| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Institut National de la Santé et de la Recherche Médicale U555 (V.V., M.F., J.D.C., P.C., J.F.H., C.d.M.), Department of Endocrine Surgery (J.F.H.), and Laboratory of Pathology (C.d.M.), Faculty of Medicine, Mediterranean University, Marseille, 13385 France; and Hospital for Endocrine Surgery (V.V.), Kiev, 252000 Ukraine
Address all correspondence and requests for reprints to: Dr. Catherine de Micco, Institut National de la Santé et de la Recherche Médicale U555, Faculté de Médecine, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 5, France. E-mail: cathy.demicco{at}medecine.univ-mrs.fr.
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
|---|
To address this issue, we first performed a pooled analysis of 269 mutations garnered from 39 previous studies. Mutations proved significantly less frequent when detected with direct sequencing than without (12.3% vs. 17%). The rate of mutation involving N-RAS exon 1 (N1) and K-RAS exon 2 (K2) was less than 1%. Mutations of codon 61 of N-RAS (N2) were significantly more frequent in follicular tumors (19%) than in papillary cancers (5%) and significantly more frequent in malignant (25%) than in benign (14%) tumors. H-RAS mutations in codons 12/13 (H1) were found in 2–3% of all types of tumors, but H-RAS mutations in codon 61 (H2) were observed in only 1.4% of tumors, and almost all of them were malignant. K-RAS mutations in exon 1 were found more often in papillary than follicular cancers (2.7% vs. 1.6%) and were sometimes correlated with special epidemiological circumstances.
The second part of this study involved analysis of 80 follicular tumors from patients living in Marseille (France) and Kiev (Ukraine). We used direct sequencing after PCR amplification of exons 1 and 2 of the three RAS genes. Common and atypical adenomas were separated using strict cytological criteria. Mutations of H1-RAS were found in 12.5% of common adenomas and one follicular carcinoma (2.9%). Mutations of N2-RAS occurred in 23.3% and 17.6% of atypical adenomas and follicular carcinomas, respectively. These results confirm the predominance of N2-RAS mutations in thyroid follicular tumors and their correlation with malignancy. They support the implication of N2-RAS mutations in the malignant progression of thyroid follicular tumors and the assumption that some atypical adenomas are precursors of follicular carcinomas.
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Activating mutations of all three RAS oncogenes (H-RAS, K-RAS, and N-RAS) in thyroid tumors were first reported in 1988 (7, 8). Those early results demonstrated that RAS mutations were more frequent in follicular than in papillary tumors and that the two types of carcinoma had different mutation patterns (9). The presence of mutations in up to 50% of microfollicular adenomas supported the contention that RAS oncogene activation was an early event in follicular thyroid tumorigenesis (10, 11).
In subsequent studies on RAS oncogenes in thyroid tumors, various laboratories reported disparate results regarding the incidence of mutations, isoform pattern (H-RAS, K-RAS, or N-RAS), and correlation of mutations with histology. The incidence of RAS oncogene mutations ranged from 0–50% in papillary cancer (12, 13, 14), 0–85% in adenomas (15, 16), 14–62% in follicular carcinomas (15, 17), and 0–60% in anaplastic carcinomas (10, 18). Although some investigators found no correlation between the mutated RAS oncogene isoform and tumor pathology (19), others reported a higher frequency of mutations in the codon 61 of H-RAS and N-RAS in follicular tumors and poorly differentiated carcinomas (15, 17). Mutations involving K-RAS or codons other than codon 61 in H-RAS and N-RAS, and mutations in other types of thyroid tumors proved uncommon (20, 21).
At least four possible explanations can be offered to account for these disparate findings. The first involves methodology because a wide variety of techniques have been used to detect mutations. In this regard, it should be emphasized that specificity has improved with increasingly wider availability of direct sequencing. Another explanation requiring further study involves environmental factors such as iodine deficiency (16, 22), radiation exposure (23, 24, 25), and food-borne carcinogens (14). A third explanation is that the small number of cases in many studies may have had a confounding effect on statistical analysis. The fourth explanation involves variations in the histological classification of follicular thyroid tumors, but the impact of such variations is difficult to evaluate because little attention has been given to morphological and biological heterogeneity of thyroid follicular tumors.
