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. 2018 Jan 4;9(11):9875-9884.
doi: 10.18632/oncotarget.23986. eCollection 2018 Feb 9.

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

Cristina Romei  1 , Raffaele Ciampi  1 , Francesca Casella  1 , Alessia Tacito  1 , Liborio Torregrossa  2 , Clara Ugolini  2 , Fulvio Basolo  2 , Gabriele Materazzi  2 , Paolo Vitti  1 , Rossella Elisei  1
Affiliations

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

Cristina Romei et al. Oncotarget. .

Abstract

Purpose: Medullary 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.

Results: This 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 methods: Fifty-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.

Conclusions: In 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.

Keywords: RET; genetic instability; medullary thyroid carcinoma; tumor clonality.

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Conflict of interest statement

CONFLICTS OF INTEREST The authors declare that there is no conflicts of interest that could affect the impartiality of the reported research.

Figures

Figure 1
Figure 1. Sanger sequencing pherograms and MLPA graphics of the case n 14
Heterozygous deletion in exon 11 encompassing codons 632–634 (panel A) is revealed by the presence of double peaks in the pherogram starting from codon 634 (see red arrow); homo/hemizygous RET somatic deletion in exon 11 encompassing codons 632–634 is shown in (panel B) and revealed by the absence of both codons 632 and 633 (see black arrow). No RET deletion was found at the germline level (panel C) as demonstrated by the wild type sequence of RET oncogene. MLPA showed that no copy number variation was found within the RET gene in the tissues with the heterozygous somatic 6 bp deletion of exon 11 (panel D) suggesting a balance between mutated and not mutated alleles. At variance, an amplification of one RET allele was observed in the tissue with apparent homozygous 6 bp deletion of exon 11 (panel E) suggesting that the amplified allele should be the mutated one.
See this image and copyright information in PMC

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