B Type RAF Kinase (BRAF) Mutational Status in Metastatic Differentiated Thyroid Cancer

Introduction: In thyroid cells, binding of TSH to its receptor increases cAMP levels, sustaining thyrocytes growth and hormone production. The main cAMP effector enzyme is protein kinase A (PKA). Praja2 is a widely expressed RING (Really Interesting New Gene) ligase, which degrades the regulatory subunits of PKA, thus controlling the strength and duration of PKA signaling in response to cAMP. Differentiated thyroid cancer expresses a functional TSH receptor, and its growth and progression are positively regulated by TSH and cAMP signaling. Aim: We aimed to analyze the expression of praja2 in a group of 36 papillary thyroid cancer (PTC), 14 benign nodules, and six anaplastic thyroid cancers (ATC). Methods: We measured praja2 mRNA levels by quantitative RT-PCR and praja2 expression by Western blot and immunohistochemistry. Possible association between praja2 mRNA and the presence of known mutations was evaluated. Results: We found a statistical significant increase of mRNA levels in PTC tissue samples, compared with benign nodules and ATC. In particular, mRNA levels were maximal in differentiated thyroid cancer (PTC), progressively decreasing in more aggressive tumors, ATC having the lowest amount of praja2 mRNA. Accordingly, higher levels of praja2 protein were detected in lysates from PTC, compared with ATC. By immunohistochemistry, in PTC sections we observed a marked increase of cytoplasmic praja2 signal, which significantly decreased in less differentiated thyroid tumors, completely disappearing in ATC. Studies in cultured cells stably expressing RET/PTC1 oncogene or mutant BRAF revealed a direct correlation between praja2 mRNA levels and malignant phenotype of transformed cells. Similar results were obtained using thyroid cancer tissues carrying the same mutations. Conclusions: praja2 is markedly overexpressed in differentiated thyroid cancer, and its levels inversely correlate with the malignant phenotype of the tumor. Thus, praja2 is a novel cancer-related gene whose expression is linked to the histotype and mutational status of the thyroid tumor.

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Proposal of a New Prognostic Model for Differentiated Thyroid Cancer with TERT Promoter Mutations

Cancers ◽

10.3390/cancers13122943 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2943

Author(s):

Jun Park ◽

Sungjoo Lee ◽

Jiyun Park ◽

Hyunju Park ◽

Chang-Seok Ki ◽

...

Keyword(s):

Thyroid Cancer ◽

Differentiated Thyroid Cancer ◽

Cox Regression ◽

Term Survival ◽

Poor Prognostic Factor ◽

Prognostic System ◽

Tert Promoter ◽

Mutational Status ◽

Tert Promoter Mutations ◽

Promoter Mutations

The role of telomerase reverse transcriptase (TERT) promoter mutations as an independent poor prognostic factor in differentiated thyroid cancer (DTC) patients is well known, but there is no prognostic system that combines the TERT promoter mutation status with tumor-node-metastasis (TNM) stage to predict cancer-specific survival (CSS). A total of 393 patients with pathologically confirmed DTC after thyroidectomy were enrolled. After incorporating wild-type TERT and mutant TERT with stages I, II, and III/IV of the AJCC TNM system 8th edition (TNM-8), we generated six combinations and calculated 10-year and 15-year CSS and adjusted hazard ratios (HRs) for cancer-related death using Cox regression. Then, a new mortality prediction model termed TNM-8T was derived based on the CSS and HR of each combination in the four groups. Of the 393 patients, there were 27 (6.9%) thyroid cancer-related deaths during a median follow-up of 14 years. Patients with a more advanced stage had a lower survival rate (10-year CSS for TNM-8T stage 1, 2, 3, and 4: 98.7%, 93.5%, 77.3%, and 63.0%, respectively; p < 0.001). TNM-8T showed a better spread of CSS (p < 0.001) than TNM-8 (p = 0.002) in the adjusted survival curves. The C-index for mortality risk predictability was 0.880 (95% CI, 0.665–0.957) in TNM-8T and 0.827 (95% CI, 0.622–0.930) in TNM-8 (p < 0.001). TNM-8T, a new prognostic system that incorporates the TERT mutational status into TNM-8, showed superior predictability to TNM-8 in the long-term survival of DTC patients.

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TERT promoter mutations and long-term survival in patients with thyroid cancer

Endocrine Related Cancer ◽

10.1530/erc-16-0219 ◽

2016 ◽

Vol 23 (10) ◽

pp. 813-823 ◽

Cited By ~ 38

Author(s):

Tae Hyuk Kim ◽

Young-Eun Kim ◽

Soomin Ahn ◽

Ji-Youn Kim ◽

Chang-Seok Ki ◽

...

