Essential genes in thyroid cancers: focus on fascin
© Samimi et al.; licensee BioMed Central Ltd. 2013
Received: 23 June 2013
Accepted: 25 June 2013
Published: 1 July 2013
Although thyroid cancers are not among common malignancies, they rank as the first prevalent endocrine cancers in human. According to the results of published studies it has been shown the gradual progress from normal to the neoplastic cell in the process of tumor formation is the result of sequential genetic events. Among them we may point the mutations and rearrangements occurred in a group of proto-oncogenes, transcription factors and metastasis elements such as P53, RAS,RET,BRAF, PPARγ and Fascin. In the present article,we reviewed the most important essential genes in thyroid cancers, the role of epithelial mesenchymal transition and Fascin has been highlighted in this paper.
KeywordsThyroid cancer Mutation Rearrangement P53 RAS RET BRAF PPARγ Fascin
Thyroid cancer is considered as a rare malignancy which accounts for 1 to 2% of different type cancers. The annual occurrence rate of thyroid cancer in different parts of the world is reported to be about 0.5 to 10 in every 100,000 persons; yet, this cancer is considered as the most prevalent malignancies of the endocrine system [1–3]. Various studies indicate that women are 2–4 times more likely to suffer from the cancer . There is no difference between the incidence of thyroid cancer between men and women before menarche and after menopause, suggesting that the increased risk of developing thyroid neoplasia in women at child bearing age could be secondary to the effects of estrogen or other pregnancy-related factors. Moreover, the rate of developing thyroid cancers increases significantly after pregnancy, especially, in the last four months of pregnancy. However, it should be noted that, those consuming contraceptive pills or other external sources of estrogen are not at an increased risk of developing thyroid cancers . Positive family history of thyroid cancer is reported in 3-5% of the affected cases [3, 6, 7]. Apart from gender and genetic factors, the body size , race , geographical distribution [10, 11] and the amount of consumed iodine  also influence the risk of developing thyroid cancers. While thyroid cancer is reported at any age, the risk of developing the malignancy increases after the age of 30. Many believe thyroid cancer becomes more invasive with aging .
In the majority of the cases, cancer presents as asymptomatic thyroid nodules. In certain cases, however, patients complaint of pain in the neck, lymphadenopathy, and bone and lung involvement.
While thyroid nodules are found in approximately 10% of the people in each society, only 4-5% of the reported cold nodules are malignant [3, 14]. In countries with iodine deficiency,where iodine prophylaxisis common, palpable thyroid nodules are reported in 4-5% of the population . Although more than 90% of thyroid nodules in the general population are benign, some of these nodules might be malignant in nature as about 0.4% of the entire mortalities from cancer occur in those with thyroid malignancies .
Pathological analysis of thyroid cancers indicates that four types of thyroid cancers, namely papillary, follicular, anaplastic and medullary thyroid cancers, are more prevalent. The first three are of the follicular cell origin, whereas the medullary carcinoma originates from para-follicular cells (C Cells) [2, 16].
Papillary thyroid carcinoma (PTC)
Papillary carcinoma is the most prevalent type of thyroid cancer, reported in about 70% of those with thyroid malignancies. Half of the cases present before the age of 40; the remaining is mainly diagnosed in the 6th and 7th decades of life. The cancer is 2–3 times more frequently reported in women. High rates of this type of thyroid cancer are seen in those exposed to high dose X-radiation during childhood. The cases of sporadic thyroid cancer account for 95% of the sufferers and only 5% of the cases are hereditary .
Lymph node involvement is common in papillary carcinoma, with metastasis to neck lymph nodes and contiguous tissues reported in 50% and 25% of the cases, respectively. Compared to other thyroid carcinomas, metastasis via blood and particularly lung involvement is more prevalent in papillary carcinoma. This comes while involvement of the bones of the central nervous system and other organs is also possible. With respect to prognosis, papillary carcinomas tend to grow very slowly compared with other types of thyroid cancer. In other words, over 90% of the sufferers now survive for more than ten years; in 80% of them the life span is about 20 years .
Follicular thyroid carcinoma (FTC)
Follicular carcinomas are less prevalent than the papillary type and account for only 15% of thyroid malignancies. Most follicular carcinomas manifest in old ages and after the age of 52. The risk is 2–5 times higher in women. The cancer mainly presents as single cold nodules. In this stage, the lymph nodes are not yet involved. This comes while distant metastasis in lungs and bones are common in many sufferers . Compared with papillary carcinoma, follicular carcinoma has a poorer prognosis, with only 30% of the sufferers living for up to 10 years after the primary treatment .
Anaplastic thyroid carcinoma (ATC)
This carcinoma accounts for about 2% to 5% of thyroid malignancies. It is considered as a highly aggressive and lethal thyroid carcinoma. It can be seen at any age; however, it is more common among those aged between 60 and 70. Women are 5 times more vulnerable of developing the cancer . In 50% of the cases, anaplastic carcinoma may occur following a long-term history of goiter, thyroid adenoma, papillary or follicular carcinoma; its risk of becoming malignant, however, is rather low.
The cancer mainly presents with a rapidly growing neck mass . The malignancy has the poorest prognosis among primary thyroid neoplasms as the afflicted subjects die between 6 to 8 months after diagnosis. The tumor is treatable if diagnosed and treated in early stages .
