High Prevalence Of BRAF Mutations Research Articles

Diagnostic performance of next-generation sequencing and genetic profiling in thyroid nodules from a single center in China.

ObjectiveThe data regarding the mutation landscape in Chinese patients with thyroid cancer are limited. The diagnostic performance of thyroid nodules by fine-needle aspiration (FNA) cytology needs optimization, especially in indeterminate nodules.MethodsA total of 1039 FNA and surgical resection samples tested using the targeted multigene next-generation sequencing (NGS) panel were retrospectively collected. The features of gene alterations in different thyroid tumors were analyzed, and the diagnostic efficacy was evaluated.ResultsAmong 1039 samples, there were 822 FNA and 217 surgical FFPE samples. Among 207 malignant thyroid resections, a total of 181 out of 193 papillary thyroid carcinomas (PTCs) were NGS-positive (93.8%), with a high prevalence of BRAF mutations (81.9%, 158/193) and a low prevalence of RAS (1.0%, 2/193) and TERT promoter mutations (3.6%, 7/193). Gene fusions, involving the RET and NTRK3 genes, were present in 20 PTCs (10.4%) and mutually exclusive with other driver mutations. Two of three follicular thyroid carcinomas harbored multiple mutations. RET gene point mutations were common in medullary thyroid carcinoma (8/11, 72.7%). The combination of cytology and DNA–RNA-based NGS analysis demonstrated superior diagnostic value (98.0%) in FNA samples. For indeterminate thyroid nodules, the diagnostic sensitivity and specificity of NGS testing were 79.2 (38/48) and 80.0% (8/10), respectively. Two mutation-positive benign cases harbored NRAS and TSHR mutations, respectively.ConclusionsOur study revealed the distinct molecular profile of thyroid tumors in the Chinese population. The combination of NGS testing and FNA cytology could facilitate the accurate diagnosis of thyroid nodules, especially for indeterminate nodules.

Associations between oncogenic risk markers and clinical outcomes among black and white colorectal cancer patients.

e16078 Background: Blacks have a 25% higher incidence of colorectal cancer compared to their white societal counterparts1. Additionally, the overall mortality rate among black colorectal cancer patients is 50% higher than that of whites2. However, little is known about the biomarkers prevalent among blacks and their possible correlation to treatment response and patient outcomes. Objective: The objective of this study is to explore disease trends that may unveil a correlation between molecular markers, pathologic stage at presentation and poor clinical outcomes among black colorectal cancer patients. Methods: De-identified patient data was obtained from The Oncology Data Services Department (Cancer Registry) of TJUH. The population cohort (n = 836) included newly diagnosed colorectal cancer patients treated at TJUH from 2000-2019, & included information regarding patient race, sex, age at presentation, stage at presentation, histological code, tumor markers: KRAS, NRAS, BRAF, MS1, treatment received, surgical findings: tumor size, lymph node involvement, presence of distant metastases at first surgery, response to chemotherapy & disease-free survival. Results: Findings reveal a higher prevalence of BRAF mutations among whites compared to blacks within this population, while black patients were diagnosed later according to AJCC pathological stage at presentation. Future analysis of this cohort will further divide the population by age ( < 50, 50-65, & > 65). This facet of the study will explore relationships between age & stage at presentation among patients of different races. Conclusions: Both oncogenic risk markers and AJCC stage at presentation differ between black and white colorectal cancer patients within this population. Additional analysis regarding age at presentation will further inform us as to how these findings may contribute to the comparatively higher incidence and mortality rates among black colorectal cancer patients. Researchers should continue to explore possible etiologies for the prevalent racial disparities seen among black colorectal cancer patients.

