Genetic Alteration In Thyroid Cancer Research Articles

Targeting NG2 relieves the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitors

BRAFV600E represents a constitutively active onco-kinase and stands as the most prevalent genetic alteration in thyroid cancer. However, the clinical efficacy of small-molecule inhibitors targeting BRAFV600E is often limited by acquired resistance. Here, we find that nerve/glial antigen 2 (NG2), also known as chondroitin sulfate proteoglycan 4 (CSPG4), is up-regulated in thyroid cancers, and its expression is increased with tumor progression in a BRAFV600E-driven thyroid cancer mouse model. Functional studies show that NG2 knockout almost does not affect tumor growth, but significantly improves the response of BRAF-mutant thyroid cancer cells to BRAF inhibitor PLX4720. Mechanistically, the blockade of ERK-dependent feedback by BRAF inhibitor can activate receptor tyrosine kinase (RTK) signaling, causing the resistance to this inhibitor. NG2 knockout attenuates the PLX4720-mediated feedback activation of several RTKs, improving the sensitivity of BRAF-mutant thyroid cancer cells to this inhibitor. Based on this finding, we propose and demonstrate an alternative strategy for targeting NG2 to effectively treat BRAF-mutant thyroid cancers by combining multiple kinase inhibitor (MKI) Sorafenib or Lenvatinib with PLX4720. Thus, this study uncovers a new mechanism in which NG2 contributes to the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitor, and provides a promising therapeutic option for BRAF-mutant thyroid cancers.

Genetic alterations in thyroid cancer mediating both resistance to BRAF inhibition and anaplastic transformation.

A subset of thyroid cancers present at advanced stage or with dedifferentiated histology and have limited response to standard therapy. Tumors harboring the BRAF V600E mutation may be treated with BRAF inhibitors; however, tumor response is often short lived due to multiple compensatory resistance mechanisms. One mode of resistance is the transition to an alternative cell state, which on rare occasions can correspond to tumor dedifferentiation. DNA sequencing and RNA expression profiling show that thyroid tumors that dedifferentiate after BRAF inhibition are enriched in known genetic alterations that mediate resistance to BRAF blockade, and may also drive tumor dedifferentiation, including mutations in the PI3K/AKT/MTOR (PIK3CA, MTOR), MAP/ERK (MET, NF2, NRAS, RASA1), SWI/SNF chromatin remodeling complex (ARID2, PBRM1), and JAK/STAT pathways (JAK1). Given these findings, recent investigations have evaluated the efficacy of dual-target therapies; however, continued lack of long-term tumor control illustrates the complex and multifactorial nature of these compensatory mechanisms. Transition to an immune-suppressed state is another correlate of BRAF inhibitor resistance and tumor dedifferentiation, suggesting a possible role for concurrent targeted therapy with immunotherapy. Investigations into combined targeted and immunotherapy are ongoing, but early results with checkpoint inhibitors, viral therapies, and CAR T-cells suggest enhanced anti-tumor immune activity with these combinations.

Gene Editing with CRISPR/Cas Methodology and Thyroid Cancer: Where Are We?

Simple SummaryThe advent of genomic editing with CRISPR/Cas9 has transformed the way we manipulate the genome, and has facilitated the investigation of tumor cell biology in vitro and in vivo. Not only we can modify genome sequence to blunt an overactivated gene or correct a mutation, but also we may modulate gene expression using CRISPR/Cas system. In this review, we present the basics of CRISPR/Cas methodology, its components and how to start a CRISPR/Cas experiment; Moreover, we present how CRISPR/Cas methodology has been applied to study the function of coding and noncoding genes in thyroid cancer and provided insights into cancer biology.Important advances on the role of genetic alterations in thyroid cancer have been achieved in the last two decades. One key reason is linked to the development of technical approaches that allowed for the mimicking of genetic alterations in vitro and in vivo and, more recently, the gene editing methodology. The CRISPR/Cas methodology has emerged as a tangible tool for editing virtually any DNA sequence in the genome. To induce a double-strand break and programmable gene editing, Cas9 endonuclease is guided by a single-guide RNA (sgRNA) that is complementary to the target sequence in DNA. The gene editing per se occurs as the cells repair the broken DNA and may erroneously change the original DNA sequence. In this review, we explore the principles of the CRISPR/Cas system to facilitate an understanding of the mainstream technique and its applications in gene editing. Furthermore, we explored new applications of CRISPR/Cas for gene modulation without changing the DNA sequence and provided a Dry Lab experience for those who are interested in starting “CRISPRing” any given gene. In the last section, we will discuss the progress in the knowledge of thyroid cancer biology fostered by the CRISPR/Cas gene editing tools.