Medullary thyroid carcinoma (MTC)
Medullary carcinoma accounts for 10% of thyroid malignancies. It is the most invasive type of cancer, on which iodine and chemotherapy are not effective. Surgery remains the only way to treat such cases; however, in cases experiencing recurrence, no successful treatment has been reported. On average, 65% of the patients may survive for 10 years .
The cancer is mainly characterized with calcitonin secretion. The cases of sporadic thyroid cancer account for 80% of the sufferers. Medullary Thyroid Carcinoma mainly occurs in the 5th and 6th decades of life and in 75% to 95% of the cases present as a single nodule. Unlike papillary, follicular and anaplastic carcinomas that originate from follicular cells, medullary carcinomas are from para-follicular cells (C-cells), located at the junction of the upper third and the lower two-third of the thyroid lobes . The majority of such tumors therefore are observed in this area. In 50% of the patients, latero-cervical lymph nodes are involved. In 15% of the patients, the symptoms of pressure imposed on esophagus and upper parts of the pulmonary system are reported. Metastasis is reported in 5% of the patients.
Age at the time of diagnosis is the most important diagnostic factor in these patients.
In 20% of the cases, genetic is the most important predisposing factor and medullary cancer is mainly known as an autosomal dominant disorder . Three kinds of hereditary medullary thyroid cancers are known:
Multiple Endocrine Neoplasia 2A (MEN 2A)
Multiple Endocrine Neoplasia 2B (MEN 2B)
Familial Medullary Thyroid Carcinoma (FMTC)
Most important genetic factors involved in different types of thyroid malignancies
Molecular mechanisms involved in the development of such malignancies are not well known. This comes while existing studies in this regard have reported that the occurrence of 6 or 7 mutations in certain proto-oncogenes during a period of 20 to 40 years is necessary to induce tumor growth .
Two families of genes are involved in the proliferation of healthy cells: Proto-oncogenes increase cellular proliferation and tumor suppressor genes stop cell division. The development of thyroid tumors is reported to be secondary to the activation of mutated oncogenes or suppression of tumor suppressor genes or both .
P53 is a tumor suppressor gene, which regulates physiologic cell growth through inducing G1-phase cell cycle arrest . Point mutation of this gene is considered as the most prevalent change linked with such tumors, particularly anaplastic thyroid carcinomas [29, 30]. The presence of these mutations determine tumor invasion. Freeman et al. reported that any changes in the expression of P53 is associated with thyroid cancer; therefore, measuring the rate of P53 expression can be considered as a diagnostic marker in identifying invasive tumors and thus patients with poor prognosis . P53 mutations are reported in 11.1% of patients with papillary carcinoma, 14.3% with follicular carcinoma and 63% with anaplastic carcinoma (in some studies mentioned to be between 75 to 83.3%). Considering the fact that P53 mutation or increased expression of the protein is more common in anaplastic carcinoma compared with other differentiated carcinomas, it could be concluded that the change in the expression rate may influence the transformation of differentiated carcinomas into the anaplasticones. Therefore, studying the expression of p53 can help identify indistinguishable thyroid cancers .
RAS family consists of three genes
N-RAS on Chromosome 1
H-RAS on Chromosome 11
K-RAS on Chromosome 12
These genes are linked to the synthesis of a group of 21 kDa proteins  that play an important role in cell growth and differentiation. Point mutation in any of these genes may result in the transformation of proto-oncogenes to oncogenes, and consequently the development of cancer . In more than 30% of human tumors, mutation is reported in the 12th, 13th and 61th codons of RAS proto-oncogene . It is to be noted that mutation in a given allele of these genes is sufficient for the activation of proto-oncogenes . The activation of RAS oncogenes is reported in many of benign and malignant thyroid tumors . Despite the fact that there are a few such tumors, the prevalence of RAS mutations in thyroid neoplasia, particularly follicular and invasive cancers, seems to be high . This comes while no significant correlation has been reported between increased RAS protein expression and the higher rate of distinction or metastasis . RAS proto-oncogene mutations are reported in 20% to 60% of thyroid tumors, especially in follicular cancers . Such mutations are also more prevalent in areas where there is little iodine in the diet . Activated RAS protein is reported in 20% of patients suffering from papillary carcinoma, 53% of those with follicular carcinoma and 6 to 50% of subjects diagnosed with anaplastic carcinoma [39–44].
Pericentric inversion of chromosome 10 involving the RET (ret proto-oncogene) gene at chromosome 10q11 is known to increase expression of the RET gene. The activation of this oncogene also encodes tyrosine kinase receptor .
RET was first discovered by Fusco et al. The activation of the gene is reported in 25% of patients with papillary thyroid cancer . Papillary thyroid cancer is characterized by chromosal rearrangements, through which the promoter and the primary sequences of a genes (R1α- NcoA4- RFG5- hTIF1- CCDC6- RFG7/hTIFR) are transferred to the terminal sequences of the RET gene, developing a fusion gene. RET/PTC fusion gene encodes a permanently active receptor . Many believe these rearrangements are the initiator of tumor formation in individuals with papillary carcinoma . In other words, the expression of RET/PTC oncogene is common in papillary thyroid cancer cells (77% in concealed papillary carcinoma vs. 47% in apparent papillary carcinoma) . RET proto-oncogene mutations are also connected with syndromes with dominant inheritance such as MEN 2A, MEN 2B and familial medullary thyroid cancer.