The purpose of this article is to describe and compare the results of assessment of RAS-oncogene mutations in 80 thyroid follicular tumors in patients from Marseille, France, and Kiev, Ukraine. Tumor diagnosis was based on strict morphological criteria. Mutations were assessed by direct sequencing of PCR-amplified sequences in exons 1 and 2 of the H-RAS, K-RAS, and N-RAS oncogenes. Findings were compared with the results of a pooled analysis of 39 previous reports on RAS-oncogene mutations in thyroid tumors, with special attention to the influence of methodology and histological classification.
|
Patients and Methods |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Tissue specimens were obtained from 33 patients treated at the Ukrainian Center of Endocrine Surgery in Kiev, Ukraine, and 47 patients treated at the Timone University Hospital Center in Marseille, France. Tumors were classified as widely invasive follicular carcinoma (WIFC) in 16 cases, minimally invasive follicular carcinoma (MIFC) in 18, atypical follicular adenoma (AFA) in 30, and classical follicular adenoma (FA) in 16. The clinicopathological features of these tumors are listed in Table 1
. The study protocol was approved by the clinical research committee of Marseille Public Hospital System.
|
DNA extraction
The unstained 20-µm tumor sections were used for RAS oncogene detection as follows. Slides were deparaffinized in xylene, washed in ethanol, and rehydrated. Any tissue surrounding the tumor, including normal thyroid, connective tissue, inflammatory cells, and necrotic or hemorrhagic zones, was carefully pared away using a scalpel under microscopic observation. The purpose of paring was to ensure that tumor cells comprised over 90% of the remaining specimen. After suspension in 400 µl of 100 mM Tris buffer (pH 8.0) containing 100 mM NaCl, 20 mM EDTA, 2% sodium dodecyl sulfate, and 80 µg proteinase K (Roche Diagnosis, Meylan, France), pared specimens were incubated for 5 d at 55 C with daily addition of 80 µg proteinase K. At the end of incubation, proteinase K was inactivated by heating for 10 min at 95 C. DNA was extracted using the QI-Amp DNA mini kit (QIAGEN, Les Ulis, France) according to the manufacturer’s tissue protocol. DNA content was quantified by spectrophotometric absorption at 260 nm and evaluation of A 260/A 280 ratio. Extracts were stored at 4 C until assayed.
PCR amplification and sequencing
Sequences of H-RAS, K-RAS, and N-RAS oncogenes in exons 1 and 2 (designated H1, H2, K1, K2, N1, and N2) were amplified using the primer-pairs listed in Table 2. The PCR mixture (50 µl) contained 0.1–0.5 µg of genomic DNA, 2 mM or 1.5 mM MgCl2 for the K1-RAS and N1-RAS oncogenes or the other RAS oncogenes, respectively, 10x concentrated PCR-buffer (QIAGEN), 200 µM of deoxyribonucleoside triphosphate (dATP, dCTP, dGTP, dTTP), 200 nM of each primer, and 1.25 U of HotStar Taq DNA Polymerase (QIAGEN). Amplification was achieved on a Cyclogen Dri-block Cycler Techne (Cambridge Ltd., Cambridge, UK). After HotStarTaq DNA-polymerase activation at 95 C for 15 min, templates were denaturated at 94 C for 2 min. This initial step was followed by 30–38 cycles of PCR, each comprising 1 min of denaturation at 94 C, 1 min of annealing (at 53 C for N2-RAS; 55 C for H1-RAS and K1-RAS oncogene; 57 C for H2-RAS and N1-RAS oncogene; and 58 C for K2-RAS oncogene), and 1 min of extension at 72 C. In the last cycle, the extension step was prolonged for 10 min. PCR products were submitted to electrophoresis on 3% agarose gel in Tris-acetate-EDTA buffer and stained with ethidium bromide. In all cases, direct sequencing was performed using an Applied Biosystem 373XL sequencer (PE Applied Biosystems, Paris, France) according to the manufacturer’s instructions on PCR products purified using a QIAGEN gel extraction kit. In samples exhibiting mutations, both sense and antisense strands were sequenced for confirmation.