Thyroid nodules in childhood-onset Hashimoto's thyroiditis: Frequency, risk factors, follow-up course and genetic alterations of thyroid cancer.

We evaluated the frequency, risk factors and the follow-up outcomes of thyroid nodules, and genetic alterations in thyroid cancer, in youth with childhood-onset Hashimoto thyroiditis (HT) residing in an iodine-sufficient country. A retrospective cohort study. A total of 213 patients (194 females, mean age 10.6years at the time of HT diagnosis) were ultrasonographically evaluated. Thyroid nodules were categorized using the Korean Thyroid Imaging Reporting and Data System (K-TIRADS) and the American College of Radiology Thyroid Imaging Reporting and Data System (ACR-TI-RADS). Thyroid nodules were detected in 40 (18.8%) patients over a median follow-up period of 3.4years, usually after the onset of puberty. A family history of thyroid disease (hazard ratio 2.1, p=.031) was predictive of thyroid nodule detection. Papillary thyroid carcinoma (PTC) was diagnosed in 9 (4.2% of all and 22.5% of nodule-positive patients). The malignant nodules had a higher K-TIRADS or ACR-TI-RADS risk level compared with benign nodules (p<.01 for both). Genetic alterations were revealed in 7 (BRAFV600E in 6 and RET-ERC1 fusion in 1) of the eight available tumour tissue samples. None showed evidence of disease over a median follow-up period of 3.4years. The nodule detection rate was 18.8%, with a 22.5% risk of malignancy among the detected nodules in childhood-onset HT patients, showing increased risk in those with a family history. Additional large-scale studies are required to evaluate the usefulness of K-TIRADS or ACR-TI-RADS risk level for the differentiation of paediatric thyroid nodules.

The role of molecular genetics in the presurgical management of thyroid nodules.

Fine-needle aspiration (FNA) is an important diagnostic tool for the evaluation of thyroid nodules. However, in almost ¼ of all nodules submitted to FNA cytology is indeterminate. Since the majority of genetic alterations in thyroid cancer have been identified, the use of molecular testing platforms has been endorsed by American Thyroid Association for management of indeterminate nodules. Several commercial tests were based on mRNA expression of FNA samples (Afirma®, Veracyte, South San Francisco, CA, USA) while others detect DNA alterations (ThyroSeq, UPMC, Pittsburgh, PA, USA). Noncommercial tests detect limited number of point mutations or re-arrangements (gene panels). Literature study included a Pubmed research for adult original studies from 2003 to 2020, focusing on terms such as "molecular tests," "nodules with indeterminate AUS/FLUS and FN/SFN cytology." Gene expression profile tests serve as "rule out" tests due to their high negative predictive value and perform better in a setting of low cancer pretest probability. Genetic alteration platforms display high positive predictive value and serve as rather "rule in" tests but their diagnostic accuracy is hampered either because a small proportion of nodules does not harbor any of these alterations targeted (gene panels) or because commonly identified RAS mutations can also be found in benign nodules. Next generation sequencing development and incorporation of other genetic markers such as miRNA can improve diagnostic accuracy of molecular tests.

The role of molecular genetics in the pre-surgical management of thyroid nodules

Introduction Fine-needle aspiration (FNA) is an important diagnostic tool for the evaluation of thyroid nodules. However in almost ¼ of all nodules submitted to FNA cytology is indeterminate. Since the majority of genetic alterations in thyroid cancer have been identified, the use of molecular testing platforms has been endorsed by American Thyroid Association (ATA) for management of indeterminate nodules. Evidence acquisition Several commercial tests are based on mRNA expression of FNA samples (Afirma ®) while others detect DNA alterations (ThyroSeq). Non commercial tests detect limited number of point mutations or re-arrangements (gene panels). Evidence synthesis Gene expression profile tests serve as "rule out" tests due to their high NPV and perform better in a setting of low cancer pre-test probability. Genetic alteration platforms display high PPV and serve as rather "rule in" tests but their diagnostic accuracy is hampered either because a small proportion of nodules does not harbor any of these alterations targeted (gene panels) or because commonly identified RAS mutations can also be found in benign nodules. Conclusions Next Generation Sequencing NGS) development and incorporation of other genetic markers such as miRNA can improve diagnostic accuracy of molecular tests.