Nowadays, RET point mutations are applied as markers for identifying hereditary and sporadic Medullary Thyroid Carcinoma (MTC) [50, 51]. In FMTC and MEN 2A, the well-known mutations in exon 10 (cordons 609, 611, 618 and 620) or 11 (codon 634) entangles the extra-cellular area of RET receptor [52, 53].
Duplication/insertion mutations in exon 11 are reported in rare cases of MEN 2A [54, 55]. RET germ line mutations are also reported in exon 13 (cordons 768, 790 and 791), 14 (codons 804 and 844) and 15 (codon 891) of patients with FMTC . While a missense mutation in codon 918 is reported in more than 90% of patients with MEN 2B, mutation at codon 881 in exon 15is a rare finding in these patients . Such variants are mainly linked with the phenotype of MEN 2B . The accurate prevalence of RET/PTC rearrangement is not well known, as the variant is seen in 2.5 to 34.5% of these patients .
Somatic changes of RET proto-oncogene are also discovered in 30 to 60% of sporadic PTC tumors, but rarely in familial cases . The abovementioned rearrangements are the only genetic variants reported in PTC patients .
In mammalian cells, three isoforms of serine threonine kinase RAF, including ARAF, BRAF and CRAF (RAF1) with different tissue expression rates, are reported . BRAF, located on chromosome7 (7q34), is responsible for controlling cell proliferation and differentiation through the MAP kinase pathway . Inappropriate and abnormal activity of such a pathway may result in a pro-mitogenic force, causing abnormal distinction and proliferation of many human cancers . BRAF mutations are the most prevalent genetic abnormality reported in papillary thyroid carcinoma. It is, however, reported in up to 50% of individuals with anaplastic carcinoma. In about 95% of the cases, mutation of nucleotide 1799, results in the substitution of valin with glutamate at residue 600 (V600E). Such a mutation, however, is not observed in distinguishable follicular and medullary neoplasia sufferers [64–67]. Abundance of BRAF mutations in papillary thyroid carcinoma puts forward this matter that suppressing the activity of BRAF can help develop new treatment modalities for the disease .
Nambaet al pointed out the link between BRAF mutation and papillary thyroid carcinoma . Similarly, Webb et al. reported the involvement of MAPK/MEK/RAF pathway in metastasis and tumor growth . Such results suggest that the analysis of BRAF mutations may pave the way for the early diagnosis of patients with papillary carcinoma .
Simultaneous mutation in RAS and BRAF has never been reported. This finding is in line with data extracted from other tumor models . Moreover, considering the fact that RAS proto-oncogene mutation is only reported in 20% of patients with papillary carcinoma, studying the simultaneous occurrence of RAS and BRAF mutation is not of much importance . However, further studies are needed to determine the importance of RET/PTC and BRAF mutations in tumorigenesis .
Most prevalent mutations noted in different types of thyroid cancers
Thyroid tumor type
Metastasis is a complex biological process that requires cancer cells to be separated from adjacent cells in a way that they could target the extracellular matrix (ECM) and the basilar membrane, and enter blood circulation. Such cells escape the immune system and reach farther tissues, resulting in the formation of secondary tumors at other locations. The process is associated with increased risk of death from cancer. Much research has been conducted to study the pathology and treatment of metastasis, especially, with respect to molecular mechanisms. Epithelial mesenchymal transition (EMT) is an important part of the metastatic cascade . They initiate metastasis and thus have attracted many researchers studying cancer and metastasis.
Fascin, as one of the proteins involved in metastasis, is very important in such a process. In mammalians, Fascin has three isoforms:
◦ Fascin-1, specific for the mesenchyme and neural system, is situated at 7p22 .
◦ Fascin-2 islimited to photo-receptor cells in the eye. Its encoding gene is in 17q25 .
◦ Fascin-3 found in testis. Its locus is in 7q31 .
From among the mentioned proteins, Fascin-1 binds to actin filaments and may form cellular protrusions such as filopodia and lamelipodia. The formation of such structures can result in higher rate of invasion and metastasis . Fascin-1 is a genetically conserved protein (493 amino acids, 55KD), linked with actin filaments in the cytoplasm from two different sites. Through arranging these filaments, Fascin-1 can organize cell movement . Immunohistochemistry (IHC) and Tissue Microarray (TMA) studies of various cancers, especially metastatic lung and pancreatic cancer, have revealed increased expression of Fascin-1 in cancerous tissues cells. For instance, healthy lung cells have no Fascin-1. This comes while IHC studies showed increased expression of Fascin-1 in 89% of such cells if they become cancerous and in the early stages of the disease. This is also true for pancreatic cancer. IHC studies showed that from among 57 persons suffering from pancreatic cancer, 95% had increased Fascin-1 expression. In another study, conducted two years later, TMA studies on 68 people suffering from this cancer showed increased expression of such protein in 97% of the cases.
IHC studies have confirmed increased Fascin-1 expression in papillary, follicular and anaplastic thyroid cancer. On the other hand, the expression of such protein is not reported in healthy individuals and those suffering from goiter . Despite the outstanding role of Fascin-1 in increasing the invasion and cellular movement, available studies have failed to link any genetic mutation with the increased expression responsible for the characteristic. The regulatory region of these genes consists of 250 base pairs and is located at the 5’-flanging end of the gene . Therefore, studying the genetic changes of the promoter region of fascin-1 as one of the factors involved in the regulation of gene expression and discovering the relation between such mutations and the rate of metastasis can pave the way for early diagnosis of those suffering from metastatic thyroid cancer.