Abstract 1606: Clinical routine massive parallel sequencing highlights clinicopathological associations of the RAS/RAF mutational module in metastatic colorectal cancer and reveals high frequency of concomitant RAS/RAF mutations

Abstract Background: Over the past few years, massive parallel sequencing (MPS) has become reliable and cost-effective, and its use in clinical practice has become a reality. A relevant role for MPS is the prediction of response to anti-EGFR agents in metastatic colorectal cancer (mCRC), where multiple exons from KRAS, NRAS, and BRAF must be sequenced simultaneously.Patients and methods: We optimized a 14-amplicon panel to assess by MPS the exonic regions of KRAS, NRAS, BRAF, and PIK3CA from formalin-fixed, paraffin-embedded specimen-extracted DNA. We analyzed the samples of a monocentric, prospective, consecutive cohort of patients affected by mCRC collected for diagnostic and research purposes at the time of diagnosis in our referral basin.Results: Over two years, we evaluated 219 mCRC specimens. We observed an unexpected, statistically significant association of RAS mutations with sex, young age, and tumor site (right colon). We further demonstrated, by transversal validation using digital polymerase chain reaction, that concomitant mutations in the KRAS/BRAF/NRAS module are not infrequent in mCRC. As anticipated by large, whole-genome studies, RAS and PIK3CA tended to be concurrently mutated. We corroborated associations such as the higher prevalence of BRAF mutations in right mCRCtumors, in concomitance with microsatellite instability. Finally, survival analysis showed that BRAF mutants had a shorter progression-free survival compared to KRAS/NRAS mutant patients and wildtype ones upon I line treatment.Conclusions: To our knowledge, this is the first monocentric, consecutive, prospectively accrued clinical mCRC cancer cohort tested on a clinical routine basis by MPS for KRAS, NRAS, BRAF, and PIK3CA. Our study has highlighted in clinical practice findings such as the concomitance of mutations in the RAS/RAF module, the co-occurrence of RAS and PIK3CA mutations, and possible associations of gender with specific mutations. These results need clinical follow-up in the context of treatment to assess their translational relevance. Citation Format: Edoardo Isnaldi, Anna Garuti, Gabriella Cirmena, Stefano Scabini, Federica Grillo, Luca Mastracci, Lorenzo Ferrando, Roberto Murialdo, Maurizio Gallo, Christine Desmedt, Roberto Fiocca, Emanuele Romairone, Alberto Ballestrero, Gabriele Zoppoli. Clinical routine massive parallel sequencing highlights clinicopathological associations of the RAS/RAF mutational module in metastatic colorectal cancer and reveals high frequency of concomitant RAS/RAF mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1606.

ID: 1034 Potential cancer predictive biomarkers: a case of papillary thyroid cancer

Thyroid cancer represents 2.1% of new cancer cases, yet it is the most common endocrine cancer and one of the fastest growing cancer types in the world. The incidence of thyroid cancer is the highest in elderly population (60-69 years), but novel data suggest decline in age when this cancer is frequently diagnosed to 50-59 years. Thyroid cancer is 2-4-fold more common in female population what is usually associated with female hormones and the differences in oxidative stress levels. Since the WHO suggest that roughly 30% of cancer can be prevented, the aim of this study was to evaluate the role of micronucleus test and comet assay as cancer predictive biomarkers.
 In this study, 36 patients with papillary thyroid cancer (PTC) were recruited in accordance with all ethical standards. The average age of the group was 52±14 years, 28:8 female:male ratio, and 33% of active smokers. Control group was matched for age, gender, and smoking habits (52±14 years, 28:8 female:male ratio, and 33% of active smokers).
 The number of micronucleated (MNed) cells in human peripheral blood lymphocytes was significantly higher (p<0.05) in PTC group (12.94±5.81) compared to control group (4.36±2.58). Additionally, the comet assay tail moment (TM) was also significantly (p<0.05) higher in the PTC group compared to control group (0.39±0.71 vs 0.14±0.05). These results indicate that people with PTC had more genome damage compared to healthy controls. The immunohistochemical analysis of thyroid revealed 97.2% BRAF positive and 20.6% RET/PTC positive samples.
 Taken together, the PTC group had more DNA damage what is associated with high prevalence of BRAF mutations and RET/PTC translocations as a consequence of disrupted genome integrity. The results imply that cytogenetic tools might be used in human biomonitoring for identification of high-risk groups but further research is needed to assess normal and cut-off values.

Oncolytic virotherapy including Rigvir and standard therapies in malignant melanoma.

