RET mutated C-cells proliferate more rapidly than non-mutated neoplastic cells

Romei, Cristina; Ramone, Teresa; Mulè, Chiara; Prete, Alessandro; Cappagli, Virginia; Lorusso, Loredana; Torregrossa, Liborio; Basolo, Fulvio; Ciampi, Raffaele; Elisei, Rossella

doi:10.1530/ec-20-0589

Cited by 3 publications

(3 citation statements)

References 29 publications

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“…As reported by Le Hiret al [16] it is likely that, in tumors caused by RET mutations, the presence of higher amounts of the long isoform can confer a selective growth advantage as demonstrated by the evidence that, in PC12 cells, the RET51 isoform displays a more prominent potential as compared to the corresponding RET9 isoforms [31,34]. This is in line with our previous evidence that sporadic MTC cases with a RET somatic mutation show a more rapid growth rate with respect to not-mutated cases in which RET51 isoform is less expressed [29].…”

Section: Discussionsupporting

confidence: 88%

“…These findings indicate that the increased rate of RET transcription and its higher expression cannot be considered as causative in RET− and RAS− cases. We recently demonstrated [29] that the prevalence of RET somatic mutations is higher in MTC of a larger tumor size, suggesting that the presence of this genetic alteration can induce a higher cell proliferation rate. According to these data, RET-mutated MTC cells could have a more active metabolic condition, thus also justifying higher levels of transcription.…”

Section: Discussionmentioning

confidence: 99%

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Higher RET Gene Expression Levels Do Not Represent anAlternative RET Activation Mechanism in Medullary Thyroid Carcinoma

et al. 2021

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This study was designed to investigate whether RET (rearranged during transfection) mRNA over-expression could be considered an alternative driver event for the development of medullary thyroid carcinoma (MTC), and if different RET isoforms could play a role in MTC tumorigenesis. Eighty-three MTC patients, whose mutational profile was previously identified by next-generation sequencing (NGS) IONS5, were included in this study. Expression analysis was performed by the quantitative reverse transcription-polymerase chain reaction technique. RET expression levels were found to be significantly higher in cases with RET somatic mutations than in cases that were negative for RET somatic mutations (p = 0.003) as well as in cases with a somatic mutation, either in RET or RAS than in cases negative for both these mutations (p = 0.01). All cases were positive for the RET51 isoform expression while only 72/83 (86.7%) were positive for RET9 isoform expression. A statistically significant higher expression of the RET51 isoform was found in cases positive for RET somatic mutation than in cases either positive for RAS mutation (p = 0.0006) or negative for both mutations (p = 0.001). According to our data, RET gene over-expression does not play a role in MTC tumorigenesis, neither as an entire gene or as an isoform. At variance, the RET gene, and in particular the RET51 isoform, is expressed higher in RET mutated cases. On the basis of these results we can hypothesize that the overexpression of RET, and in particular of RET51, could potentiate the transforming activity of mutated RET, making these cases more aggressive.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Higher RET Gene Expression Levels Do Not Represent anAlternative RET Activation Mechanism in Medullary Thyroid Carcinoma

et al. 2021

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“…Another relevant result of our study has been the evidence that the AF of the driver mutation detected in the tumoral tissue DNA was significantly higher in cases where the same mutation was detected in the pre-operative ctDNA respect to those that had a negative pre-operative ctDNA. We previously demonstrated that MTC with a higher RET mutation AF are usually bigger and have a higher growth rate (24) and this may be the cause of the release in the blood of a greater number of tumoral cells and/or DNA, that are responsible of the ctDNA detection, already before surgery. When we compared the positivity of pre-operative ctDNA with serum levels of Ct and CEA, we observed that both biomarkers, but mainly CEA, levels were higher in those cases presenting a positive pre-operative ctDNA.…”

Section: Association Between Ctdna Detection and Serum Ct And Cea Levelsmentioning

confidence: 99%

Pre- and Post-operative Circulating Tumoral DNA in Patients With Medullary Thyroid Carcinoma