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

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.

EGFR inhibition enhances the antitumor efficacy of a selective BRAF V600E inhibitor in thyroid cancer cell lines.

BRAF V600E is the most common genetic alteration in thyroid cancer and is indicative of a relatively poor prognosis. A selective inhibitor of BRAF V600E has been proposed as a novel treatment for patients with thyroid cancer exhibiting BRAF V600E mutations. However, this inhibitor has demonstrated a limited therapeutic effect. In the present study, possible adaptive mechanisms of resistance of thyroid cancer cells to the specific BRAF V600E inhibitor, PLX4032, were investigated. MTT assays were performed to determine the anti-proliferative efficiencies and half maximal inhibitory concentration (IC50) of inhibitory treatments. The level of phosphorylated ERK was used to evaluate the activity of the mitogen assisted protein kinase (MAPK) pathway. Flow cytometry was performed to evaluate the rate of apoptosis. The IC50 measurements of PLX4032 in K1 and BCPAP cells were 0.550 and 1.772 µM, respectively. Co-treatment with an endothelial growth factor receptor (EGFR) inhibitor decreased the IC50 of PLX4032 to 0.206 µM, and prolonged the inhibitory effect of PLX4032 in K1 cells. In cells treated with PLX4032 alone, the MAPK pathway was reactivated after 24 h. However, the addition of an EGFR inhibitor suppressed this reactivation and increased the rate of apoptosis. In summary, the present study demonstrated that thyroid cancer harboring the BRAF V600E mutation was resistant to a selective BRAF inhibitor due to reactivation of the MAPK pathway. Co-treatment with an EGFR inhibitor increased antitumor efficacy and suppressed resistance to the BRAF V600E inhibitor.

The Genetics of Papillary Microcarcinomas of the Thyroid: Diagnostic and Prognostic Implications.

Papillary microcarcinoma of the thyroid (mPTC) is defined by the WHO as a papillary thy-roid cancer measuring 10mm or less in diameter and it is nowadays a topic of intense debate among the members of the medical community due to its apparent “epidemic” rise. Although these tumors follow almost always an indolent clinical course and carry an excellent prognosis, it is known that a small sub-set may display a potentially aggressive behavior. Nevertheless, we still lack an accurate way of predict-ing those which will cause significant disease. In an attempt to address this problem, a number of clini-co-pathologic features have been studied as poor prognostic markers in mPTC, and their association with known genetic alterations in thyroid cancer has been evaluated. Herein we review the present knowledge concerning mPTC’s genetic profile, namely the prevalence of BRAF (V600E), RAS and TERT promoter mutations and RET/PTC and PAX8-PPARG rearrangements and report the results of the evaluation in the putative prognostic value of these genetic alterations in mPTC.

Analysis of BRAF and RAS genetic alterations in thyroid cancer in the Greek population