The treatment of metastatic melanoma has evolved from an era where interferon and chemotherapy were the mainstay of treatments to an era where immunotherapy has become the frontline. Ipilimumab (IgG1 CTLA-4 inhibitor), nivolumab (IgG4 PD-1 inhibitor), pembrolizumab (IgG4 PD-1 inhibitor) and nivolumab combined with ipilimumab have become first-line therapies in patients with metastatic melanoma. In addition, the high prevalence of BRAF mutations in melanoma has led to the discovery and approval of targeted molecules, such as vemurafenib (BRAF kinase inhibitor) and trametinib (MEK inhibitor), as they yielded improved responses and survival in malignant melanoma patients. This is certainly a burgeoning time in immunotherapy drug development, and the aforementioned efforts along with the recent US Food and Drug Administration approval of talimogene laherparepvec (T-VEC), a recombinant oncolytic herpes virus, have paved the way to exploring the role of additional oncolytic viruses, such as the echovirus Rigvir, as new and innovative treatment modalities in patients with melanoma. Herein, we discuss the current standard of care treatment in melanoma with an emphasis on immunotherapy and oncolytic viruses in development.

Oncogene-induced senescence distinguishes indolent from aggressive forms of pulmonary and non-pulmonary Langerhans cell histiocytosis

The clonal/neoplastic nature of Langerhans cell histiocytosis (LCH) has recently been demonstrated by a high prevalence of BRAF mutations, including pulmonary LCH (PLCH). We hypothesized that BRAF-induced senescence, as demonstrated in nevi and melanoma, is involved in the pathogenesis of LCH and PLCH. In a series of pulmonary (19 cases) and non-pulmonary LCH (19 cases), including five aggressive cases, we investigated occurrence of the BRAF V600E mutation by molecular analysis and/or immunohistochemistry using a validated antibody (VE1). The expression of cell-senescence markers p16INK4a and p21CIP1/WAF1 was also immunohistochemically investigated. We demonstrated that 6/19 cases of LCH and 12/19 cases of PLCH were VE1 positive, matching with molecular analysis, and in all cases both p16INK4a and p21CIP1/WAF1 were expressed, irrespective of BRAF mutation status. Interestingly, all the aggressive cases did not express p16INK4a, thus suggesting that loss of senescence control could be related to clinical aggressiveness of LCH, as in melanoma.

Thyroid cancer genetics: how close are we to personalizing clinical management?

Author for correspondence: Genomic Medicine Institute, Cleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, OH 44195, USA and Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA and Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA and Thyroid Cancer Center, Endocrinology & Metabolism Institute, Cleveland Clinic, Cleveland, OH 44195, USA and Stanley Shalom Zielony Institute of Nursing Excellence, Cleveland Clinic, Cleveland, OH 44195, USA and Department of Genetics, & CASE Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA Tel.: +1 216 444 3440 Fax: +1 216 636 0655 engc@ccf.org Thyroid cancer genetics: how close are we to personalizing clinical management?

Fisetin: A Natural Fist against Melanoma?

Melanoma has now become the subject of targeted therapies, based upon the high prevalence of B-raf mutations in melanoma. However, while initial responses to B-raf inhibitors are impressive, resistance is extremely common, suggesting that melanoma is not addicted to B-raf. In their report, Syed et al. demonstrate that fisetin, a natural product without well established mechanisms, has activity against melanoma. Their report suggests that "nontargeted therapies" need to become part of our armamentarium against melanoma, given that targeted therapies do not target all of the pathways required for melanoma growth.

High Prevalence of B-RAF Mutation in Papillary Carcinoma of the Thyroid in North-East Italy

B-RAF V600E mutation is frequently observed in several tumors, including papillary thyroid carcinomas (PTCs), where it is considered of potential diagnostic and prognostic value. The reported prevalence of B-RAF mutation in PTCs in different Italian populations varies from 14% to 69%. The authors investigate the prevalence and utility of the B-RAF V600E mutation in a series of 91 fine needle aspiration biopsies (FNABs) of the thyroid and in 60 histologically proven PTCs in a well-defined north Italian population. In their series, the B-RAF mutation was detected in 43 (72%) PTCs and was more frequent in classic (34 out of 44, 77%) versus variant follicular PTCs (PTCVF; 9 out of 16, 56%). In all, 41 (46%) FNABs showed B-RAF mutation and corresponded to histologically proven PTCs (33 classic type and 8 PTCVF), which had been cytologically classified as malignant (28 cases), atypical/suspicious (10), inadequate (1), and benign (2). B-RAF mutations were never seen in non-PTC/ PTCVF FNAB cases, implying a 100% positive predictive value.These data demonstrate a high prevalence of B-RAF mutations in the present study population, underscoring the possibility of strong regional differences in B-RAF mutation prevalence in PTCs and further confirming its high diagnostic value on FNAB.

