Hyperfunctioning Papillary Thyroid Carcinoma with a BRAF Mutation: The First Case Report and a Literature Review

Introduction: Hyperfunctioning papillary thyroid carcinoma (PTC) is rare and consequently, little information on its molecular etiology is available. Although BRAF V600E (BRAF c.1799T>A, p.V600E) is a prominent oncogene in PTC, its mutation has not yet been reported in hyperfunctioning PTC. Case Presentation: Ultrasonography detected a 26-mm nodule in the right lobe of the thyroid gland of a 48-year-old man. Thyroid function tests indicated that he was hyperthyroid with a TSH level of 0.01 mIU/L (reference range: 0.05–5.00) and a free thyroxine level of 23.2 pmol/L (reference range: 11.6–21.9). TSHR autoantibodies were <0.8 IU/L (reference value: <2.0 IU/L). The 99mTc thyroid scintigram revealed a round, right-sided focus of tracer uptake by the nodule with a decreased uptake in the remainder of the gland. The patient underwent total thyroidectomy because fine-needle aspiration cytology revealed a malignancy. The histopathological diagnosis was conventional PTC. Subsequent mutational analysis of BRAF (exon 15), TSHR (exons 1–10), GNAS (exons 7–10), EZH1 (exon 16), KRAS, NRAS, HRAS (codons 12, 13, and 61), and TERT promoter (C250T and C228T) identified a heterozygous point mutation in BRAF V600E in a tumor tissue sample. In addition, we identified a TSHR D727E polymorphism (TSHR c.2181C>G, p.D727E) in both the tumor and the surrounding normal thyroid tissue. Discussion and Conclusions: We report a case of hyperfunctioning PTC with a BRAF V600E mutation for the first time. Our literature search yielded 16 cases of hyperfunctioning thyroid carcinoma in which a mutational analysis was conducted. We identified TSHR mutations in 13 of these cases. One case revealed a combination of TSHR and KRAS mutations; the other case revealed a TSHR mutation with a PAX8/PPARG rearrangement. These findings suggest that the concomitant activation of oncogenes (in addition to constitutive activation of the TSHR-cyclic AMP cascade) are associated with the malignant phenotype in hyperfunctioning thyroid nodules.

Download Full-text

SUN-LB78 Hyperfunctioning Papillary Thyroid Carcinoma With a BRAF Mutation

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.2109 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Shinsuke Shinkai ◽

Kenji Ohba ◽

Akio Matsushita ◽

Go Kuroda ◽

Yuki Sakai ◽

...

Keyword(s):

Papillary Thyroid Carcinoma ◽

Thyroid Carcinoma ◽

Braf Mutation ◽

Reference Range ◽

Mutational Analysis ◽

Color Doppler ◽

Driver Mutations ◽

Histopathological Diagnosis ◽

Thyroid Function Tests ◽

Papillary Thyroid

Abstract Background: Hyperfunctioning papillary thyroid carcinoma (PTC) is a rare tumor and accounts for less than 0.1% of all thyroid tumors. Information about its driver mutations is limited. Our literature search yielded 16 cases wherein a mutational analysis was conducted. Thyrotropin receptor (TSHR) mutations were identified in 11 of these cases. One case revealed a combination of TSHR and KRAS mutations. No mutations were identified in the other four cases. BRAFV600E is a prominent oncogene in PTC; however, hyperfunctioning PTC with this mutation has not yet been reported. Clinical Case: In a 48-year-old man, ultrasonography (US) during an annual medical checkup revealed a nodule at the right lobe of the thyroid gland. He visited the outpatient clinic for further evaluation. Thyroid function tests indicated that he was hyperthyroid with TSH level of 0.01 mIU/L (reference range: 0.05-5.00), free thyroxine level of 1.8 ng/dL (reference range: 0.9-1.7), and free triiodothyronine level of 4.3 pg/mL (reference range: 2.3-4.0). Serum thyroglobulin was 62.1 ng/mL (reference range: <33.7) and TSHR autoantibodies (TRAb) was <0.8 IU/L (reference range: <2.0 IU/L). B-mode US revealed a hypoechoic, heterogeneous nodule with largest diameter of 25 mm, and it had a jagged border and microcalcification. Color Doppler US revealed increased intranodular vascularity. The 99mTc thyroid scintigram revealed a round, right-sided focus of tracer uptake by the nodule with suppression in the remainder of the gland. These findings were consistent with an autonomously-functioning thyroid nodule. The patient underwent total thyroidectomy because fine-needle aspiration cytology revealed a malignant cytological diagnosis. The histopathological diagnosis of the patient was PTC, tall cell variant, pT2, pEx0, pN1b, and M0. Subsequent mutational analysis of BRAF (exon 15), TSHR (exons 9 and 10), GNAS (exons 7-10), KRAS, NRAS, HRAS (codons 12, 13, and 61), and TERT promoter (C250T and C228T) only identified a heterozygous point mutation in BRAFV600E in tissue samples. Conclusion: We report for the first time a case of hyperfunctioning papillary thyroid carcinoma with a BRAF mutation.