In the past decade, many studies have been conducted on genetic changes and molecular biology of thyroid cancer to improves the accuracy of diagnosis and the effectiveness of treatment modalities. From among them the mutations and rearrangements of certain proto-oncogenes as well transcription and metastatic factors such as P53, RAS, RET, BRAF, PPARγ and Fascin are of great importance. In view of the fact that the available methods are not capable of diagnosing thyroid cancer in early stages, detection of differentiated mutations may be an effective method in this regard. It seems that in various cancerous cells, there are different and very special mechanisms for metastasis processes. Genetic studies can also help identify the reason behind changes noted in the expression of suppressor genes or metastatic activators in order to find effective solutions to prevent malignant variants of these cancers.
Papillary thyroid carcinoma
Follicular thyroid carcinoma
Anaplastic thyroid carcinoma
Medullay thyroid carcinoma
- MEN 2A:
Multiple endocrine neoplasia 2A
- MEN 2B:
Multiple endocrine neoplasia 2B
Familial medullary thyroid carcinoma
Proxisome proliferator activated receptor gamma
Paired box gene 8
Extra cellular matrix
Epithelial mesenchymal transition
Mitogen- activated protein kinase.
The authors would like to thank Dr. Soroush Seifirad for reviewing the manuscript and for his helpful suggestion and advice.
- Cobin R, Gharib H, Bergman D, Clark O, Cooper D, Daniels G, Dickey R, Duick D, Garber J, Hay I: AACE/AAES medical/surgical guidelines for clinical practice: management of thyroid carcinoma. American Association of Clinical Endocrinologists. American College of Endocrinology. Endocr Pract 2001, 7: 202.View ArticlePubMedGoogle Scholar
- Haghpanah V, Soliemanpour B, Heshmat R, Mosavi-Jarrahi A, Tavangar S, Malekzadeh R, Larijani B: Endocrine cancer in Iran: based on cancer registry system. Indian J Cancer 2006, 43: 80. 10.4103/0019-509X.25889View ArticlePubMedGoogle Scholar
- Larijani B, Shirzad M, Mohagheghi M, Haghpanah V, Mosavi-Jarrahi A, Tavangar S, Vassigh A, Hossein-Nezhad A, Bandarian F, Baradar-Jalili R: Epidemiologic analysis of the Tehran cancer institute data system registry (TCIDSR). Asian Pac J Cancer Prev 2004, 5: 36–39.PubMedGoogle Scholar
- Glattre E, Haldorsen T: Positive correlation between parity and incidence of thyroid cancer: new evidence based on complete Norwegian birth cohorts. Int J Cancer 1991, 49: 831–836. 10.1002/ijc.2910490606View ArticlePubMedGoogle Scholar
- Memon A, Darif M, Al-Saleh K, Suresh A: Epidemiology of reproductive and hormonal factors in thyroid cancer: Evidence from a case–control study in the Middle East. Int J Cancer 2002, 97: 82–89. 10.1002/ijc.1573View ArticlePubMedGoogle Scholar
- Mack WJ, Preston-Martin S, Bernstein L, Qian D, Xiang M: Reproductive and hormonal risk factors for thyroid cancer in Los Angeles County females. Cancer Epidemiol Biomarkers Prev 1999, 8: 991–997.PubMedGoogle Scholar
- Amoli MM, Yazdani N, Amiri P, Sayahzadeh F, Haghpanah V, Tavangar SM, Amirzargar A, Ghaffari H, Nikbin B, Larijani B: HLA-DR association in papillary thyroid carcinoma. Dis Markers 2010, 28: 49–53. 10.1155/2010/130276PubMed CentralView ArticlePubMedGoogle Scholar
- Maso LD, Vecchia CL, Franceschi S, Preston-Martin S, Ron E, Levi F, Mack W, Mark SD, McTiernan A, Kolonel L: A pooled analysis of thyroid cancer studies. V. Anthropometric factors. Cancer Causes Control 2000, 11: 137–144. 10.1023/A:1008938520101View ArticleGoogle Scholar
- Spitz MR, Sider JG, Katz RL, Pollack ES, Newell GR: Ethnic patterns of thyroid cancer incidence in the United States, 1973–1981. Int J Cancer 1988, 42: 549–553. 10.1002/ijc.2910420413View ArticlePubMedGoogle Scholar
- Laurberg P, Nøhr S, Pedersen K, Hreidarsson A, Andersen S, Pedersen IB, Knudsen N, Perrild H, Jørgensen T, Ovesen L: Thyroid disorders in mild iodine deficiency. Thyroid 2000, 10: 951–963. 10.1089/thy.2000.10.951View ArticlePubMedGoogle Scholar
- Yazdani N, Sayahpour FA, Haghpanah V, Amiri P, Shahrabi-Farahani M, Moradi M, Mirmiran A, Khorsandi M-T, Larijani B, Mostaan LV: Survivin gene polymorphism association with papillary thyroid carcinoma. Pathol Res Pract 2012, 208: 100–103. 10.1016/j.prp.2011.12.009View ArticlePubMedGoogle Scholar