New Targeted Molecular Therapies for Dedifferentiated Thyroid Cancer

Dedifferentiated thyroid cancer (DeTC) derived from follicular epithelium is often incurable because it does not respond to radioiodine, radiotherapy, or chemotherapy. In cases, RET/PTC rearrangements are found in 30%–40%, RAS mutations in about 10%, and BRAF mutations in around 40%–50%, with no overlap between these mutations results in papillary thyroid cancer, while a higher prevalence of BRAF mutations (up to 70%) has been observed in DeTC. The identification of these activating mutations in DeTC makes this malignancy an excellent model to examine the effect of tyrosine kinase inhibitors (TKIs). Clinical trials with several TKIs targeting RET, and to a lesser extent BRAF, and other TKRs have shown positive results, with about one-third of DeTC showing a reduction in tumor size up to 50%, with the longest treatment duration of approximately three-four years. Angiogenesis inhibitors have also shown promising activity in DeTC. Progress is being made toward effective targeted DeTC therapy. The possibility of testing the sensitivity of primary DeTC cells from each subject to different TKIs could increase the effectiveness of the treatment.

Selectively Targeting Mutant BRAF in Thyroid Cancer

Selectively Targeting Mutant BRAF in Thyroid Cancer

Selecting subjects for a therapeutic target in colorectal cancer (CRC): Using a clinical database to enrich for patients harboring the BRAFV600E mutation

11003 Introduction: The BRAFV600E mutation (BRAF) causes constitutive activation of the RAS-induced MAPK pathway and is found in 10% of colon cancers. B-RAF inhibitors are in early clinical development, but their development in CRC will be challenging unless subsets of patients (pts) with higher rates of BRAF can be defined. The mutation rate in rectal tumors, the concordance between primary and metastases, and the prognostic/predictive significance of BRAF are current gaps in knowledge. Methods: 481 primary tumors and 80 matched primary-metastasis (prim-met) pairs were analysed from a pre-defined cohort of pts with CRC based on age (≥ 70 vs < 70 years), gender, tumor site (right-R, left-L and rectum), stage (A to C vs D) and ≥ 2 years follow-up. BRAF was assessed by routine sequencing of exon 15 and by a mutant-specific PCR assay. KRAS (KRAS-codon 12 and 13) and MSI (Bethesda markers) status were also examined. Results: Overall prevalence of BRAF was 11%. BRAF (see table ) was independently associated with increasing age, female gender and R-sided cancer, but not with stage. Mutations were rare in rectal cancers. BRAF was associated with inferior overall survival in stage D pts (log-rank, p = 0.0003; HR 0.38, 95% CI, 0.10–0.51). Survival analysis will be further stratified by treatment received. No difference in outcome was seen in preliminary analysis of earlier stage cancers. Mutation frequencies in the prim-met pairs were 38% (30/80) and 1.3% (1/80) for KRAS and BRAF, respectively. Overall concordance was 88% (70/80) for KRAS and 100% (80/80) for BRAF status. Conclusions: The development of selective B-Raf inhibitors in CRC is potentially more attractive due to the ability to define patient subsets with a higher prevalence of BRAF mutations. Analysis of the primary tumor reliably predicts the status of metastatic disease in the same patient. The association between BRAFand poor outcome will need to be considered when interpreting the result of studies targeting this mutation. [Table: see text] [Table: see text]