Download Full-text

Preoperative RAS Mutational Analysis Is of Great Value in Predicting Follicular Variant of Papillary Thyroid Carcinoma

BioMed Research International ◽

10.1155/2015/697068 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 12

Author(s):

Tae Sook Hwang ◽

Wook Youn Kim ◽

Hye Seung Han ◽

So Dug Lim ◽

Wan-Seop Kim ◽

...

Keyword(s):

Papillary Thyroid Carcinoma ◽

Thyroid Carcinoma ◽

Thyroid Nodules ◽

Mutational Analysis ◽

Braf V600e ◽

Papillary Thyroid ◽

Follicular Variant ◽

Ras Mutation ◽

Ras Mutations ◽

Codon 61

Follicular variant of papillary thyroid carcinoma (FVPTC), particularly the encapsulated subtype, often causes a diagnostic dilemma. We reconfirmed the molecular profiles in a large number of FVPTCs and investigated the efficacy of the preoperative mutational analysis in indeterminate thyroid nodules. BRAF V600E/K601E and RAS mutational analysis was performed on 187 FVPTCs. Of these, 132 (70.6%) had a point mutation in one of the BRAF V600E (n=57), BRAF K601E (n=11), or RAS (n=64) genes. All mutations were mutually exclusive. The most common RAS mutations were at NRAS codon 61. FNA aspirates from 564 indeterminate nodules were prospectively tested for BRAF and RAS mutation and the surgical outcome was correlated with the mutational status. Fifty-seven and 47 cases were positive for BRAF and RAS mutation, respectively. Twenty-seven RAS-positive patients underwent surgery and all except one patient had FVPTC. The PPV and accuracy of RAS mutational analysis for predicting FVPTC were 96% and 84%, respectively. BRAF or RAS mutations were present in more than two-thirds of FVPTCs and these were mutually exclusive. BRAF mutational analysis followed by N, H, and KRAS codon 61 mutational analysis in indeterminate thyroid nodules would streamline the management of patients with malignancies, mostly FVPTC.

Download Full-text

Seven-year follow-up of a juvenile female with papillary thyroid carcinoma with poor outcome, BRAF mutation and loss of expression of iodine-metabolizing genes

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302008000800017 ◽

2008 ◽

Vol 52 (8) ◽

pp. 1313-1316 ◽

Cited By ~ 3

Author(s):

Gisele Oler ◽

Claudia D. Nakabashi ◽

Rosa Paula M. Biscolla ◽

Janete M. Cerutti

Keyword(s):

