scholarly journals Exomic Sequencing of Medullary Thyroid Cancer Reveals Dominant and Mutually Exclusive Oncogenic Mutations in RET and RAS

2013 ◽  
Vol 98 (2) ◽  
pp. E364-E369 ◽  
Author(s):  
Nishant Agrawal ◽  
Yuchen Jiao ◽  
Mark Sausen ◽  
Rebecca Leary ◽  
Chetan Bettegowda ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Somatic Mutations ◽  
Medullary Thyroid Cancer ◽  
Driver Mutations ◽  
High Confidence ◽  
Kras Mutations ◽  
Protein Coding ◽  
Medullary Thyroid ◽  
Oncogenic Mutations ◽  
Independent Cohort

Abstract Context: Medullary thyroid cancer (MTC) is a rare thyroid cancer that can occur sporadically or as part of a hereditary syndrome. Objective: To explore the genetic origin of MTC, we sequenced the protein coding exons of approximately 21,000 genes in 17 sporadic MTCs. Patients and Design: We sequenced the exomes of 17 sporadic MTCs and validated the frequency of all recurrently mutated genes and other genes of interest in an independent cohort of 40 MTCs comprised of both sporadic and hereditary MTC. Results: We discovered 305 high-confidence mutations in the 17 sporadic MTCs in the discovery phase, or approximately 17.9 somatic mutations per tumor. Mutations in RET, HRAS, and KRAS genes were identified as the principal driver mutations in MTC. All of the other additional somatic mutations, including mutations in spliceosome and DNA repair pathways, were not recurrent in additional tumors. Tumors without RET, HRAS, or KRAS mutations appeared to have significantly fewer mutations overall in protein coding exons. Conclusions: Approximately 90% of MTCs had mutually exclusive mutations in RET, HRAS, and KRAS, suggesting that RET and RAS are the predominant driver pathways in MTC. Relatively few mutations overall and no commonly recurrent driver mutations other than RET, HRAS, and KRAS were seen in the MTC exome.

RAS-mutated sporadic medullary thyroid cancer: A single-center experience.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6584-6584
Author(s):  
Spandana Brown ◽  
Stephen K. Gruschkus ◽  
Steven G. Waguespack ◽  
Ramona Dadu ◽  
Mark Zafereo ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Systemic Therapy ◽  
Medullary Thyroid Cancer ◽  
Stage Iv ◽  
Cancer Center ◽  
Kras Mutations ◽  
Medullary Thyroid ◽  
Ras Mutations ◽  
Stage Iv Disease ◽  
Tertiary Cancer Center

6584 Background: Activating RAS mutations are recognized as important drivers in sporadic medullary thyroid cancer (sMTC), with a reported prevalence between 0-43%. However, few studies have looked at correlations between RAS-mutated sMTC and clinicopathologic features. Methods: Patients with sMTC diagnosed between 1992 – 2019 with NGS testing for RET and RAS mutations seen at a tertiary cancer center were retrospectively evaluated. The objective was to analyze demographic and clinical features among patients with RAS-mutated sMTC and to evaluate associations between these features and overall survival (OS). Analyses were performed to correlate patient demographics and pathologic staging with treatment characteristics, disease course, and OS. Results: We identified 42 patients (50% female) with RAS-mutated sMTC out of 218 pts with sMTC. Median age at diagnosis was 50 years (range 24-78 years). 26 (62%) patients had stage IV disease at time of diagnosis. 28 (67%) of patients had HRAS mutations and 14 (33%) had KRAS mutations. HRAS Q61R was the most common HRAS mutation type (n = 19, 45%). Median follow-up time was 64 months (range 23-274 months) during which 11 (26%) patients died. The median OS was 16.2 years, with 5- and 10- year OS of 88% and 73% respectively. Of the 20 (48%) patients who received systemic therapy, 79% had stage IV disease and tended to be older (median age 54). Median time from diagnosis to initiation of systemic therapy was 33 months. Factors associated with worse OS included distant metastases at diagnosis, shorter time interval between diagnosis and treatment, and Ctn/CEA doubling times < 6 months. HRAS Q61R mutations were associated with a better prognosis, with 100% 10-year OS compared with 10-year OS of 39% and 51% (p = 0.02) for other HRAS and KRAS mutations respectively. Conclusions: At a tertiary cancer center, patients with RAS-mutated sMTC had a 10-year OS rate of 73%, with significantly worse OS in patients with HRAS/KRAS mutations other than HRAS Q61R. In comparison, prior studies have reported 10-year OS rates between ~71-90% in sMTC and 10-year OS rates as low as 56% for more aggressive RET M918T sMTC mutations. The findings here are consistent with other studies that have suggested patients with RAS-mutated sMTC are at intermediate risk for aggressive disease, though there are limited data on OS rates in RAS or RAS-/RET- sMTC. Future research comparing outcomes between various RAS mutations and in comparison to RET+ and RAS-/RET- patients is needed, especially as systemic therapy use in RAS-mutated sMTC evolves.