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

P82a: Molecular biomarkers in preoperative diagnosis of thyroid cancer

Preoperative differential diagnosis of benign thyroid nodules and thyroid cancer is an important issue of endocrinology. Preoperative identification of a tumor type allows a surgeon to determine an adequate surgical treatment and reduce complications. The cytological analysis of samples obtained by the fine-needle aspiration biopsy is limited in sensitivity and specificity and the core biopsy is not safe to be used in patients with thyroid nodes smaller than 2 cm. The most promising area in the preoperative diagnosis of malignant tumors is molecular biomarkers, which can be used to determine the surgical treatment and indications for the target therapy. BRAF V600E is the most frequent genetic alteration in thyroid cancer. It activates the MAP-kinase pathway which causes changes in expression levels of extracellular matrix proteins and some of their receptors. Changes in the expression of integrin receptors and their ligands, such as osteopontin and thrombospondin-1, contribute to tumor cell proliferation and migration. The C-Jun pathway is also very important in pathogenesis of thyroid cancer. Changes in its activity can affect the expression of GSTP enzyme which participates in hormone metabolism. Altered MiRNA expression has been observed in a variety of cancer states allowing their potential use as cancer biomarkers. The aim of this study was to evaluate integrins, angiogenic factors, GSTP and MiRNAs as potential biomarkers for the diagnosis and prognosis of thyroid cancer. 112 samples of papillary thyroid cancer (PTC) and 120 samples of benign nodular neoplasms were analyzed. The expression levels of the studied genes were determined by RT-PCR. The results were confirmed by immunohistochemical analysis. The BRAF V600E mutation was determined by allele-specific real-time PCR. The results showed that GSTP can be used for clinical settings as a cancer-specific marker for thyroid neoplasms with 83–88% sensitivity, 70–80% specificity and 76–84% diagnostic accuracy. Higher expression levels of integrins α 2, α 5, α v, α 9, β 1, β 3 and IL-8, angiogenin, and VEGF were observed in malignant tumors in comparison with the normal thyroid tissue ( p p

C-Met-mediated reactivation of PI3K/AKT signaling contributes to insensitivity of BRAF(V600E) mutant thyroid cancer to BRAF inhibition.

BRAF (V600E) mutation is the most commonly detected genetic alteration in thyroid cancer. Unlike its high treatment response to selective BRAF inhibitor (PLX4032) in metastatic melanoma, the treatment response in thyroid cancer is reported to be low. The purpose of this study is to investigate the resistance mechanism responsible for this low treatment response to BRAF inhibitor in order to maximize the effect of targeted therapy. We examined the expression of feedback regulation mechanisms and alterations in the upper signal transduction pathway in thyroid cancer cell lines harboring BRAF mutation. Also, we investigated the effect of dual inhibition from combinatorial therapy. Two thyroid cancer cell lines, 8505C (anaplastic thyroid cancer) and BCPAP (papillary thyroid cancer) were selected and treated with PLX4032 and its drug sensitivity were examined and compared. Further investigation on the changes in signals responsible for the different treatment response to PLX4032 was carried out and the same experiment was performed on orthotopic xenograft mouse models. Unlike BCPAP cells, 8505C cells presented drug resistance to PLX4032 treatment and this was mainly due to increased expression of c-Met. Effective inhibitions of c-Met, p-AKT, and p-ERK were achieved after dual treatment with BRAF inhibitor (PLX4032) and c-Met inhibitor (PHA665752). Similar results were confirmed by in vivo study with orthotopic xenograft mouse model. c-Met-mediated reactivation of the PI3K/AKT pathway and MAPK pathway contributes to the relative insensitivity of BRAF (V600E) mutant anaplastic thyroid cancer cells to PLX4032. Dual inhibition of BRAF and c-Met leads to sustained treatment response. © 2015 Wiley Periodicals, Inc.

Abstract 4697: Quantitation of BRAF V600E alleles predicts papillary thyroid cancer progression

Abstract BACKGROUND: BRAF V600E is the most common genetic alteration in thyroid cancer. However, there is still controversy regarding its clinicopathological significance and clonal mutation frequency. To clarify these inconsistent results, we investigated the association between the allelic frequency of BRAF V600E and the clinicopathological features in classic papillary thyroid carcinoma (PTC). DESIGN: Tumor tissues from 321 patients with classic PTC were microdissected under a dissecting microscope and analyzed for the presence or absence of the BRAF mutation and mutant allelic percentage using quantitative pyrosequencing. RESULTS: BRAF V600E was found in 264 (82.2%) of 321 classic PTC. In the BRAF V600E-positive tumors, the mutant allelic frequency varied from 8% to 41% of total BRAF alleles (median, 20%). The frequency of BRAF V600E alleles directly correlated with tumor size (R-squared = 0.162, P&amp;lt;0.001) and number of metastatic lymph nodes (R-squared = 0.063, P&amp;lt;0.001). Out of 264 BRAF-positive PTCs, 136 (51%) had ≥20% of BRAF mutant alleles. Extrathyroidal extension and lymph node metastasis were more frequent in PTCs with high (≥20%) abundance of mutant alleles than in those with low abundance of mutant alleles (55% vs 37%, P=0.003 and 62% vs 46%, P=0.012, respectively). However, if the mutant allelic percentage was not considered, the presence of BRAF V600E was only associated with extrathyroidal extension, but not with tumor size and lymph node metastasis. CONCLUSION: High abundance of BRAF V600E alleles predicts tumor progression in classic PTC. We suggest that the clonal, subclonal, or oligoclonal occurrence of BRAF V600E mutation may have different biological and clinicopathological significance in the PTC. Citation Format: Chan Kwon Jung, Min Hee Kim, Ja Seong Bae, Dong Jun Lim, Hyoungnam Lee, So Ra Jeon, Gyeong Sin Park. Quantitation of BRAF V600E alleles predicts papillary thyroid cancer progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4697. doi:10.1158/1538-7445.AM2014-4697