|
A pooled analysis including 39 previously published reports focusing on RAS oncogene mutations in thyroid tumors was performed. The purpose of this analysis was to gain better insight into the incidence of RAS oncogene mutations and clinicopathological correlations in a large patient population. Selection of reports for inclusion in this pooled analysis was based on the thoroughness of study data regarding methodology, histology, and RAS oncogene mutations (8, 9, 10, 11, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47). The histological tumor type, the method used to detect mutations, and the presence or absence, type, and location of mutations were noted in all cases. If mentioned, data on iodine intake, radiation exposure, or other epidemiological factors were also noted.
Statistical analysis
Correlations between clinicopathological variables and RAS mutations were analyzed using the 
2 or Fischer’s exact test. A P value less than 0.05 was considered as significant.
|
Results |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Results on RAS mutations found in our study are detailed in Table 3. Their correlation with tumor histology is shown in Fig. 1.
|
|
GTC) at codon 12 resulting in an amino acid change from Gly to Val. It was found in two FA from French patients (12.5%) and one MIFC from a Ukrainian patient (5.5%). Reexamination of the slides of the two FA confirmed the absence of cellular atypia and revealed no special feature as compared with nonmutated tumors. The difference in the incidence of H-RAS mutation between the FA and FC subgroups was not statistically significant (P = 0.1), indicating that H1-RAS mutations occur in benign as well as in malignant follicular tumors.
N2-RAS mutations were found in seven AFA (23.3%), four MIFC (22.2%), and two WIFC (12.5%). In one MIFC, it was a CAAAAA transversion at codon 61 resulting in an amino acid change from Gln to Lys. In the other 12 cases, CAACGA transitions at codon 61 resulting in a Gln to Arg change were found. Reexamination of these slides confirmed characteristic features of AFA and MIFC differing only with regard to the presence of invasive properties in the MIFC. Growth pattern was heterogeneous, with unevenly distributed compact areas. The appearance of follicular cells was polymorphous, with frequently enlarged eosinophilic or clear cytoplasms. Nuclei were enlarged and often overlapping, but they retained their rounded shape. Nuclear chromatin exhibited a dusty appearance with dispersed clumping creating a salt-and-pepper effect. The difference in the incidence of N2-RAS mutation was statistically significant between FA (0%) and AFA (23.3%; P = 0.038), as well as between FA (0%) and MIFC (17.6%; P = 0.026). Conversely, the difference in the incidence of N2-RAS mutation between AFA (23.3%) and FC (17.6%) was not significant (2 = 0.37; P > 0.5). The observed difference in the incidence of N2-RAS mutation between MIFC (22.2%) and WIFC (12.5%) was not statistically significant (2 = 0.56; P > 0.3).
Clinicopathological features of mutated cases are given in Table 4. No correlation was found between the incidence of N2-RAS mutation and any of the following parameters: age, sex, tumor size, metastasis, and geographical origin (France or Ukraine). The only pathological parameter significantly correlated with N2-RAS mutations in follicular tumors was association with multinodular goiter (2 = 5.2; P < 0.05).
