Prognostic Significance of Circulating RET M918T Mutated Tumor DNA in Patients With Advanced Medullary Thyroid Carcinoma

Cote, Gilbert J.; Evers, Caitlin; Hu, Mimi I.; Grubbs, Elizabeth G.; Williams, Michelle D.; Hai, Tao; Duose, Dzifa Y.; Houston, Michal R.; Bui, Jacquelin H.; Mehrotra, Meenakshi; Waguespack, Steven G.; Busaidy, Naifa L.; Cabanillas, Maria E.; Habra, Mouhammed Amir; Luthra, Rajyalakshmi; Sherman, Steven I.

doi:10.1210/jc.2017-01039

Cited by 62 publications

(57 citation statements)

References 37 publications

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“…So far, only a few studies investigated the role of ctDNA in thyroid cancer. Cote et al 59 measured the ctDNA for RET M918T mutation in patients with medullary thyroid carcinoma (MTC) through droplet digital PCR and found the detection of RET M918T ctDNA strongly correlated with worse overall survival and more accurately predicted a worse outcome than calcitonin doubling time. Sandulache et al 60 tested anaplastic thyroid carcinoma (ATC) and found that the concordance between the tumor and cfDNA was high for BRAF , PIK3CA , NRAS and PTEN , and moderate for TP53 .…”

Section: Discussionmentioning

confidence: 99%

Genomic landscape of metastatic papillary thyroid carcinoma and novel biomarkers for predicting distant metastasis

Lan

Bao²,

et al. 2020

Cancer Science

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Papillary thyroid carcinoma (PTC) is the most common malignancy of the thyroid gland, with a relatively high cure rate. Distant metastasis (DM) of PTC is uncommon, but when it occurs, it significantly decreases the survival of PTC patients. The molecular mechanisms of DM in PTC have not been systematically studied. We performed whole exome sequencing and GeneseeqPrime (425 genes) panel sequencing of the primary tumor, plasma and matched white blood cell samples from 20 PTC with DM and 46 PTC without DM. We identified somatic mutations, gene fusions and copy number alterations and analyzed their relationships with DM of PTC. BRAF‐V600E was identified in 73% of PTC, followed by RET fusions (14%) in a mutually exclusive manner (P < 0.0001). We found that gene fusions (RET, ALK or NTRK1) (P < 0.01) and chromosome 22q loss (P < 0.01) were independently associated with DM in both univariate and multivariate analyses. A nomogram model consisting of chromosome 22q loss, gene fusions and three clinical variables was built for predicting DM in PTC (C‐index = 0.89). The plasma circulating tumor DNA (ctDNA) detection rate in PTC was only 38.9%; however, it was significantly associated with the metastatic status (P = 0.04), tumor size (P = 0.001) and invasiveness (P = 0.01). In conclusion, gene fusions and chromosome 22q loss were independently associated with DM in PTC and could serve as molecular biomarkers for predicting DM. The ctDNA detection rate was low in non–DM PTC but significantly higher in PTC with DM.

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Section: Discussionmentioning

confidence: 99%

Genomic landscape of metastatic papillary thyroid carcinoma and novel biomarkers for predicting distant metastasis

Lan

Bao²,

et al. 2020

Cancer Science

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“…10 Given Furthermore, its use in a patient with advanced sMTC with a confirmed somatic RET M918T mutation resulted in tumour regression, a drop in serum calcitonin and symptom improvement. 10 Given Furthermore, its use in a patient with advanced sMTC with a confirmed somatic RET M918T mutation resulted in tumour regression, a drop in serum calcitonin and symptom improvement.…”

Section: Somatic Ret Mutationsmentioning

confidence: 95%

“…32 The M918T-mutated tumour DNA can also be identified in peripheral blood, and there is some evidence that circulating M918T-mutated DNA portends a worse overall survival and more accurately predicts outcome than calcitonin doubling time. 10 Given the established role of RET in hMTC and that almost half of sMTCs harbour somatic RET mutations, most efforts at novel drug development have focussed on inhibiting RET and RET-related pathways ( Figure 2). This has resulted in the licensing of tyrosine kinase inhibitors (TKI) with specificity for RET, vandetanib and cabozantinib.…”

