Study of BRAF and RAS Mutations in Thyroid Nodules with Indeterminate Cytology and Papillary Thyroid Cancer

OBJECTIVES Thyroid cancer Treatment decision-making is often guided by tumor tissue molecular analysis. The aim of this study was the detection of BRAF, NRAS and HRAS mutations in Georgian patients with thyroid cancer and determination of the frequency of these mutations in the respective populations. SETTING Diagnostic molecular laboratory located in Tbilisi, Georgia. PARTICIPANTS 116 patients with thyroid cancer participated in the study. PRIMARY AND SECONDARY OUTCOME MEASURES Genetic change is the main force of thyroid tumor development, based on new methods of managing thyroid cancer. The latest significant genetic discovery in thyroid cancer is the BRAF-T1799A (V600E) transformation (the gene for B-type RAF kinase, BRAF). Since the initial report of this breakthrough in thyroid cancer years ago, rapid progress has been made. The BRAF mutation is the most common genetic change in thyroid cancer. BRAF and NRAS mutations are frequent genetic alterations found in thyroid nodules. These molecular markers establish a differential diagnosis and facilitate clinical decision-making. Prevalence of thyroid nodule-associated mutations has not been studied in Georgia. We evaluated BRAF, NRAS and HRAS mutations in Georgian patients with indeterminate cytology or diagnosed with papillary thyroid cancer (PTC). RESULTS BRAF (V600E), NRAS (G12C, G12D, Q61R, and Q61K) and HRAS (G12C, G13R, and Q61R) were determined in the DNA extracted from fine needle aspirate specimens. In total, 116 patient samples were analyzed using competitive-specificTaqMan PCR (Cast PCR TM). In these samples, 36 were diagnosed as papillary thyroid carcinoma, and 80 were indeterminate by Bethesda system for reporting thyroid cytopathology (BSRTC III-V). BRAF (V600E) mutation was the most frequent genetic alteration found in 31% of all analyzed samples. Specifically, this mutation was present in 61% of PTC cases and 18% of cases classified as indeterminate (BSRTC III-V). NRAS mutations were present in 16% of PTC and 30% of indeterminate cytology samples. NRAS G12D and Q61R were most prevalent at 36.6% and 40% of all NRAS mutations. BSRTC IV category of indeterminate cytology had the highest frequency of NRAS mutations at 43%. From analyzed samples, HRAS (Q61R) mutation was present in only one PTC case.

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Highly Sensitive and Specific Molecular Test for Mutations in the Diagnosis of Thyroid Nodules: A Prospective Study of BRAF-Prevalent Population

International Journal of Molecular Sciences ◽

10.3390/ijms21165629 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5629 ◽

Cited By ~ 1

Author(s):

Yoon Young Cho ◽

So Young Park ◽

Jung Hee Shin ◽

Young Lyun Oh ◽

Jun-Ho Choe ◽

...

Keyword(s):

Thyroid Cancer ◽

Prospective Study ◽

Thyroid Nodules ◽

Needle Aspiration ◽

Genetic Alterations ◽

Braf V600e ◽

Molecular Testing ◽

Molecular Test ◽

Indeterminate Cytology ◽

A Prospective Study

Molecular testing offers more objective information in the diagnosis and personalized decision making for thyroid nodules. In Korea, as the BRAF V600E mutation is detected in 70–80% of thyroid cancer specimens, its testing in fine-needle aspiration (FNA) cytology specimens alone has been used for the differential diagnosis of thyroid nodules until now. Thus, we aimed to develop a mutation panel to detect not only BRAF V600E, but also other common genetic alterations in thyroid cancer and to evaluate the diagnostic accuracy of the mutation panel for thyroid nodules in Korea. For this prospective study, FNA specimens of 430 nodules were obtained from patients who underwent thyroid surgery for thyroid nodules. A molecular test was devised using real-time PCR to detect common genetic alterations in thyroid cancer, including BRAF, N-, H-, and K-RAS mutations and rearrangements of RET/PTC and PAX8/PPARr. Positive results for the mutation panel were confirmed by sequencing. Among the 430 FNA specimens, genetic alterations were detected in 293 cases (68%). BRAF V600E (240 of 347 cases, 69%) was the most prevalent mutation in thyroid cancer. The RAS mutation was most prevalently detected for indeterminate cytology. Among the 293 mutation-positive cases, 287 (98%) were diagnosed as cancer. The combination of molecular testing and cytology improved sensitivity from 72% (cytology alone) to 89% (combination), with a specificity of 93%. We verified the excellent diagnostic performance of the mutation panel applicable for clinical practice in Korea. A plan has been devised to validate its performance using independent FNA specimens.