- Williams E, Doniach I, Bjarnason O, Michie W: Thyroid cancer in an iodide rich area. A histopathological study. Cancer 1977, 39: 215–222. 10.1002/1097-0142(197701)39:1<215::AID-CNCR2820390134>3.0.CO;2-#View ArticlePubMedGoogle Scholar
- Davies L, Welch HG: Increasing incidence of thyroid cancer in the United States, 1973–2002. J Am Med Assoc 2006, 295: 2164–2167. 10.1001/jama.295.18.2164View ArticleGoogle Scholar
- Castro MR, Gharib H: Thyroid nodules and cancer. When to wait and watch, when to refer. Postgrad Med 2000, 107: 113.View ArticlePubMedGoogle Scholar
- Mortensen J, Woolner LB, Bennett WA: Gross and microscopic findings in clinically normal thyroid glands. J Clin Endocrinol Metab 1955, 15: 1270–1280. 10.1210/jcem-15-10-1270View ArticlePubMedGoogle Scholar
- Roth LM: Tumors of the Thyroid Gland. Am J Surg Pathol 1993, 17: 1196.View ArticleGoogle Scholar
- McNicol A: Functional Endocrine Pathology. Histopathology 1992, 20: 92. 92 10.1111/j.1365-2559.1992.tb00931.xView ArticleGoogle Scholar
- Gilliland FD, Hunt WC, Morris DM, Key CR: Prognostic factors for thyroid carcinoma. Cancer 1997, 79: 564–573. 10.1002/(SICI)1097-0142(19970201)79:3<564::AID-CNCR20>3.0.CO;2-0View ArticlePubMedGoogle Scholar
- Wartofsky L, Van Nostrand D: Thyroid cancer: a comprehensive guide to clinical management. New Jersey: Humana Pr Inc; 2006.View ArticleGoogle Scholar
- Kebebew E, Greenspan FS, Clark OH, Woeber KA, McMillan A: Anaplastic thyroid carcinoma. Cancer 2005, 103: 1330–1335. 10.1002/cncr.20936View ArticlePubMedGoogle Scholar
- Donghi R, Longoni A, Pilotti S, Michieli P, Della Porta G, Pierotti MA: Gene p53 mutations are restricted to poorly differentiated and undifferentiated carcinomas of the thyroid gland. J Clin Investig 1993, 91: 1753. 10.1172/JCI116385PubMed CentralView ArticlePubMedGoogle Scholar
- Demeter J, De Jong S, Lawrence A, Paloyan E: Anaplastic thyroid carcinoma: risk factors and outcome. Surgery 1991, 110: 956.PubMedGoogle Scholar
- Zhang Q, Yang C, Guo Z, Zeng Z, Yang A, Lai F: Prognostic factors of medullary thyroid carcinoma. Chin J Otorhinolaryngol Head Neck Surg 2008, 43: 939.Google Scholar
- Hyer S, Vini L, Harmer C: Medullary thyroid cancer: multivariate analysis of prognostic factors influencing survival. Eur J Surg Oncol 2000, 26: 686–690. 10.1053/ejso.2000.0981View ArticlePubMedGoogle Scholar
- Saad MF, Ordonez NG, Rashid RK, Guido JJ, Hill CS Jr, Hickey RC, Samaan NA: Medullary carcinoma of the thyroid. A study of the clinical features and prognostic factors in 161 patients. Medicine 1984, 63: 319.View ArticlePubMedGoogle Scholar
- Peto R: Epidemiology, multistage models, and short-term mutagenicity tests. Orig Human Cancer 1977, 4: 1403–1428.Google Scholar
- Weinberg RA: Tumor suppressor genes. Science 1991, 254: 1138–1146. 10.1126/science.1659741View ArticlePubMedGoogle Scholar
- Levine AJ: The p53 tumor-suppressor gene. N Engl J Med 1992, 326: 1350–1352. 10.1056/NEJM199205143262008View ArticlePubMedGoogle Scholar
- Freeman J, Carroll C, Asa S, Ezzat S: Genetic events in the evolution of thyroid cancer. J Otolaryngol 2002, 31: 202–206. 10.2310/7070.2002.21690View ArticlePubMedGoogle Scholar
- Nakamura T, Yana I, Kobayashi T, Shin E, Karakawa K, Fujita S, Miya A, Mori T, Nishisho I, Takai S: p53 gene mutations associated with anaplastic transformation of human thyroid carcinomas. Cancer Sci 1992, 83: 1293–1298. 10.1111/j.1349-7006.1992.tb02761.xGoogle Scholar
- Zou M, Shi Y, Farid N: p53 mutations in all stages of thyroid carcinomas. J Clin Endocrinol Metab 1993, 77: 1054–1058. 10.1210/jc.77.4.1054PubMedGoogle Scholar
- Bos JL: The ras gene family and human carcinogenesis. Mutat Res Rev Genet Toxicol 1988, 195: 255–271. 10.1016/0165-1110(88)90004-8View ArticleGoogle Scholar
- Barbacid M: Ras genes. Annu Rev Biochem 1987, 56: 779–827. 10.1146/annurev.bi.56.070187.004023View ArticlePubMedGoogle Scholar
- Bos JL: Ras oncogenes in human cancer: a review. Cancer Res 1989, 49: 4682.PubMedGoogle Scholar
- Suárez HG: Genetic alterations in human epithelial thyroid tumours. Clin Endocrinol 1998, 48: 531–546. 10.1046/j.1365-2265.1998.00443.xView ArticleGoogle Scholar