Section: Somatic Ret Mutationsmentioning

confidence: 99%

The role of molecular genetics in the clinical management of sporadic medullary thyroid carcinoma: A systematic review

Fussey

Vaidya

Kim

et al. 2019

Clinical Endocrinology

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Medullary thyroid carcinoma (MTC) is a malignant tumour of the neural crest-derived parafollicular C cells. Due to the recent increase in incidence of papillary thyroid carcinoma, MTC now comprises only 1%-2% of all thyroid cancers, 1 but accounts for a significant proportion of thyroid cancer morbidity and mortality. The rate of regional and distant metastasis at presentation is up to 35% and 13%, respectively, 2 and there has been no trend towards earlier stage at diagnosis or improved overall survival in recent decades. 3 Abstract Background: The significant variation in the clinical behaviour of sporadic medullary thyroid carcinoma (sMTC) causes uncertainty when planning the management of these patients. Several tumour genetic and epigenetic markers have been described, but their clinical usefulness remains unclear. The aim of this review was to evaluate the evidence for the use of molecular genetic and epigenetic profiles in the risk stratification and management of sMTC.Methods: MEDLINE and Embase databases were searched using the MeSH terms "medullary carcinoma", "epigenetics", "molecular genetics", "microRNAs"; and free text terms "medullary carcinoma", "sporadic medullary thyroid cancer", "sMTC", "RET", "RAS" and "miR". Articles containing less than ten subjects, not focussing on sMTC, or not reporting clinical outcomes were excluded. Risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale. Results:Twenty-three studies met the inclusion criteria, and key findings were summarized in themes according to the genetic and epigenetic markers studied. There is good evidence that somatic RET mutations predict higher rates of lymph node metastasis and persistent disease, and worse survival. There are also several good quality studies demonstrating associations between certain epigenetic markers such as tumour miR-183 and miR-375 expression and higher rates of lymph node and distant metastasis, and worse survival. Conclusions:There is a growing body of evidence that tumour genetic and epigenetic profiles can be used to risk stratify patients with sMTC. Further research should focus on the clinical applicability of these findings by investigating the possibility of tailoring management to an individual's tumour mutation profile.

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“…A rapid method for DNA extraction from FNB for RET mutation analysis by PCR with the intention of targeted therapy was developed in 1998 (291). Furthermore, in the recent study by Cote et al (292) the presence of somatic RET mutation in plasma was evaluated in 50 patients with RET p.M918T mutations detected in tumor tissue. In 16 of these patients the somatic RET mutation was detected in circulating cell-free DNA in plasma and by a blood test.…”

Section: Molecular Biology In Mtcmentioning

confidence: 99%

A Nationwide Study of Multiple Endocrine Neoplasia Type 2A in Norway: Predictive and Prognostic Factors for the Clinical Course of Medullary Thyroid Carcinoma

Opsahl

Brauckhoff

Schlichting

et al. 2016

Thyroid

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Prognostic Significance of Circulating RET M918T Mutated Tumor DNA in Patients With Advanced Medullary Thyroid Carcinoma

Cited by 62 publications

References 37 publications

Genomic landscape of metastatic papillary thyroid carcinoma and novel biomarkers for predicting distant metastasis

Genomic landscape of metastatic papillary thyroid carcinoma and novel biomarkers for predicting distant metastasis

The role of molecular genetics in the clinical management of sporadic medullary thyroid carcinoma: A systematic review

A Nationwide Study of Multiple Endocrine Neoplasia Type 2A in Norway: Predictive and Prognostic Factors for the Clinical Course of Medullary Thyroid Carcinoma

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