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A mouse model of BRAF V600E mutated papillary thyroid cancer imitating sporadic conditions

Endocrine Abstracts ◽

10.1530/endoabs.56.oc9.3 ◽

2018 ◽

Author(s):

Iva Jakubikova ◽

Elin Schoultz ◽

Ellen Johansson ◽

Shawn Liang ◽

Konrad Patyra ◽

...

Keyword(s):

Thyroid Cancer ◽

Mouse Model ◽

Papillary Thyroid Cancer ◽

Braf V600e ◽

Papillary Thyroid

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Molecular Diagnostics of Thyroid Tumors

Archives of Pathology & Laboratory Medicine ◽

10.5858/2010-0664-rair.1 ◽

2011 ◽

Vol 135 (5) ◽

pp. 569-577 ◽

Cited By ~ 2

Author(s):

Yuri E. Nikiforov

Keyword(s):

Thyroid Cancer ◽

Molecular Markers ◽

Fine Needle Aspiration ◽

Thyroid Nodules ◽

Needle Aspiration ◽

Genetic Alterations ◽

Braf V600e ◽

Fine Needle ◽

Molecular Alterations ◽

Diagnostic Use

Abstract Context.—Thyroid cancer is the most common type of endocrine malignancy and its incidence is steadily increasing. Papillary carcinoma and follicular carcinoma are the most common types of thyroid cancer and represent those tumor types for which use of molecular markers for diagnosis and prognostication is of high clinical significance. Objective.—To review the most common molecular alterations in thyroid cancer and their diagnostic and prognostic utility. Data Sources.—PubMed (US National Library of Medicine)–available review articles, peer-reviewed original articles, and experience of the author. Conclusions.—The most common molecular alterations in thyroid cancer include BRAF and RAS point mutations and RET/PTC and PAX8/PPARγ rearrangements. These nonoverlapping genetic alterations are found in more than 70% of papillary and follicular thyroid carcinomas. These molecular alterations can be detected in surgically resected samples and fine-needle aspiration samples from thyroid nodules and can be of significant diagnostic use. The diagnostic role of BRAF mutations has been studied most extensively, and recent studies also demonstrated a significant diagnostic utility of RAS, RET/PTC, and PAX8/PPARγ mutations, particularly in thyroid fine-needle aspiration samples with indeterminate cytology. In addition to the diagnostic use, BRAF V600E mutation can also be used for tumor prognostication, as this mutation is associated with higher rate of tumor recurrence and tumor-related mortality. The use of these and other emerging molecular markers is expected to improve significantly the accuracy of cancer diagnosis in thyroid nodules and allow more individualized surgical and postsurgical management of patients with thyroid cancer.

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Epigenetically upregulated WIPF1 plays a major role in BRAF V600E-promoted papillary thyroid cancer aggressiveness

Oncotarget ◽

10.18632/oncotarget.13400 ◽

2016 ◽

Vol 8 (1) ◽

pp. 900-914 ◽

Cited By ~ 5

Author(s):

Tao Zhang ◽

Xiaopei Shen ◽

Rengyun Liu ◽

Guangwu Zhu ◽

Justin Bishop ◽

...

