RET mutation heterogeneity in primary advanced medullary thyroid cancers and their metastases

Abstract

PurposeMedullary Thyroid Cancer (MTC) whose pathogenesis is strictly related to RET proto-oncogene alterations, has been shown to have a heterogenic RET mutation profile in subpopulations of MTC. The aim of our study was to investigate the RET somatic mutation profile in primary MTC and in the corresponding metastatic tissues in a series of advanced metastatic cases.ResultsThis study demonstrated that in about 20% of cases a different RET mutation profile can be found when comparing primary tumor and its corresponding metastases. Furthermore in 8% of tumors, RET intratumor heterogeneity was observed We also showed that in some cases an imbalance of RET copy number was present. We confirmed a high prevalence (90%) of RET somatic mutations in advanced tumors.Materials and MethodsFifty-six MTC patients (50 somatic and 6 hereditary cases) have been included in the study and a total of 209 specimens have been analysed by direct sequencing. Multiplex ligation-dependent probe amplification (MLPA) has been used to investigate amplification/deletion of RET alleles.ConclusionsIn conclusion, this study showed a genetic intra- and intertumor heterogeneity in MTC, But in only 20% of CASES These results could justify the relatively moderate level of aggressiveness of the disease with respect to more aggressive human tumors that are characterized by a high rate of mutation and heterogeneity.

A Narrative Review of Genetic Alterations in Primary Thyroid Epithelial Cancer

“…As reported in a large series [ 86 ], RET mutations are almost always mutually exclusive, and only in few cases, multiple RET somatic mutations are present, suggesting that MTC is a rather stable tumor. This evidence was also reported in additional studies [ 87 , 88 ] that demonstrated that only in about 20% of cases a different RET mutation profile could be found when comparing primary tumor and its corresponding metastases. NGS studies have also allowed the definition of the frequency of the mutated allele (AF) and have demonstrated that larger tumors not only are characterized by a higher prevalence of RET somatic mutations [ 89 ] but also have a higher AF corresponding to a higher number of mutated cells.…”

Medullary thyroid carcinoma beyond surgery: advances, challenges, and perspectives

“…Also, mutations in codons 618, 603, 634, 768, 804, and 883 and partial deletion of the RET gene have been described in a few tumors (Dvorakova et al 2008, Elisei et al 2008, Romei et al 2016. However, the mutations are not uniform throughout the tumor, suggesting that sporadic MTC might have a polyclonal origin or that these mutations are secondary events of MTC tumorigenesis (Eng et al 1996b, Romei et al 2018.…”

RET Copy Number Alteration in Medullary Thyroid Cancer Is a Rare Event Correlated with RET Somatic Mutations and High Allelic Frequency

“…In the present study, the majority of samples (86.7%) are diploid for the RET gene suggesting substantial genomic stability of this thyroid cancer histotype. The genomic stability of MTC was already appreciated in previous studies of our group showing that only 8% of sporadic MTC showed more than one somatic mutation and that only 20% of cases have different mutational profiles when comparing the primary with the corresponding metastatic tissues [ 21 , 22 ]. Supporting our data, Fisk et al also found a few genomic alterations when analysing sporadic MTC by array-CGH [ 17 ].…”