|
Because direct sequencing is the only means of definitely proving mutation, we compared the overall incidence of mutations found in all studies (n = 39) and studies including confirmation of mutation by direct sequencing (n = 22; Table 5). We first analyzed a subset of 27 studies in which estimation of the incidence of RAS mutation was based on analysis of all three RAS oncogene isoforms, i.e. H-RAS, K-RAS, and N-RAS, in the same tumors (Table 5; Refs. 8, 9, 10, 14, 15, 16, 17, 19, 20, 21, 22, 23, 24, 25, 27, 28, 29, 30, 33, 37, 38, 40, 41, 44, 45, 48, 49). Next, we pooled the results of studies in which any of the H-RAS, K-RAS, and N-RAS isoforms were analyzed to know their respective prevalence (Table 5). The overall rate of mutations was significantly lower when estimated with direct sequencing than without (12.3% vs. 17%; P < 0.01). Overestimation of H2-RAS and N1-RAS mutations was particularly frequent without sequencing (1.3% and 0.3% vs. 2.9% and 1%, respectively; P < 0.01 and P < 0.05). The most common mutations in thyroid tumors affected N2-RAS in codon 61. The rate of mutation involving N2-RAS oncogenes was significantly higher than the rate of mutations involving the H1-RAS, H2-RAS, and K1-RAS oncogenes, i.e. 8% vs. 3.2%, 1.3%, or 1.8%, respectively (P < 10-6). The least frequent mutations involved N1-RAS (0.3%) and K2-RAS (0.4%).
|
and illustrated in Fig. 2. For comparison, results of our study on follicular adenomas and carcinomas have been repeated in Table 6 after those of pooled analysis. For anaplastic carcinomas, subtypes of follicular tumors and subtypes of papillary cancers, the number of cases in which detection of the three isoforms of RAS was performed was too small for statistical analysis. Mutations involving H1-RAS were found in 2–3% of all tumors, with no significant correlation with any specific class. Mutations involving N1-RAS and K2-RAS were equally rare in all tumors (0–2%). Mutations involving H2-RAS were rare, but they were significantly more frequent in follicular carcinomas than in benign tumors (5% vs. 0.5%; P < 0.02). Regarding mutations involving K1-RAS, the difference in prevalence was not significant between papillary (2.3%) and follicular cancer (1.6%), but it was significantly higher for malignant (papillary and follicular carcinoma) than benign thyroid tumors (colloid nodules and adenoma; P < 10-4). Mutations in codon 61 of N-RAS accounted for more than 50% of RAS mutations observed in thyroid tumors. These mutations were more frequent in follicular tumors than in other histotypes (P < 10-7), and their prevalence was significantly higher in carcinoma (25%) than in adenoma (14%; P < 0.03). They were found in 5% of papillary cancers, but the histological subtype of these cases was not specified.
|
|
GTC, resulting in Gly to Val substitution, accounted for 62% of exon 1 mutations. The prevalence of this mutation was the same in all the histological types. In 15.5% of cases, mutations in exon 1 affecting codons 12 (GGTAGT), 13 (GGCAGC), or 15 (CCGTCG) resulted in Gly to Ser substitution. Interestingly, this type of mutation was found almost exclusively in thyroid papillary or anaplastic carcinomas and sometimes showed geographical concentration (14). Mutations in exon 2 affecting codon 61 resulted in Gln to Arg changes in 66.6% of cases (CAGCGG or CAACGA) and Gln to Lys changes in 25.3% of cases (CAGAAG or CAAAAA). These mutations involved follicular tumors in 68% of cases, including 67% that were malignant. |
Discussion |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
A major limitation for the study of RAS oncogene mutations in thyroid tumors has been the small number of cases in individual series. To overcome this problem, we performed a pooled analysis of 229 cases of RAS mutations described in 39 previous publications and compared the findings with data from our own study of 80 follicular thyroid tumors. Preliminary findings of pooled analysis indicated that detection of RAS mutations was less frequent using direct sequencing than other methods (12.3% vs. 17%). This may be due in part to the inability of direct sequencing to detect a low proportion of mutated alleles in polyclonal tumors or samples including a proportion of normal tissue. However, similar results were found in several large studies in which tumors of all histological types were analyzed using a highly sensitive screening method followed by direct sequencing to confirm mutations (20, 21, 25). An alternative explanation is that some studies using highly sensitive but less specific screening methods without confirming mutations by direct sequencing may have overestimated RAS mutations. Because direct sequencing is the gold standard in mutation detection, we chose it in our study to ensure the most reliable results. To avoid dilution of mutated alleles in heterogeneous tissues, we studied homogeneous tumors with well defined histology and pared off normal thyroid tissue from sections under microscopic examination before nucleic acid extraction so that tumor cells represented more than 90% of the sample.