Papillary Thyroid Carcinoma Tall Cell Variant

The most common of the aggressive variant of papillary thyroid carcinoma (PTC) is the tall cell variant (TCV). Because there are serious prognostic and management implications to a diagnosis of TCV, we review the entity to inform clinicians about the many facets of TCV. The TCV of PTC is characterized by cells having the nuclear features of PTC and whose height is at least twice or thrice their width. There is disagreement regarding the proportion of tall cells and the cell height required to diagnose TCV. In view of its blurred definition and rarity, studies have shown that TCV is still underdiagnosed. We propose that PTC be diagnosed as TCV if it is composed of > or =50% tall cells. The latter should have a height that is at least twice their width, an eosinophilic cytoplasm, and the nuclear features of PTC. Whatever its definition, there is a consensus that TCV has a higher recurrence and death rate than classical PTC. Most authorities believe that TCV's worse prognosis is related to its older age at presentation, larger tumor size, and high frequency of extrathyroid extension (ETE). However, in a recent article, TCV without ETE was shown to have a more aggressive behavior than classical PTC without ETE independent of age, gender, and tumor size. The aggressive behavior of TCV could be related to the high expression of Muc1 and matrix metalloproteinase and to the higher prevalence of B-RAF mutations when compared to classical PTC. The importance of TCV is accentuated by the fact that it is overrepresented in those fluorodeoxyglucose positron-emission tomogram (FDG-PET)-positive thyroid carcinomas that are refractory to radioactive iodine (RAI) therapy constituting 20% of these incurable tumors. TCV is a biologically and clinically aggressive form of PTC that is still underdiagnosed. TCV is overrepresented in patients with RAI refractory disease. It has a high prevalence of B-RAF mutations making the latter an attractive target in RAI refractory cases. Imaging modalities that can detect RAI refractory disease such as FDG-PET scanning are needed in many patients and a requirement in those with extensive ETE. More studies are needed to identify those TCV that become RAI refractory and develop effective target therapies against these incurable carcinomas.

Thyroid epithelial tumours

The traditional classification of thyroid tumours is derived from follicular and ‘C’ cells and based on morphology and clinical features, but molecular studies have shown the involvement of distinct genes in each of these tumours. The high prevalence of papillary microcarcinoma in thyroid glands removed for other reasons underpinned the alteration of the TNM classification of thyroid tumors. Molecular studies showed that the high prevalence of BRAF mutations in papillary carcinomas, reaching ≤70% in some series, contrasts with lower levels of this mutation in cases of follicular variants. Follicular variants of papillary carcinoma share oncogene changes with follicular tumours, making the differential diagnosis of follicular lesions a challenge. Hyalinizing trabecular tumour has the same RET oncogene rearrangement encountered in many papillary carcinomas, raising the possibilty that it is a variant of papillary carcinoma. The ‘mixed medullary-follicular cell carcinoma’ is of uncertain histogenesis and merits separate classification.

Pyrophosphorolysis DetectsB-RAFMutations in Primary Uveal Melanoma

Mutations in the genes that control cell proliferation in cutaneous melanoma are generally uncommon in uveal melanoma. Despite the absence of known activating mutations, the RAF-MEK-ERK, or mitogen-activated protein kinase (MAPK), pathway is usually activated in uveal melanoma. An assay with increased potential to identify mutations is now available, and this study was therefore conducted to reanalyze uveal melanoma cell lines and primary tumors for this mutation. Eleven uveal melanoma cell lines and 45 primary uveal melanomas were analyzed for mutations in exon 15 of the B-RAF gene by using pyrophosphorolysis-activated polymerization (PAP). Mutations were validated by sequencing of the PAP product. B-RAF mutations were detected in cell lines OCM-1 and -3 (V600E) and in six primary uveal melanomas. The V600K mutation was detected in one primary uveal melanoma, for which the V600E assay turned out to be sensitive as well. Direct sequencing of the exon 15 PCR product did not reveal the mutations found with the PAP-assay, indicating a low frequency of the mutant allele in primary samples. Because of the very sensitive PAP technology, B-RAF mutations were found in cell lines and primary uveal melanomas, which suggests that they may occasionally play a role in the activation of the MAPK pathway in uveal melanoma and indicates a higher prevalence of B-RAF mutations in uveal melanoma than was reported earlier. However, the relative scarcity of the B-RAF mutation excludes an elemental role for this mutation in uveal melanoma.