Ciampi

Romei

Ramone

et al. 2022

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context Measurement of driver mutations in circulating tumoral DNA (ctDNA) obtained by liquid biopsy has been shown to be a sensitive biomarker in several human tumors. Objective The aim of this study was to evaluate the clinical relevance of pre- and post-operative ctDNA in sporadic medullary thyroid cancer (sMTC). Methods We studied pre- and post-operative ctDNA in 26 and 23 sMTC patients, respectively. ctDNA results were correlated to serum calcitonin (Ct), carcino-embryonic antigen (CEA) and other clinical/pathological features. Results Twentysix/29 (89.7%) sMTC were mutated either for RET or RAS and 3/29 (10.3%) were negative. Four/26 (15.4%) cases showed a positive pre-operative ctDNA with a significantly higher presence of RET M918T mutation (P=0.0468). Patients with a positive pre-operative ctDNA showed a higher variation allele frequency value of the somatic driver mutation (P=0.0434) and they showed a higher frequency of persistent disease (P=0.0221). Post-operative ctDNA was positive only in 3/23 (13%) sMTC and no one was positive in pre-operative ctDNA. Higher values of both Ct (P=0.0307) and CEA (P=0.0013) were found in positive ctDNA cases. Finally, the 7 cases harboring either pre- or post-operative positive ctDNA, had a persistent disease (P=0.0005) showing a higher post-operative serum Ct when compared to cases with negative ctDNA (P=0.0092). Conclusions pre-operative ctDNA in MTC is not useful for diagnostic purposes, but it can be useful for predicting the outcome of the disease. In our series post-operative ctDNA showed a potential in monitoring the response to therapies but further studies are required to confirm our results.

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Clinical Evolution of Sporadic Medullary Thyroid Carcinoma With Biochemical Incomplete Response After Initial Treatment

Prete

Gambale

Torregrossa

et al. 2023

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context The clinical response after surgery is a determinant in the management of patients with medullary thyroid carcinoma (MTC). In case of excellent or structural incomplete response, the follow-up strategies are well designed. Conversely, in case of biochemical incomplete response (BiR) the management is not clearly defined. Purpose To evaluate the overall and per-site prevalence of structural disease detection in sporadic MTC patients with BiR and to assess the predictive value of various clinical, biochemical, and genetics features. Methods We evaluated data of 599 consecutive patients surgically treated for sporadic MTC (2000-2018) and followed-up at Endocrine Unit of the University Hospital of Pisa. Results After a median of 5 months from surgery, 145/599 (24.2%) patients were classified as BiR. Structural disease was detected in 64/145 (44.1%), after a median time of 3.3 years. In 73.6% structural disease was detected at a single site, prevalently cervical lymph nodes. Among several others, at the time of first evaluation after surgery, only basal calcitonin (bCTN) and stage IVa/b were independent predictive factors. Also, structural disease was more frequent in patients with shorter CTN doubling time and somatic RET mutation. Conclusions In sporadic MTC patients with BiR the risk of detection of structural disease was about 50% at 10 years. Higher bCTN levels and staging predicted the risk of detecting structural disease. According to these findings, a stricter follow-up should be reserved to MTC with BiR and elevated values of bCTN and to those with an advanced stage. Long follow-up should anyway be considered for all BiR patients since 50% of them develop structural disease within 10 years.

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RET mutated C-cells proliferate more rapidly than non-mutated neoplastic cells

Cited by 3 publications

References 29 publications

Higher RET Gene Expression Levels Do Not Represent anAlternative RET Activation Mechanism in Medullary Thyroid Carcinoma

Higher RET Gene Expression Levels Do Not Represent anAlternative RET Activation Mechanism in Medullary Thyroid Carcinoma

Pre- and Post-operative Circulating Tumoral DNA in Patients With Medullary Thyroid Carcinoma

Clinical Evolution of Sporadic Medullary Thyroid Carcinoma With Biochemical Incomplete Response After Initial Treatment

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