In addition to confirming the low overall incidence of RAS mutation in thyroid tumors, the three major findings of our metaanalysis are that RAS oncogene mutations are significantly more frequent in malignant than benign tumors, they involve exon 2 (at codon 61) more often than exon 1, and they predominate in follicular tumors over other tumor types. These tumor-specific differences are consistent not only with the general biology of RAS oncogenes (51) but also with the initial findings concerning RAS oncogene activation in thyroid tumors (9, 56).
The most common mutations in exon 1 are transversions affecting the H-RAS and K-RAS at an equal rate. Whereas H1-RAS mutations show no specific correlation with any tumor type or with malignancy, K1-RAS mutations are found mainly in malignant tumors and, in some cases (mutation in codons 12, 13, or 15 leading to a Gly to Ser change), are strongly correlated with the papillary phenotype. The Gly to Ser substitution in codons 12, 13, or 15 of RAS oncogene could represent a genetic defect implicated in the genesis of some papillary cancers. It is noteworthy that Gly to Ser changes at position 12 of K-RAS oncogene were found in a series of papillary tumors in Thailand but not in Japan. This could indicate involvement of a specific environmental agent (14). Food contamination by N-nitroso compounds has been implicated on the basis of experimental studies showing that nitrosamines preferentially induce mutations in exon 1 of H-RAS or K-RAS oncogenes (10, 53).
Most mutations in exon 2 are transitions at position 61 involving N-RAS oncogenes. The frequency of these mutations is significantly correlated with follicular phenotype and malignancy, but they are also found in some adenomas. The presence of RAS mutations in benign thyroid tumors and the observation of self-limiting proliferation after transfection of human thyroid cells with mutant RAS (55) have been considered as evidence that RAS mutation is unrelated to malignant transformation (57). However, this interpretation is inconsistent with the observation of a higher rate of mutation in malignant than benign thyroid tumors. Thus, the significance of RAS oncogene mutation in benign thyroid tumors can still only be speculated upon, especially in the absence of data concerning histological subtypes. Problems in the histological diagnosis of follicular thyroid tumors, e.g. interlaboratory variability, have further confused the situation.
The purpose of our study was to evaluate the occurrence of RAS mutations in morphologically well defined benign and malignant follicular tumors. We found no mutations involving H2-RAS, K1-RAS, K2-RAS, or N1-RAS. These findings are consistent with the conclusion of pooled analysis that such mutations are uncommon in follicular tumors. Observation of mutations involving H1-RAS in only two adenomas and one carcinoma is also in agreement with literature analysis showing a low overall incidence (2–3%) of H1-RAS mutations in thyroid tumors without significant correlation with histology or malignancy. These findings are also consistent with experimental results showing that transfection of human thyroid follicular cells with mutant (Val-12) H-RAS oncogene induces proliferation without transformation or loss of differentiation (55). This body of evidence demonstrates that mutant (Val-12) H-RAS oncogene does not cause malignant transformation, although it may be involved in some events initiating thyroid tumorigenesis.