RET Somatic Mutations Are Not an Early Event in the Tumoral Transformation of Sporadic Medullary Thyroid Cancer

2011 ◽  
pp. P1-716-P1-716
Author(s):  
Cristina Romei ◽  
Barbara Cosci ◽  
Clara Ugolini ◽  
Valeria Bottici ◽  
Eleonora Molinaro ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Somatic Mutations ◽  
Medullary Thyroid Cancer ◽  
Early Event ◽  
Medullary Thyroid

scholarly journals IGF2 is a Potential Factor in RAI-refractory Non-medullary Thyroid Cancer

2020 ◽  
Author(s):  
Thomas Crezee ◽  
Marika H. Tesselaar ◽  
Martin Jaeger ◽  
Katrin Rabold ◽  
Willem E. Corver ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Growth Factor ◽  
Molecular Mechanisms ◽  
Medullary Thyroid Cancer ◽  
Residual Disease ◽  
Plasma Concentrations ◽  
Predictive Biomarkers ◽  
Primary Tumors ◽  
Medullary Thyroid ◽  
Independent Cohort

Abstract Background: Non-medullary thyroid cancer (NMTC) is the most frequent endocrine tumor with in most cases a good prognosis after thyroidectomy and 131I radioactive iodide (RAI) ablation. In contrast, 30-40% of patients with metastatic NMTC are unresponsive to 131I RAI treatment as a result of tumor dedifferentiation. Currently, underlying molecular mechanisms of NMTC dedifferentiation still remain elusive and predictive biomarkers are lacking. In the present study we therefore aim to identify molecular biomarkers in primary tumors that are associated with RAI refractoriness. Methods: A retrospective cohort of 63 NMTC patients, including all histological subtypes, was gathered for this study and consisted of RAI-sensitive differentiated NMTC patients (N=35) and RAI-refractory (poorly) differentiated NMTC patients (N=28). RAI sensitivity was defined as the response to RAI of residual disease after primary surgery (persistence and/or progression versus regression). Total DNA and RNA were extracted from archived formalin-fixed paraffin embedded (FFPE) tumor tissues. Extensive intratumoral mutation profiling, gene fusions analysis, TERT promoter mutation analysis and FFPE-compatible RNA sequencing were performed in all patients. In eight NMTC patients, available from an independent cohort, total circulating IGF2 concentrations were determined using ELISA before and after undergoing primary treatment.Results: RAI-refractory NMTC patients were diagnosed at an older age and displayed less favorable TNM staging as compared to RAI-sensitive NMTC patients. Genetic analyses revealed an increased mutational load in RAI-refractory NMTC, including mutations in AKT1, PTEN, TP53 and TERT promoter. Transcriptomic analyses revealed profound differential expression of insulin-like growth factor 2 (IGF2) with up to 100-fold higher expression in RAI-refractory NMTC as compared to RAI-sensitive NMTC cases. By ELISA we found significant lower IGF2 plasma concentrations after surgery and subsequent 131I RAI therapy in patients with NMTC compared to pretreatment baseline. Conclusions: Important clinical, genetic and transcriptomic differences between patients with RAI-sensitive NMTC and RAI-refractory NMTC were identified. Most notably an increased expression of IGF2 in RAI-refractory tumors. Plasma levels of IGF2 decreased post-therapy in NMTC patients from an independent cohort. These findings suggest that the tumor-promoting growth factor IGF2 has a potential role in acquiring RAI refractoriness.

Abstract #1101 The Value of Calcitonin Calcium Stimulation Test Levels as Predictors of Medullary Thyroid Cancer.

2018 ◽  
Vol 24 ◽  
pp. 273-274
Author(s):  
Corin Badiu ◽  
Mara Baet ◽  
Ruxandra Dobrescu ◽  
Andra Caragheorgheopol ◽  
Corneci Cristina
Keyword(s):  
Thyroid Cancer ◽  
Medullary Thyroid Cancer ◽  
Stimulation Test ◽  
Medullary Thyroid ◽  
Calcium Stimulation

Immunoscintigraphy in Medullary Thyroid Cancer Using an 123I- or 111ln-Labelled Monoclonal Anti-CEA Antibody Fragment

1986 ◽  
Vol 25 (06) ◽  
pp. 227-231 ◽  
Author(s):  
Chr. Eilles ◽  
W. Spiegel ◽  
W. Becker ◽  
W. Börner ◽  
Chr. Reiners
Keyword(s):  
Bone Marrow ◽  
Thyroid Cancer ◽  
Potassium Iodide ◽  
Medullary Thyroid Cancer ◽  
Elevated Serum ◽  
Antibody Fragment ◽  
Special Importance ◽  
Medullary Thyroid ◽  
Medullary Cancer ◽  
Serum Cea

The monoclonal anti-CEA F(ab’)2 fragment MAb BW 431/31, labelled with 123I or111 In, was used for immunoscintigraphy (IS) in 9 patients with medullary cancer of the thyroid (CCC). The results of 11 studies lead to the following conclusions: 1) When using radioiodine as a label for MAb in IS, potassium iodide is absolutely necessary to block the thyroid which is of special importance in patients with thyroid cancer; 2) Preinjection of “cold” MAb reduces the relatively high unspecific uptake (especially in bone marrow) of MAb BW 431/31, which is of special importance for the antibody labelled with 111 In; 3) IS with MAb BW 413/31 in patients with CCC and elevated serum CEA is positive only in cases with large secondaries; and 4) In patients with CCC and several manifestations of secondaries, only a single (large) metastasis may be apparent.

NTRK3 receptor expression is strictly associated with medullary thyroid cancer RET mutation status

2014 ◽  
Author(s):  
Malgorzata Oczko-Wojciechowska ◽  
Michal Swierniak ◽  
Malgorzata Kowalska ◽  
Agnieszka Pawlaczek ◽  
Monika Kowal ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Medullary Thyroid Cancer ◽  
Receptor Expression ◽  
Mutation Status ◽  
Medullary Thyroid ◽  
Ret Mutation
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