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Braf V600e ◽

Papillary Thyroid ◽

Cancer Aggressiveness

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BRAF V600E Decreases Survival in Patients with Papillary Thyroid Cancer–Related Lymph Node Metastases

Clinical Thyroidology ◽

10.1089/ct.2021;33.403-405 ◽

2021 ◽

Vol 33 (9) ◽

pp. 403-405

Author(s):

Lilah F. Morris-Wiseman

Keyword(s):

Thyroid Cancer ◽

Lymph Node ◽

Papillary Thyroid Cancer ◽

Lymph Node Metastases ◽

Braf V600e ◽

Papillary Thyroid ◽

Node Metastases

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Serum osteopontin can improve papillary thyroid cancer risk assessment of Bethesda III thyroid nodules: a preliminary study

Endocrine Oncology ◽

10.1530/eo-21-0005 ◽

2021 ◽

Author(s):

Taha Ulutan Kars ◽

Mustafa Kulaksizoglu ◽

İbrahim Kılınç

Keyword(s):

Thyroid Cancer ◽

Cancer Risk ◽

Papillary Thyroid Cancer ◽

Thyroid Nodules ◽

Cancer Risk Assessment ◽

Papillary Thyroid ◽

Operating Characteristics ◽

Discriminative Performance ◽

Thyroid Cancer Risk ◽

Preliminary Study

Objective: Thyroid cancer can be detected in 5–10% of patients with thyroid nodules. Management may be a challenge if fine-needle aspiration biopsy yields Bethesda III findings. Most of these cases undergo surgery and are ultimately found benign. Our aim was to evaluate whether serum osteopontin can accurately estimate thyroid cancer risk in cases with cytologically Bethesda III thyroid nodules and, thereby, decrease the number of unnecessary surgical interventions. Design and Methods: We obtained blood samples of cases with repeated cytologically Bethesda III thyroid nodules before surgery, and followed up the pathology results after thyroidectomy. We evaluated serum osteopontin from 36 patients with papillary thyroid cancer and compared them with 40 benign cases. Results: Serum osteopontin levels in patients with papillary thyroid cancer are significantly higher than in benign cases (mean serum osteopontin: 10.48 ± 3.51 ng/mL vs 6.14 ± 2.29 ng/mL, p<0.001). The area under the receiver operating characteristics curve was 0.851, suggesting that serum osteopontin could have considerable discriminative performance. Conclusions: In our preliminary study, high serum osteopontin levels can predict the risk of papillary thyroid cancer in thyroid nodules with Bethesda III cytology. Further studies are necessary to confirm these findings.

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Correlation between F18-FDG PET/CT Imaging and BRAF V600E Genetic Mutation for the Early Assessment of Treatment Response in Papillary Thyroid Cancers

Journal of Personalized Medicine ◽

10.3390/jpm10020052 ◽

2020 ◽

Vol 10 (2) ◽

pp. 52

Author(s):

Andra Piciu ◽

Maria-Iulia Larg ◽

Doina Piciu

Keyword(s):

Thyroid Cancer ◽

Prognostic Factors ◽

Papillary Thyroid Cancer ◽

Genetic Mutation ◽

Braf V600e Mutation ◽

Braf V600e ◽

Papillary Thyroid ◽

Early Assessment ◽

Pet Ct ◽

Ct Evaluation

In thyroid neoplastic pathology, the BRAF V600E mutation is shown to be involved in the oncogenesis of papillary thyroid cancer and its subtypes. The purpose of this study is to evaluate the correlation between the mutation of the BRAF V600E oncogene and the pathological standardized uptake values (SUV) at the F18-fluorodeoxyglucose (F18-FDG) positron emission tomography/computed tomography (PET/CT) evaluation, for a group of 20 patients with radically treated (total thyroidectomy and radioiodine therapy) papillary thyroid cancer, with subclinical persistent disease, at 6 months after the initial treatment. We analyzed the correlations between the values of SUV and the presence of the BRAF mutation as well with other prognostic factors such as stage, age, specific tumor markers (thyroglobulin and anti-thyroglobulin), extrathyroid extension, the presence of metastatic lymph nodes or distant metastasis. The value of SUV in the case of BRAF+ (positive) patients was higher than in the negative ones, but without statistical significance, thus, the values of the SUV cannot be a predictable factor for the presence of the genetic mutation. There was a statistically significant correlation in BRAF+ subgroup between the SUV values and the positive resection limit following surgery, showing a higher SUV value in the PET/CT evaluation. No correlation was observed between the aforementioned prognostic factors involved in papillary thyroid cancer and the BRAF V600E mutation.

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