Keyword(s):

Thyroid Cancer ◽

Survival Rate ◽

Cancer Patients ◽

Differentiated Thyroid Cancer ◽

Promoter Mutation ◽

Papillary Cancer ◽

Term Survival ◽

Extrathyroidal Invasion ◽

Mutational Status ◽

Promoter Mutations

TERT promoter mutations are emerging prognostic biomarkers in multiple cancers and are found in highly aggressive thyroid cancer. Our aim is to investigate the prognostic value of these mutations for the outcome of thyroid cancer-related mortality in a large cohort of thyroid cancer patients. This was a retrospective study of 409 patients (393 with differentiated thyroid cancer) with a median age of 44 years (range 16–81 years) and median follow-up of 13 years (interquartile range 11–16 years). Analyses of associations between mutational status and various clinicopathological variables were performed. TERT promoter mutations were identified in 32 (9.8%) papillary, 11 (16.7%) follicular and seven (43.8%) poorly differentiated/anaplastic thyroid cancer patients. The presence of TERT promoter mutations was associated with factors such as increased age (P < 0.001), extrathyroidal invasion (P = 0.01), increased stage at diagnosis (P < 0.001) and dedifferentiated histological type (P = 0.001). A TERT promoter mutation was independently associated with poorer overall survival in patients with differentiated thyroid cancer (10-year survival rate, 66.2% vs 98.3% for wild type; adjusted HR, 7.18; 95% CI: 2.77–18.59) and in patients with papillary cancer (74.2% vs 99.3%; 14.20; 3.03–66.68). Concomitant TERT and BRAF mutations worsened the survival rate of patients with papillary cancer (82.6% vs 99.4% for exclusively BRAF mutation alone; 5.62; 1.85–17.09). In conclusion, the presence of TERT promoter mutations is independently associated with increased mortality in patients with differentiated thyroid cancer. The results suggest that inclusion of TERT promoter mutation analysis with conventional clinicopathological evaluation can lead to better prognostication and management for individual patients.

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Abstract #805414: Poorly-Differentiated Thyroid Cancer in a Family With Multiple Members with a Novel Dicer1 Mutation, C.3675C > A (P.TYR1225*)

Endocrine Practice ◽

10.1016/s1530-891x(20)39625-7 ◽

2020 ◽

Vol 26 ◽

pp. 276

Author(s):

Diana Chang

Keyword(s):

Thyroid Cancer ◽

Differentiated Thyroid Cancer ◽

Poorly Differentiated

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No Reason for Hypothyroidism. Five year follow-up results after combined thyroidectomy and Radio Ablation Therapy for differentiated thyroid cancer

Zeitschrift für Gastroenterologie ◽

10.1055/s-0031-1285752 ◽

2011 ◽

Vol 49 (08) ◽

Author(s):

N Emmanouilidis ◽

WH Knapp ◽

J Klempnauer ◽

GFW Scheumann

Keyword(s):

Thyroid Cancer ◽

Differentiated Thyroid Cancer ◽

Ablation Therapy

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Radioiodide Treatment of Pulmonary Metastases of Differentiated Thyroid Cancer

Nuklearmedizin ◽

10.1055/s-0037-1620881 ◽

1979 ◽

Vol 18 (02) ◽

pp. 86-90 ◽

Cited By ~ 26

Author(s):

V. Zamrazil ◽

D. Pohunková ◽

S. Röhling ◽

J. Němec

Keyword(s):

Thyroid Cancer ◽

Bone Metastases ◽

Differentiated Thyroid Cancer ◽

Pulmonary Metastases ◽

Survival Rates ◽

Younger Patients ◽

131I Uptake ◽

Young Subjects ◽

Radioiodide Therapy ◽

Diagnosis Of Thyroid Cancer

Pulmonary metastases were found in 123 out of 840 patients with thyroid cancer between 1955-1977. 87 patients with pulmonary metastases of differentiated cancer were studied in detail, including an evaluation of prognostically important factors. In 66 of them, the induction of 131I uptake in metastases was attempted, in half of them successfully. Uptake was achieved more frequently in younger subjects, in papillary cancers and in patients with fine pulmonary metastases on chest films. Survival (not corrected for age) was evaluated 10 and 15 years following the diagnosis of thyroid cancer and was found to be 29,1 % and 12,2%, respectively. Significantly higher survival rates were seen in younger patients, in patients with the fine type of pulmonary metastases, in the absence of bone metastases and, particularly, in patients with induced 131I uptake in metastases. Papillary cancers were found to have higher survival rates in males and in young subjects only, in the whole group the survival rates were independent of either microscopic type or sex. It is believed that biologic behaviour of distant (pulmonary) metastases may be influenced by radioiodide therapy.