- Lemoine N, Mayall E, Wyllie F, Williams E, Goyns M, Stringer B, Wynford-Thomas D: High frequency of ras oncogene activation in all stages of human thyroid tumorigenesis. Oncogene 1989, 4: 159.PubMedGoogle Scholar
- Kim D, McCabe C, Buchanan M, Watkinson J: Oncogenes in thyroid cancer. Clin Otolaryngol Allied Sci 2003, 28: 386–395. 10.1046/j.1365-2273.2003.00732.xView ArticlePubMedGoogle Scholar
- Shi Y, Zou M, Schmidt H, Juhasz F, Stensky V, Robb D, Farid NR: High rates of ras codon 61 mutation in thyroid tumors in an iodide-deficient area. Cancer Res 1991, 51: 2690.PubMedGoogle Scholar
- Wright P, Lemoine N, Mayall E, Wyllie F, Hughes D, Williams E, Wynford-Thomas D: Papillary and follicular thyroid carcinomas show a different pattern of ras oncogene mutation. Br J Cancer 1989, 60: 576. 10.1038/bjc.1989.316PubMed CentralView ArticlePubMedGoogle Scholar
- Fukushima T, Suzuki S, Mashiko M, Ohtake T, Endo Y, Takebayashi Y, Sekikawa K, Hagiwara K, Takenoshita S: BRAF mutations in papillary carcinomas of the thyroid. Oncogene 2003, 22: 6455–6457. 10.1038/sj.onc.1206739View ArticlePubMedGoogle Scholar
- Garcia-Rostan G, Zhao H, Camp RL, Pollan M, Herrero A, Pardo J, Wu R, Carcangiu ML, Costa J, Tallini G: Ras mutations are associated with aggressive tumor phenotypes and poor prognosis in thyroid cancer. J Clin Oncol 2003, 21: 3226–3235. 10.1200/JCO.2003.10.130View ArticlePubMedGoogle Scholar
- Quiros RM, Ding HG, Gattuso P, Prinz RA, Xu X: Evidence that one subset of anaplastic thyroid carcinomas are derived from papillary carcinomas due to BRAF and p53 mutations. Cancer 2005, 103: 2261–2268. 10.1002/cncr.21073View ArticlePubMedGoogle Scholar
- Santarpia L, El-Naggar AK, Cote GJ, Myers JN, Sherman SI: Phosphatidylinositol 3-kinase/akt and ras/raf-mitogen-activated protein kinase pathway mutations in anaplastic thyroid cancer. J Clin Endocrinol Metab 2008, 93: 278–284.View ArticlePubMedGoogle Scholar
- Hou P, Liu D, Shan Y, Hu S, Studeman K, Condouris S, Wang Y, Trink A, El-Naggar AK, Tallini G: Genetic alterations and their relationship in the phosphatidylinositol 3-kinase/Akt pathway in thyroid cancer. Clin Cancer Res 2007, 13: 1161–1170. 10.1158/1078-0432.CCR-06-1125View ArticlePubMedGoogle Scholar
- Learoyd DL, Marsh DJ, Richardson AL, Twigg SM, Delbridge L, Robinson BG: Genetic testing for familial cancer: consequences of RET proto-oncogene mutation analysis in multiple endocrine neoplasia, type 2. Arch Surg 1997, 132: 1022. 10.1001/archsurg.1997.01430330088015View ArticlePubMedGoogle Scholar
- Fusco A, Grieco M, Santoro M, Berlingieri M, Pilotti S, Pierotti M, Della Porta G, Vecchio G: A new oncogene in human thyroid papillary carcinomas and their lymph-nodal metastases. Nature 1987, 328: 170–172. 10.1038/328170a0View ArticlePubMedGoogle Scholar
- Hansford JR, Mulligan LM: Multiple endocrine neoplasia type 2 andRET: from neoplasia to neurogenesis. J Med Genet 2000, 37: 817–827. 10.1136/jmg.37.11.817PubMed CentralView ArticlePubMedGoogle Scholar
- Viglietto G, Chiappetta G, Martinez-Tello FJ, Fukunaga FH, Tallini G, Rigopoulou D, Visconti R, Mastro A, Santoro M, Fusco A: RET/PTC oncogene activation is an early event in thyroid carcinogenesis. Oncogene 1995, 11: 1207.PubMedGoogle Scholar
- Grieco M, Santoro M, Berlingieri MT, Melillo RM, Donghi R, Bongarzone I, Pierotti MA, Della Ports G, Fusco A, Vecchiot G: PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 1990, 60: 557–563. 10.1016/0092-8674(90)90659-3View ArticlePubMedGoogle Scholar
- Lips C, Landsvater RM, Hoppener J, Geerdink RA, Blijham G, van Veen JMJS, van Gils A, de Wit MJ, Zewald RA, Berends M: Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med 1994, 331: 828–835. 10.1056/NEJM199409293311302View ArticlePubMedGoogle Scholar
- Ishizaka Y, Shima H, Sugimura T, Nagao M: Detection of phosphorylated retTPC oncogene product in cytoplasm. Oncogene 1992, 7: 1441.PubMedGoogle Scholar
- Heshmati HM, Gharib H, Khosla S, Abu-Lebdeh HS, Lindor NM, Thibodeau SN: Genetic testing in medullary thyroid carcinoma syndromes: mutation types and clinical significance. In Mayo Clinic; 27–30 May 1997. Rochester: Elsevier; 1997:430–436.Google Scholar