Quantification of BRAF V600E alleles predicts papillary thyroid cancer progression.

The BRAF V600E mutation is the most common genetic alteration in thyroid cancer. However, its clinicopathological significance and clonal mutation frequency remain unclear. To clarify the inconsistent results, we investigated the association between the allelic frequency of BRAF V600E and the clinicopathological features of classic papillary thyroid carcinoma (PTC). Tumour tissues from two independent sets of patients with classic PTC were manually microdissected and analysed for the presence or absence of the BRAF mutation and the mutant allelic frequency using quantitative pyrosequencing. For external validation, the Cancer Genome Atlas (TCGA) data were analysed. The BRAF V600E mutation was found in 264 (82.2%) out of 321 classic PTCs in the training set. The presence of BRAF V600E was only associated with extrathyroidal extension and the absence of thyroiditis. In BRAF V600E-positive tumours, the mutant allelic frequency varied from 8 to 41% of the total BRAF alleles (median, 20%) and directly correlated with tumour size and the number of metastatic lymph nodes. Lymph node metastases were more frequent in PTCs with a high (≥20%) abundance of mutant alleles than in those with a low abundance of mutant alleles (P=0.010). These results were reinforced by validation dataset (n=348) analysis but were not reproduced in the TCGA dataset. In a population with prevalent BRAF mutations, quantitative analysis of the BRAF mutation could provide additional information regarding tumour behaviour, which is not reflected by qualitative analysis. Nonetheless, prospective studies are needed before the mutated allele percentage can be considered as a prognostic factor.

Molecular Analysis of Thyroid Tumors

Thyroid cancer is the most common endocrine malignancy, and its incidence is rising in the USA and other countries. Papillary and follicular thyroid carcinomas are the two most common types of thyroid cancer. Non-overlapping genetic alterations, including BRAF and RAS point mutations, and RET/PTC and PAX8/PPARγ rearrangements, are found in more than 70% of papillary and follicular thyroid carcinomas. These represent the most common genetic alterations in thyroid cancer, as well as molecular markers of diagnostic and prognostic significance. The use of these and other emerging molecular markers will likely improve the diagnosis of malignancy in thyroid nodules as well as facilitate more individualized operative and postoperative management. Herein, we provide a brief overview of the common genetic alterations in papillary and follicular thyroid carcinoma and discuss the diagnostic and prognostic significance thereof.

Review of the genetics of thyroid tumours: diagnostic and prognostic implications

Thyroid nodules are common, but only a small proportion harbour malignancy. Despite this, the frequency of thyroid cancer is on the increase and thyroid malignancy is the most common endocrine malignancy. Preoperative diagnosis is based on ultrasound and radionucleotide imaging as well as the fine-needle aspiration biopsy (FNAB). These biopsies yield a large proportion of indeterminate results due to inadequate material for cytological diagnosis, or due to the cytological similarity of FAs and follicular carcinomas. Recent advances in the understanding of the molecular pathogenesis of thyroid malignancy have led to the detection of characteristic genetic alterations in FNABs. This technology has the potential to increase the specificity of this test, combining cytological with genetic testing to reduce the number of indeterminate results, thereby reducing the number of thyroidectomies performed for benign disease. This review examines the evidence for the presence of the common genetic alterations in thyroid cancer and outlines the pathological and clinical correlations of these mutations. The practicality and utility of measuring these genetic alterations in FNAB specimens is also outlined as well as the potential for these tests to alter primary management and follow-up of patients with nodular thyroid disease. It is likely that a combination of molecular testing and cytological examination of FNAB specimens will prove to be the most efficient and specific method of diagnosing thyroid cancer preoperatively.

