. For the purpose of this study, all mutations in RET exons 10 and 11, both hereditary and sporadic, were classified as MEN2A-like, whereas both germline and somatic mutations in RET exon 16 were classified as MEN2B-like

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