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Confronting the practice of surgery on differentiated thyroid cancer with current guidelines in Germany

Nuklearmedizin ◽

10.1055/s-0038-1625203 ◽

2005 ◽

Vol 44 (05) ◽

pp. 185-191 ◽

Cited By ~ 4

Author(s):

H. Wieler ◽

S. Birtel ◽

E. Ostwald-Lenz ◽

K. P. Kaiser ◽

H. P. Becker ◽

...

Keyword(s):

Thyroid Cancer ◽

Differentiated Thyroid Cancer ◽

Survival Rates ◽

Perioperative Morbidity ◽

Referral Hospitals ◽

Principles Of Treatment ◽

Current Guidelines ◽

Papillary Microcarcinomas ◽

Retrospective Multicenter Study

Summary:Aim: For the surgical therapy of differentiated thyroid cancer precise guidelines are applied by the German medical societies. In a retrospective multicenter study, we investigated the following issues: Are the current guidelines respected?. Is there a difference concerning the surgical radicalism and the outcome?. Does the perioperative morbidity increase with the higher radicalism of the procedure?. Patients, methods: Data gained from 102 patients from 17 regional referral hospitals who underwent surgery for thyroid cancer and a following radioiodine treatment (mean follow up: 42.7 [24-79] months) were analyzed. At least 71 criterias were analyzed in a SPSS file. Results: 46.1% of carcinomas were incidentally detected during goiter surgery. The thyroid cancer (papillary n = 78; follicular n = 24) occurred in 87% unilateral and in 13% bilateral. Papillary carcinomas <1 cm were detected in 25 cases; in five of these cases (20%) contralateral carcinomas <1 cm were found. There were significant differences concerning the surgical radicalism: a range from hemithyroidectomy to radical thyroidectomy with lateral neck dissection. Analysis of the histopathologic reports revealed that lymph node dissection was not performed according to guidelines in 55% of all patients. The perioperative morbidity was lower in departments with a high case load. The postoperative dysfunction of the recurrent laryngeal nerve (mean: 7.9% total / 4.9% nerves at risk) variated highly, depending on differences in radicalism and hospitals. Up to now these variations in surgical treatment have shown no differences in their outcome and survival rates, when followed by radioiodine therapy. Conclusion: Current surgical regimes did not follow the guidelines in more than 50% of all cases. This low acceptance has to be discussed. The actual discussion about principles of treatment regarding, the socalled papillary microcarcinomas (old term) has to be respected within the current guidelines.

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Relationship between Thyroglobulin and Tumor Detectabilily with Thallium-201 in Differentiated Thyroid Cancer

Nuklearmedizin ◽

10.1055/s-0038-1632238 ◽

2000 ◽

Vol 39 (01) ◽

pp. 10-15 ◽

Cited By ~ 1

Author(s):

S. P. Müller ◽

Ch. Reiners ◽

A. Bockisch ◽

Katja Brandt-Mainz

Keyword(s):

Thyroid Cancer ◽

Differentiated Thyroid Cancer ◽

Roc Analysis ◽

Tsh Suppression ◽

Significant Difference ◽

Test Specificity ◽

The Relationship ◽

Tumor Scintigraphy ◽

Tsh Stimulation

Summary Aim: Tumor scintigraphy with 201-TICI is an established diagnostic method in the follow-up of differentiated thyroid cancer. We investigated the relationship between thyroglobulin (Tg) level and tumor detectability. Subject and methods: We analyzed the scans of 122 patients (66 patients with proven tumor). The patient population was divided into groups with Tg above (N = 33) and below (N = 33) 5 ng/ml under TSH suppression or above (N = 33) and below (N = 33) 50 ng/ml under TSH stimulation. Tumor detectability was compared by ROC-analysis (True-Positive-Fraction test, specificity 90%). Results: There was no significant difference (sensitivity 75% versus 64%; p = 0.55) for patients above and below 5 ng/ml under TSH suppression and a just significant difference (sensitivity 80% versus 58%; p = 0.04) for patients above and below 50 ng/ml under TSH stimulation. In 18 patients from our sample with tumor, Tg under TSH suppression was negative, but 201-TICI-scan was able to detect tumor in 12 patients. Conclusion: Our results demonstrate only a moderate dependence of tumor detectability on Tg level, probably without significant clinical relevance. Even in patients with slight Tg elevation 201-TICI scintigraphy is justified.

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