Our data also corroborate results of previous studies showing that N-RAS mutation in codon 61 is the predominant RAS mutation in follicular thyroid tumors (9, 20). In addition, our data show that N2-RAS mutations occur only in carcinomas and atypical adenomas. Nonatypical benign follicular tumors never exhibited these mutations. Because histological subtypes of thyroid adenomas have rarely been analyzed separately in previous studies, there is little information on the prevalence of N2-RAS mutations in atypical adenomas. One study comprising a total of 17 atypical adenomas found 5 mutations in codon 12 of H-RAS but made no mention of codon 61 or of tumor histology. Because the same study demonstrated several cases of Hürthle cell carcinomas associated with H-RAS mutations, the possibility that the atypical adenomas were also of the Hürthle-cell type cannot be ruled out. A separate analysis will be necessary to settle this issue because Hürthle-cell tumors represent a special phenotype (18, 36). Our series did not include any case of Hürthle-cell tumor. To our knowledge, N2-RAS mutations have been reported in only two cases of atypical adenomas defined on the basis of strict morphological criteria like those used in our study (35). In this regard, it should be emphasized that the significance of cellular atypia in follicular tumors remains controversial. Although they are regarded as benign tumors, several properties suggestive of malignancy, such as DNA copy depletion (58), loss of heterozygosity (59), alteration of thyroid-peroxidase expression (60, 61), increased proliferation (62), or spectral pattern by proton magnetic resonance (22, 63), are found in atypical adenomas as well as in carcinomas. Evidence that the incidence and type of N2-RAS mutations is similar in carcinomas and atypical adenomas further supports the hypothesis that such mutations are implicated in malignant progression and that atypical adenomas have started that progression: they might represent the preinvasive form of follicular thyroid carcinoma.
|
Footnotes |
|---|
Abbreviations: AFA, Atypical follicular adenoma; FA, follicular adenoma; MIFC, minimally invasive follicular carcinoma; WIFC, widely invasive follicular carcinoma.
Received August 12, 2002.
Accepted February 21, 2003.
|
References |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
A mutation of ras genes and infrequent p53 gene mutation in rat transplantable thyroid carcinoma lines from tumors induced in vivo by N-bis(2-hydroxypropyl)nitrosamine. Cancer Lett 100:55–62[CrossRef][Medline]
This article has been cited by other articles:
 |
|
 |
|
  S. Hoshi, N. Hoshi, M. Okamoto, J. Paiz, T. Kusakabe, J. M. Ward, and S. Kimura Role of NKX2-1 in N-bis(2-hydroxypropyl)-nitrosamine-induced thyroid adenoma in mice Carcinogenesis, September 1, 2009; 30(9): 1614 - 1619. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Fedele, D. Palmieri, G. Chiappetta, R. Pasquinelli, I. De Martino, C. Arra, G. Palma, T. Valentino, G. M Pierantoni, G. Viglietto, et al. Impairment of the p27kip1 function enhances thyroid carcinogenesis in TRK-T1 transgenic mice Endocr. Relat. Cancer, June 1, 2009; 16(2): 483 - 490. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J P. Couto, H Prazeres, P Castro, J Lima, V Maximo, P Soares, and M Sobrinho-Simoes How molecular pathology is changing and will change the therapeutics of patients with follicular cell-derived thyroid cancer J. Clin. Pathol., May 1, 2009; 62(5): 414 - 421. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Liu, P. Hou, M. Ji, H. Guan, K. Studeman, K. Jensen, V. Vasko, A. K. El-Naggar, and M. Xing Highly Prevalent Genetic Alterations in Receptor Tyrosine Kinases and Phosphatidylinositol 3-Kinase/Akt and Mitogen-Activated Protein Kinase Pathways in Anaplastic and Follicular Thyroid Cancers J. Clin. Endocrinol. Metab., August 1, 2008; 93(8): 3106 - 3116. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F Frasca, C Nucera, G Pellegriti, P Gangemi, M Attard, M Stella, M Loda, V Vella, C Giordano, F Trimarchi, et al. BRAF(V600E) mutation and the biology of papillary thyroid cancer Endocr. Relat. Cancer, March 1, 2008; 15(1): 191 - 205. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M Cavaco, P. F Batista, C. Martins, A. Banito, F. do Rosario, E. Limbert, L. G Sobrinho, and V. Leite Familial non-medullary thyroid carcinoma (FNMTC): analysis of fPTC/PRN, NMTC1, MNG1 and TCO susceptibility loci and identification of somatic BRAF and RAS mutations Endocr. Relat. Cancer, March 1, 2008; 15(1): 207 - 215. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Salajegheh, E B Petcu, R A Smith, and A K-Y Lam Follicular variant of papillary thyroid carcinoma: a diagnostic challenge for clinicians and pathologists Postgrad. Med. J., February 1, 2008; 84(988): 78 - 82. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Santarpia, A. K. El-Naggar, G. J. Cote, J. N. Myers, and S. I. Sherman Phosphatidylinositol 3-Kinase/Akt and Ras/Raf-Mitogen-Activated Protein Kinase Pathway Mutations in Anaplastic Thyroid Cancer J. Clin. Endocrinol. Metab., January 1, 2008; 93(1): 278 - 284. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Xing BRAF Mutation in Papillary Thyroid Cancer: Pathogenic Role, Molecular Bases, and Clinical Implications Endocr. Rev., December 1, 2007; 28(7): 742 - 762. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. M. Tsygankova, G. V. Prendergast, K. Puttaswamy, Y. Wang, M. D. Feldman, H. Wang, M. S. Brose, and J. L. Meinkoth Downregulation of Rap1GAP Contributes to Ras Transformation Mol. Cell. Biol., October 1, 2007; 27(19): 6647 - 6658. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Wang, P. Hou, H. Yu, W. Wang, M. Ji, S. Zhao, S. Yan, X. Sun, D. Liu, B. Shi, et al. High Prevalence and Mutual Exclusivity of Genetic Alterations in the Phosphatidylinositol-3-Kinase/Akt Pathway in Thyroid Tumors J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2387 - 2390. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Xing Gene Methylation in Thyroid Tumorigenesis Endocrinology, March 1, 2007; 148(3): 948 - 953. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Vasko, A. V. Espinosa, W. Scouten, H. He, H. Auer, S. Liyanarachchi, A. Larin, V. Savchenko, G. L. Francis, A. de la Chapelle, et al. Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion PNAS, February 20, 2007; 104(8): 2803 - 2808. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Hou, D. Liu, Y. Shan, S. Hu, K. Studeman, S. Condouris, Y. Wang, A. Trink, A. K. El-Naggar, G. Tallini, et al. Genetic Alterations and Their Relationship in the Phosphatidylinositol 3-Kinase/Akt Pathway in Thyroid Cancer Clin. Cancer Res., February 15, 2007; 13(4): 1161 - 1170. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. A. B. Knostman, S. M. Jhiang, and C. C. Capen Genetic Alterations in Thyroid Cancer: The Role of Mouse Models Vet. Pathol., January 1, 2007; 44(1): 1 - 14. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Fikaris, A. E. Lewis, A. Abulaiti, O. M. Tsygankova, and J. L. Meinkoth Ras Triggers Ataxia-telangiectasia-mutated and Rad-3-related Activation and Apoptosis through Sustained Mitogenic Signaling J. Biol. Chem., November 17, 2006; 281(46): 34759 - 34767. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Matsukuma, M. Yoshihara, F. Kasai, A. Kato, A. Yoshida, M. Akaike, O. Kobayashi, H. Nakayama, Y. Sakuma, T. Yoshida, et al. Rapid and Simple Detection of Hot Spot Point Mutations of Epidermal Growth Factor Receptor, BRAF, and NRAS in Cancers Using the Loop-Hybrid Mobility Shift Assay J. Mol. Diagn., September 1, 2006; 8(4): 504 - 512. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J Di Cristofaro, M Silvy, A Lanteaume, M Marcy, P Carayon, and C De Micco Expression of tpo mRNA in thyroid tumors: quantitiative PCR analysis and correlation with alterations of ret, Braf , ras and pax8 genes. Endocr. Relat. Cancer, June 1, 2006; 13(2): 485 - 495. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Chiloeches and R. Marais Is BRAF the Achilles' Heel of Thyroid Cancer? Clin. Cancer Res., March 15, 2006; 12(6): 1661 - 1664. [Full Text] [PDF]