Multiple Genetic Alterations in Papillary Thyroid Cancer are Associated with Younger Age at Presentation

There is a significant gender and age disparity in thyroid cancer incidence and outcome. The molecular basis for these divergent clinical presentations and outcome are essentially unknown. The primary tumor genotype in 217 patients with papillary thyroid cancer was determined for six common somatic genetic alterations (RET/PTC1, RET/PTC3, and NTRK1 rearrangements, and BRAF V600E, KRAS, and NRAS hotspot mutations) by PCR and direct sequencing, and nested PCR. Univariate and multivariate analyses were performed to determine the association of genetic changes and age, gender, and other clinicopathologic factors. One hundred twenty-one of the 190 conventional papillary thyroid carcinoma samples (63.7%) had at least one genetic alteration, and 27 of the samples (14.2%) had more than one alteration. In the follicular variant of papillary thyroid carcinomas, 13 of the 27 samples (48.1%) had at least one genetic alteration and three of the 27 samples (11.1%) had more than one. The presence of multiple genetic alterations was associated with younger age at diagnosis (P=0.034), mean difference of 8 y earlier. We found no significant association with the number or type of genetic alterations present by gender, tumor size, extent of tumor differentiation, multicentricity, lymph node metastasis, distant metastases, TNM stage, and the AMES risk group. The association of multiple genetic alterations and younger age were independent of tumor size, lymph node or distant metastasis, TNM stage, or AMES risk group. Multiple genetic alterations are more common in younger patients with papillary thyroid cancer, but there is no difference in the type or number of genetic alterations by gender. Our findings suggest that multiple genetic alterations in thyroid cancer may be associated with earlier disease initiation and or progression.

Genetic Alterations in Thyroid Cancer: The Role of Mouse Models

Thyroid carcinomas are the most common endocrine neoplasms in humans, with a globally increasing incidence. Thyroid follicular cells and neuroendocrine (parafollicular) C cells are each susceptible to neoplastic transformation, resulting in thyroid cancers of differing phenotypes with unique associated genetic mutations and clinical outcomes. Over the past 15 years, several sophisticated genetically engineered mouse models of thyroid cancer have been created to further our understanding of the genetic events leading to thyroid carcinogenesis in vivo. The most significant mouse models of papillary, follicular, anaplastic, and medullary thyroid carcinoma are highlighted, with particular emphasis on the relationship between the relevant oncogenes in these models and genetic events in the naturally occurring human disease. Limitations of each model are presented, and the need for additional models to better recapitulate certain aspects of the human disease is discussed.

BRAF mutation in thyroid cancer

Genetic alteration is the driving force for thyroid tumorigenesis and progression, based upon which novel approaches to the management of thyroid cancer can be developed. A recent important genetic finding in thyroid cancer is the oncogenic T1799A transversion mutation of BRAF (the gene for the B-type Raf kinase, BRAF). Since the initial report of this mutation in thyroid cancer 2 years ago, rapid advancements have been made. BRAF mutation is the most common genetic alteration in thyroid cancer, occurring in about 45% of sporadic papillary thyroid cancers (PTCs), particularly in the relatively aggressive subtypes, such as the tall-cell PTC. This mutation is mutually exclusive with other common genetic alterations, supporting its independent oncogenic role, as demonstrated by transgenic mouse studies that showed BRAF mutation-initiated development of PTC and its transition to anaplastic thyroid cancer. BRAF mutation is mutually exclusive with RET/PTC rearrangement, and also displays a reciprocal age association with this common genetic alteration in thyroid cancer. The T1799A BRAF mutation occurs exclusively in PTC and PTC-derived anaplastic thyroid cancer and is a specific diagnostic marker for this cancer when identified in cytological and histological specimens. This mutation is associated with a poorer clinicopathological outcome and is a novel independent molecular prognostic marker in the risk evaluation of thyroid cancer. Moreover, preclinical and clinical evaluations of the therapeutic value of novel specific mitogen-activated protein kinase pathway inhibitors in thyroid cancer are anticipated. This newly discovered BRAF mutation may prove to have an important impact on thyroid cancer in the clinic.