Enhanced B-Raf protein expression is independent of V600E mutant status in thyroid carcinomas

BRAF (7q24) encodes a serine/threonine protein kinase, and its expression level varies in different tissues. Although a high prevalence of BRAF mutation has been suggested as an important event in thyroid tumorigenesis, little is known about the expression pattern of B-Raf in the thyroid. Thus, we examined the expression of B-Raf in various neoplastic and nonneoplastic thyroid tissues and compared it with BRAF mutational status. Normal and hyperplastic thyroid tissues showed focal and faint immunoreactivity for B-Raf, especially in cuboidal follicular cells of small follicles. In contrast, diffuse expression of B-Raf was observed in follicular adenomas and well-differentiated carcinomas. The missense point mutation BRAF(V600E) was identified in 42% (13/31 cases) of papillary carcinomas and 33% (5/15 cases) of undifferentiated carcinomas but not in normal thyroid tissues, nodular hyperplasia, follicular adenomas, or follicular carcinomas. The immunohistochemical expression of B-Raf did not correlate with BRAF mutational status. Moreover, Western blotting revealed that B-Raf expression in thyroid carcinoma cell lines was also independent of BRAF mutation. Serum or fibroblast growth factor-1 stimulation further activates ERK1/2 in heterozygous BRAF(V600E)-positive carcinoma cells as well as BRAF(V600E) mutation-negative carcinoma cells. In conclusion, heterogeneous focal expression of wild-type B-Raf in nonneoplastic tissues may play a role in the growth or functional activity of thyroid follicular cells. In contrast, diffuse expression of wild-type and/or mutant B-Raf may be involved in the tumorigenic process resulting in activation of the mitogen-activated protein kinase signaling pathway in cooperation with other genetic abnormalities and activation of ligand-receptor signaling pathways.

BRAF V599E Mutation is Not Age Dependent: It is Present in Common Melanocytic Nevi in Both Children and Adults

BRAF encodes a serine‐threonine kinase, which acts in the RAS/RAF/MAPK pathway transducing regulatory signals from RAS to MEK1/2. Somatic mutations in BRAF have been identified in 53–80% of primary melanomas and 70–90% of common melanocytic nevi. More than 90% of these mutations consist of a valine to glutamate substitution at codon 599 (V599E) of exon 15. While a high prevalence of BRAF mutations in common melanocytic nevi has been reported in adults, nevi in children have not been studied. Of interest, we have previously shown that Spitz nevi in children do not harbor mutations in BRAF. To investigate the association of BRAF mutations with patient age, we studied common melanocytic nevi in children for the V599E activating mutation. Tumor cells were microdissected from 6 common melanocytic nevi in children 10 years of age or younger, and analyzed for the V599E mutation in BRAF by allele‐specific PCR and gel electrophoresis. In 6 of 6 (100%) nevi, the V599E mutant allele was observed. Our data suggest that similar genetic pathways are involved in the development of common melanocytic nevi in children and adults. The absence of BRAF mutations in Spitz nevi in children is therefore associated with tumor type, not patient age.

Molecular Analysis of Structural Abnormalities in Papillary Thyroid Carcinoma Genome

Rearrangements of the RET proto-oncogene (RET/PTC) and BRAF gene mutations are the major genetic alterations in the etiopathogenesis of papillary thyroid carcinoma (PTC). We have analyzed a series of 118 benign and malignant follicular cell-derived thyroid tumors for RET/PTC rearrangements and BRAF gene mutations. Oncogenic rearrangements of RET proto-oncogene was revealed by semiquantitative RT-PCR of simultaneously generated fragments corresponding to tyrosine kinase (TK) and extracellular RET domains. The clear quantitative shift toward the TK fragment is indicative for the presence of RET rearrangements. The overall frequency of RET/PTC rearrangements in PTC was 14% (12 of 85), including 7 RET/PTC1, 2 RET/PTC3, 1 deltaRFP/RET and 2 apparently uncharacterized rearrangements. The most common T1796A transversion in BRAF gene was detected in 55 of 91 PTC (60%) using mutant-allele-specific PCR. We also identified two additional mutations: the substitution G1753A (E585K) and a case of 12-bp deletion in BRAF exon 15. Moreover, there was no overlap between PTC harboring BRAF and RET/PTC mutations, which altogether were present in 75.8% of cases (69 of 91). Taken together, our observations are consistent with the notion that BRAF mutations appear to be an alternative pathway to oncogenic MAPK activation in PTCs without RET/PTC activation. Neither RET/PTC rearrangements nor BRAF muta-tions were detected in any of 3 follicular thyroid carcinomas, 11 follicular adenomas and 13 nodular goiters. The high prevalence of BRAF mutations and RET/PTC rearrangements in PTCs and the specificity of these alterations to PTC make them potentially important markers for the preoperative tumor diagnosis.