|
|
|
|
|
|
B. Ouyang, J. A. Knauf, E. P. Smith, L. Zhang, T. Ramsey, N. Yusuff, D. Batt, and J. A. Fagin Inhibitors of Raf Kinase Activity Block Growth of Thyroid Cancer Cells with RET/PTC or BRAF Mutations In vitro and In vivo. Clin. Cancer Res., March 15, 2006; 12(6): 1785 - 1793. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Foukakis, A. Y. M. Au, G. Wallin, J. Geli, L. Forsberg, R. Clifton-Bligh, B. G. Robinson, W.-O. Lui, J. Zedenius, and C. Larsson The Ras Effector NORE1A Is Suppressed in Follicular Thyroid Carcinomas with a PAX8-PPAR{gamma} Fusion J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 1143 - 1149. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Castro, A. P. Rebocho, R. J. Soares, J. Magalhaes, L. Roque, V. Trovisco, I. Vieira de Castro, M. Cardoso-de-Oliveira, E. Fonseca, P. Soares, et al. PAX8-PPAR{gamma} Rearrangement Is Frequently Detected in the Follicular Variant of Papillary Thyroid Carcinoma J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 213 - 220. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Sarquis, F. Weber, L. Shen, C. E. Broelsch, S. M. Jhiang, J. Zedenius, A. Frilling, and C. Eng High Frequency of Loss of Heterozygosity in Imprinted, Compared with Nonimprinted, Genomic Regions in Follicular Thyroid Carcinomas and Atypical Adenomas J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 262 - 269. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Wu, E. Mambo, Z. Guo, S. Hu, X. Huang, S. M. Gollin, B. Trink, P. W. Ladenson, D. Sidransky, and M. Xing Uncommon Mutation, but Common Amplifications, of the PIK3CA Gene in Thyroid Tumors J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4688 - 4693. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M Xing BRAF mutation in thyroid cancer Endocr. Relat. Cancer, June 1, 2005; 12(2): 245 - 262. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Wagner, R. Arciaga, A. Siperstein, M. Milas, I. Warshawsky, S. Sethu, K. Reddy, and M. K. Gupta Thyrotropin Receptor/Thyroglobulin Messenger Ribonucleic Acid in Peripheral Blood and Fine-Needle Aspiration Cytology: Diagnostic Synergy for Detecting Thyroid Cancer J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 1921 - 1924. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J Di Cristofaro, V Vasko, V Savchenko, S Cherenko, A Larin, M D Ringel, M Saji, M Marcy, J F Henry, P Carayon, et al. ret/PTC1 and ret/PTC3 in thyroid tumors from Chernobyl liquidators: comparison with sporadic tumors from Ukrainian and French patients Endocr. Relat. Cancer, March 1, 2005; 12(1): 173 - 183. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Kohrle Guard Your Master: Thyroid Hormone Receptors Protect Their Gland of Origin from Thyroid Cancer Endocrinology, October 1, 2004; 145(10): 4427 - 4429. [Full Text] [PDF]
|
|
|
|
|
|
P. Chinnappa, L. Taguba, R. Arciaga, C. Faiman, A. Siperstein, A. E. Mehta, S. K. Reddy, C. Nasr, and M. K. Gupta Detection of Thyrotropin-Receptor Messenger Ribonucleic Acid (mRNA) and Thyroglobulin mRNA Transcripts in Peripheral Blood of Patients with Thyroid Disease: Sensitive and Specific Markers for Thyroid Cancer J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3705 - 3709. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Xing, V. Vasko, G. Tallini, A. Larin, G. Wu, R. Udelsman, M. D. Ringel, P. W. Ladenson, and D. Sidransky BRAF T1796A Transversion Mutation in Various Thyroid Neoplasms J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1365 - 1368. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