Papillary Thyroid Carcinoma ◽

Thyroid Carcinoma ◽

Braf Mutation ◽

Thyroid Tissue ◽

Braf V600e Mutation ◽

Braf V600e ◽

Papillary Thyroid ◽

Genetic Event ◽

Mutational Status

BACKGROUND: Recent studies reported that BRAF V600E mutation, the most prevalent genetic event found in papillary thyroid carcinoma, is an independent poor prognostic marker. Additionally, it correlates with a less differentiated tumor stage due to reduced expression of key genes involved in iodine metabolism. We previously described a patient with BRAF V600E mutation in primary tumor and a new mutation (V600E+K601del) in the matched-lymph node metastases. In the present study we report an unusual clinical behavior of PTC and correlate with BRAF mutational status and level of expression of TSHR and NIS. METHODS: Quantitative PCR (qPCR) was used to evaluate the NIS and TSHR level of expression in matched papillary thyroid carcinoma and adjacent normal tissue. RESULTS: In this study, we presented a seven-year follow up of a juvenile papillary thyroid carcinoma patient who had an aggressive tumor harboring BRAF mutation, and failed to conventional therapy. We found a markedly decrease of NIS and TSHR expression in primary PTC compared to adjacent normal thyroid tissue. CONCLUSION: Our findings suggest that BRAF mutational status and decreased NIS and TSHR expression in this patient may reduce radioiodine uptake and lead to a negative response to radioiodine therapy.

Download Full-text

Mixed histiocytosis with BRAF (V600E) mutation and papillary thyroid carcinoma

Endocrine Abstracts ◽

10.1530/endoabs.63.ep150 ◽

2019 ◽

Author(s):

Francoise Archambeaud ◽

Pauline Vital ◽

Gilles Russ ◽

Isabelle Pommepuy ◽

Julien Haroche ◽

...

Keyword(s):

Papillary Thyroid Carcinoma ◽

Thyroid Carcinoma ◽

Braf V600e Mutation ◽

Braf V600e ◽

Papillary Thyroid

Download Full-text

Faculty Opinions recommendation of BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1120437.576634 ◽

2008 ◽

Author(s):

Sissy Jhiang ◽

Krystian Jazdzewski

Keyword(s):

Papillary Thyroid Carcinoma ◽

Thyroid Carcinoma ◽

Braf V600e Mutation ◽

Braf V600e ◽

Papillary Thyroid ◽

Follow Up Study

Download Full-text

BRAFV600E MUTATION IN PAPILLARY THYROID CARCINOMA. CLINICAL AND METHODOLOGICAL ASPECTS

Problems in oncology ◽

10.37469/0507-3758-2019-65-1-16-26 ◽

2019 ◽

Vol 65 (1) ◽

pp. 16-26

Author(s):

Pavel Rumyantsev ◽

Petr Nikiforovich ◽

Andrey Poloznikov ◽

Andrey Abrosimov ◽

Vladimir Saenko ◽

...

Keyword(s):

Papillary Thyroid Carcinoma ◽

Thyroid Carcinoma ◽

Kinase Inhibitors ◽

Anaplastic Carcinoma ◽

Braf V600e ◽

Papillary Thyroid ◽

Brafv600e Mutation ◽

Wide Range ◽

Methodological Aspects

Mutation BRAFV600E is highly specific for papillary thyroid carcinoma. It’s detected in 40-70% of all papillary thyroid carcinoma cases. Moreover this mutation is noticed in anaplastic carcinoma in 40-50%.This fact gives a chance to select patients and provide targeted therapy with multi-kinase inhibitors in cases of unresectable anaplastic carcinoma. The influence of BRAF V600E mutation for response to radioactive iodine therapy requires more evidence-based research. Existing methods for determining the BRAFV600E mutation have different accuracy, availability and cost. Other methodological aspects are also associated with the sample preparation of biological material, the quality of reagents, and the cross-validation of research results. In this review, on the basis of our own experience and literature data, the indications for determining the mutation of the BRAFV600E gene in clinical practice are refined, and a comprehensive comparative analysis of modern research methods has been conducted. This review is focused on a wide range of specialists of different types: oncologists, endocrinologists, radiologists, pathologists, and biologists.

Download Full-text

Identification of Differentially Expressed Genes Associated with Papillary Thyroid Carcinoma

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207323666200402085832 ◽

2020 ◽

Vol 23 (6) ◽

pp. 546-553

Author(s):

Hongyuan Cui ◽

Mingwei Zhu ◽

Junhua Zhang ◽

Wenqin Li ◽

Lihui Zou ◽

...