- Marsh DJ, Robinson BG, Andrew S, Richardson AL, Pojer R, Schnitzler M, Mulligan LM, Hyland VJ: A rapid screening method for the detection of mutations in the RET proto-oncogene in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma families. Genomics 1994, 23: 477–479. 10.1006/geno.1994.1526View ArticlePubMedGoogle Scholar
- Höppner W, Ritter MM: A duplication of 12 bp in the critical cysteine rich domain of the RET proto-oncogene results in a distinct phenotype of multiple endocrine neoplasia type 2A. Hum Mol Genet 1997, 6: 587. 587 10.1093/hmg/6.4.587View ArticlePubMedGoogle Scholar
- Höppner W, Dralle H, Brabant G: Duplication of 9 base pairs in the critical cysteine-rich domain of the RET proto-oncogene causes multiple endocrine neoplasia type 2A. Hum Mutat 1998, 11: S128-S130. 10.1002/humu.1380110143View ArticleGoogle Scholar
- Mulligan LM, Marsh D, Robinson B, Schuffenecker I, Zedenius J, Lips C, Gagel R, Takai SI, Noll W, Fink M: Genotype-phenotype correlation in multiple endocrine neoplasia type 2: report of the International RET Mutation Consortium. J Intern Med 1995, 238: 343–346. 10.1111/j.1365-2796.1995.tb01208.xView ArticlePubMedGoogle Scholar
- Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, van Amstel HKP, Lips CJM, Nishisho I, Takai SI: The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. J Am Med Assoc 1996, 276: 1575–1579. 10.1001/jama.1996.03540190047028View ArticleGoogle Scholar
- Gimm O, Marsh DJ, Andrew SD, Frilling A, Dahia PLM, Mulligan LM, Zajac JD, Robinson BG, Eng C: Germline dinucleotide mutation in codon 883 of the RETproto-oncogene in multiple endocrine neoplasia Type 2B without codon 918 mutation. J Clin Endocrinol Metab 1997, 82: 3902–3904. 10.1210/jc.82.11.3902View ArticlePubMedGoogle Scholar
- Wajjwalku W, Nakamura S, Hasegawa Y, Miyazaki K, Satoh Y, Funahashi H, Matsuyama M, Takahashi M: Low Frequency of Rearrangements of the ret and trk Proto-oncogenes in Japanese Thyroid Papillary Carcinomas. Cancer Sci 1992, 83: 671–675. 10.1111/j.1349-7006.1992.tb01963.xGoogle Scholar
- Nikiforova MN, Biddinger PW, Caudill CM, Kroll TG, Nikiforov YE: PAX8-PPAR [gamma] rearrangement in thyroid tumors: RT-PCR and immunohistochemical analyses. Am J Surg Pathol 2002, 26: 1016. 10.1097/00000478-200208000-00006View ArticlePubMedGoogle Scholar
- Daum G, Eisenmann-Tappe I, Fries HW, Troppmair J, Rapp UR: The ins and outs of Raf kinases. Trends Biochem Sci 1994, 19: 474. 10.1016/0968-0004(94)90133-3View ArticlePubMedGoogle Scholar
- Lang J, Boxer M, MacKie R: Absence of exon 15 BRAF germline mutations in familial melanoma. Hum Mutat 2003, 21: 327–330. 10.1002/humu.10188View ArticlePubMedGoogle Scholar
- Avruch J, Khokhlatchev A, Kyriakis JM, Luo Z, Tzivion G, Vavvas D, Zhang XF: Ras activation of the Raf kinase. Recent Prog Horm Res 2001, 56: 127–156. 10.1210/rp.56.1.127View ArticlePubMedGoogle Scholar
- Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA: High prevalence of BRAF mutations in thyroid cancer. Cancer Res 2003, 63: 1454.PubMedGoogle Scholar
- Begum S, Rosenbaum E, Henrique R, Cohen Y, Sidransky D, Westra WH: BRAF mutations in anaplastic thyroid carcinoma: implications for tumor origin, diagnosis and treatment. Mod Pathol 2004, 17: 1359–1363. 10.1038/modpathol.3800198View ArticlePubMedGoogle Scholar
- Soares P, Trovisco V, Rocha AS, Feijao T, Rebocho AP, Fonseca E, Vieira de Castro I, Cameselle-Teijeiro J, Cardoso-Oliveira M, Sobrinho-Simoes M: BRAF mutations typical of papillary thyroid carcinoma are more frequently detected in undifferentiated than in insular and insular-like poorly differentiated carcinomas. Virchows Arch 2004, 444: 572–576.View ArticlePubMedGoogle Scholar
- Takano T, Ito Y, Hirokawa M, Yoshida H, Miyauchi A: BRAFV600E mutation in anaplastic thyroid carcinomas and their accompanying differentiated carcinomas. Br J Cancer 2007, 96: 1549–1553. 10.1038/sj.bjc.6603764PubMed CentralView ArticlePubMedGoogle Scholar
- Cohen Y, Xing M, Mambo E, Guo Z, Wu G, Trink B, Beller U, Westra WH, Ladenson PW, Sidransky D: BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst 2003, 95: 625–627. 10.1093/jnci/95.8.625View ArticlePubMedGoogle Scholar
- Namba H, Nakashima M, Hayashi T, Hayashida N, Maeda S, Rogounovitch TI, Ohtsuru A, Saenko VA, Kanematsu T, Yamashita S: Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J Clin Endocrinol Metab 2003, 88: 4393–4397. 10.1210/jc.2003-030305View ArticlePubMedGoogle Scholar
- Webb CP, Van Aelst L, Wigler MH, Vande Woude GF: Signaling pathways in Ras-mediated tumorigenicity and metastasis. Proc Natl Acad Sci 1998, 95: 8773. 10.1073/pnas.95.15.8773PubMed CentralView ArticlePubMedGoogle Scholar
- Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE: Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 2002, 418: 934. 934 10.1038/418934aView ArticlePubMedGoogle Scholar
- Soares P, Trovisco V, Rocha AS, Lima J, Castro P, Preto A, Máximo V, Botelho T, Seruca R, Sobrinho-Simões M: BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene 2003, 22: 4578–4580. 10.1038/sj.onc.1206706View ArticlePubMedGoogle Scholar
- Kroll TG, Sarraf P, Pecciarini L, Chen CJ, Mueller E, Spiegelman BM, Fletcher JA: PAX8-PPARgamma 1 fusion in oncogene human thyroid carcinoma. Sci Signal 2000, 289: 1357.Google Scholar
- Wu Y, Guo SW: Peroxisome proliferator-activated receptor-gamma and retinoid X receptor agonists synergistically suppress proliferation of immortalized endometrial stromal cells. Fertil Steril 2009, 91: 2142–2147. 10.1016/j.fertnstert.2008.04.012View ArticlePubMedGoogle Scholar
- Ros P, Rossi DL, Acebrón A, Santisteban P: Thyroid-specific gene expression in the multi-step process of thyroid carcinogenesis. Biochimie 1999, 81: 389–396. 10.1016/S0300-9084(99)80086-8View ArticlePubMedGoogle Scholar
- Giordano TJ, Au AYM, Kuick R, Thomas DG, Rhodes DR, Wilhelm KG, Vinco M, Misek DE, Sanders D, Zhu Z: Delineation, functional validation, and bioinformatic evaluation of gene expression in thyroid follicular carcinomas with the PAX8-PPARG translocation. Clin Cancer Res 2006, 12: 1983–1993. 10.1158/1078-0432.CCR-05-2039View ArticlePubMedGoogle Scholar
- Kondo T, Ezzat S, Asa SL: Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer 2006, 6: 292–306. 10.1038/nrc1836View ArticlePubMedGoogle Scholar
- Castro P, Rebocho A, Soares R, Magalhaes J, Roque L, Trovisco V, de Castro IV, Cardoso-de-Oliveira M, Fonseca E, Soares P: PAX8-PPARγ rearrangement is frequently detected in the follicular variant of papillary thyroid carcinoma. J Clin Endocrinol Metab 2006, 91: 213–220. 10.1210/jc.2005-1336View ArticlePubMedGoogle Scholar
- Bullock MD, Sayan AE, Packham GK, Mirnezami AH: MicroRNAs: critical regulators of epithelial to mesenchymal (EMT) and mesenchymal to epithelial transition (MET) in cancer progression. Biol Cell 2012, 104: 3–12. 10.1111/boc.201100115View ArticlePubMedGoogle Scholar
- De Arcangelis A, Georges-Labouesse E, Adams JC: Expression of fascin-1 the gene encoding the actin-bundling protein fascin-1, during mouse embryogenesis. Gene Expr Patterns 2004, 4: 637–643. 10.1016/j.modgep.2004.04.012View ArticlePubMedGoogle Scholar
- Tubb BE, Bardien-Kruger S, Kashork CD, Shaffer LG, Ramagli LS, Xu J, Siciliano MJ, Bryan J: Characterization of Human Retinal Fascin Gene (< i > FSCN2</i>) at 17q25: Close Physical Linkage of Fascin and Cytoplasmic Actin Genes. Genomics 2000, 65: 146–156. 10.1006/geno.2000.6156View ArticlePubMedGoogle Scholar
- Tubb B, Mulholland DJ, Vogl W, Lan ZJ, Niederberger C, Cooney A, Bryan J: Testis fascin (FSCN3): a novel paralog of the actin-bundling protein fascin expressed specifically in the elongate spermatid head. Exp Cell Res 2002, 275: 92–109. 10.1006/excr.2002.5486View ArticlePubMedGoogle Scholar
- Adams JC: Roles of fascin in cell adhesion and motility. Curr Opin Cell Biol 2004, 16: 590–596. 10.1016/j.ceb.2004.07.009View ArticlePubMedGoogle Scholar
- Kureishy N, Sapountzi V, Prag S, Anilkumar N, Adams JC: Fascins, and their roles in cell structure and function. Bioessays 2002, 24: 350–361. 10.1002/bies.10070View ArticlePubMedGoogle Scholar
- Chen G, Zhang FR, Ren J, Tao LH, Shen ZY, Lv Z, Yu SJ, Dong BF, Xu LY, Li EM: Expression of fascin in thyroid neoplasms: a novel diagnostic marker. J Cancer Res Clin Oncol 2008, 134: 947–951. 10.1007/s00432-008-0374-6View ArticlePubMedGoogle Scholar
- Hashimoto Y, Loftis DW, Adams JC: Fascin-1 promoter activity is regulated by CREB and the aryl hydrocarbon receptor in human carcinoma cells. PLoS One 2009, 4: e5130. 10.1371/journal.pone.0005130PubMed CentralView ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.