Keyword(s):

Papillary Thyroid Carcinoma ◽

Thyroid Carcinoma ◽

Differentially Expressed Genes ◽

Molecular Mechanisms ◽

Cellular Proliferation ◽

Mrna Level ◽

Thyroid Tissue ◽

Differentially Expressed ◽

Thyroid Tumors ◽

Papillary Thyroid

Objective: Next-generation sequencing (NGS) was performed to identify genes that were differentially expressed between normal thyroid tissue and papillary thyroid carcinoma (PTC). Materials & Methods: Six candidate genes were selected and further confirmed with quantitative real-time polymerase chain reaction (qRT-PCR), and immunohistochemistry in samples from 24 fresh thyroid tumors and adjacent normal tissues. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was used to investigate signal transduction pathways of the differentially expressed genes. Results: In total, 1690 genes were differentially expressed between samples from patients with PTC and the adjacent normal tissue. Among these, SFRP4, ZNF90, and DCN were the top three upregulated genes, whereas KIRREL3, TRIM36, and GABBR2 were downregulated with the smallest p values. Several pathways were associated with the differentially expressed genes and involved in cellular proliferation, cell migration, and endocrine system tumor progression, which may contribute to the pathogenesis of PTC. Upregulation of SFRP4, ZNF90, and DCN at the mRNA level was further validated with RT-PCR, and DCN expression was further confirmed with immunostaining of PTC samples. Conclusion: These results provide new insights into the molecular mechanisms of PTC. Identification of differentially expressed genes should not only improve the tumor signature for thyroid tumors as a diagnostic biomarker but also reveal potential targets for thyroid tumor treatment.

Download Full-text

Analysis of the Role of FRMD5 in the Biology of Papillary Thyroid Carcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms22136726 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6726

Author(s):

Agata M. Gaweł ◽

Maciej Ratajczak ◽

Ewa Gajda ◽

Małgorzata Grzanka ◽

Agnieszka Paziewska ◽

...

Keyword(s):

Papillary Thyroid Carcinoma ◽

Thyroid Carcinoma ◽

Endocrine System ◽

Metastatic Potential ◽

Multidrug Resistant ◽

Thyroid Tumor ◽

Braf V600e ◽

Papillary Thyroid ◽

Spheroid Formation

Background: Thyroid carcinoma (TC) is the most common endocrine system malignancy, and papillary thyroid carcinoma (PTC) accounts for >80% of all TC cases. Nevertheless, PTC pathogenesis is still not fully understood. The aim of the study was to elucidate the role of the FRMD5 protein in the regulation of biological pathways associated with the development of PTC. We imply that the presence of certain genetic aberrations (e.g., BRAF V600E mutation) is associated with the activity of FRMD5. Methods: The studies were conducted on TPC1 and BCPAP (BRAF V600E) model PTC-derived cells. Transfection with siRNA was used to deplete the expression of FRMD5. The mRNA expression and protein yield were evaluated using RT-qPCR and Western blot techniques. Proliferation, migration, invasiveness, adhesion, spheroid formation, and survival tests were performed. RNA sequencing and phospho-kinase proteome profiling were used to assess signaling pathways associated with the FRMD5 expressional status. Results: The obtained data indicate that the expression of FRMD5 is significantly enhanced in BRAF V600E tumor specimens and cells. It was observed that a drop in intracellular yield of FRMD5 results in significant alternations in the migration, invasiveness, adhesion, and spheroid formation potential of PTC-derived cells. Importantly, significant divergences in the effect of FRMD5 depletion in both BRAF-wt and BRAF-mutated PTC cells were observed. It was also found that knockdown of FRMD5 significantly alters the expression of multidrug resistant genes. Conclusions: This is the first report highlighting the importance of the FRMD5 protein in the biology of PTCs. The results suggest that the FRMD5 protein can play an important role in controlling the metastatic potential and multidrug resistance of thyroid tumor cells.

Download Full-text