RET; ret proto-oncogene (10q11.2)

Gene Summary

Gene:RET; ret proto-oncogene
Aliases: PTC, MTC1, HSCR1, MEN2A, MEN2B, RET51, CDHF12, CDHR16, RET-ELE1
Summary:This gene, a member of the cadherin superfamily, encodes one of the receptor tyrosine kinases, which are cell-surface molecules that transduce signals for cell growth and differentiation. This gene plays a crucial role in neural crest development, and it can undergo oncogenic activation in vivo and in vitro by cytogenetic rearrangement. Mutations in this gene are associated with the disorders multiple endocrine neoplasia, type IIA, multiple endocrine neoplasia, type IIB, Hirschsprung disease, and medullary thyroid carcinoma. Two transcript variants encoding different isoforms have been found for this gene. Additional transcript variants have been described but their biological validity has not been confirmed. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:proto-oncogene tyrosine-protein kinase receptor Ret
Updated:14 December, 2014


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 14 December 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 14 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (14)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Multiple Endocrine Neoplasia Type 2aRET mutations in Multiple Endocrine Neoplasia - type 2A View Publications614
Pheochromocytoma and ParagangliomaRET and Pheochromocytoma and Paraganglioma View Publications342
Adrenocortical CancerRET and Adrenocortical Cancer View Publications272
Thyroid CancerRET mutations in Familial Medullary Thyroid Carcinoma View Publications259
Multiple Endocrine Neoplasia Type 2bRET mutations in Multiple Endocrine Neoplasia Type 2b View Publications235
Thyroid CancerRET-PTC1 Rearangements in Papillary Thyroid Cancer
The PTC1 fusion gene is present in approximately 30% of papillary thyroid carcinomas. It involves an inversion of 10q which fuses the RET protooncogene to the D10S170 (H4) gene. High incidence of RET/PTC1 rearrangements have been reported in thyroid cancers in people living in areas adjacent to Chernobyl following the nuclear accident. SCID mice transplanted with normal human thyroid tissues and then exposed to radiation preferentially developed RET/PTC1 compared to other RET rearrangements (Mizuno,2000). A FISH study (Nikiforova, 2000) suggests that RET and PTC1 are more frequently juxtaposed in the nucleus of thyroid cells compared to other cells. This close proximity of the genes in thyroid cells may promote the PTC1 fusion since a single radiation track may be sufficient to produce a double-strand break in each gene at the same site in the nucleus.
View Publications213
Thyroid CancerRET-PTC3 (RET-ELE1) Rearangements in Papillary Thyroid Cancer
The RET gene is frequently involved in structural rearrangements with either PCT1 (CCDC6) or PCT3 (NCOA4), resulting in chimeric fusion proteins which are characteristic of Papillary Thyroid Cancer. Detection of this may aid differential diagnosis of papillary vs. follicular thyroid cancer.
View Publications146
Lung CancerRET and Lung Cancer View Publications79
Thyroid CancerRET Rearrangements Following Exposure to Ionizing Radiation View Publications62
Thyroid CancerRET-NTRK1 Rearangements in Papillary Thyroid Cancer View Publications35
Lung Cancer, Non-Small CellRET and Non-Small Cell Lung Cancer View Publications32
Lung CancerRET-KIF5B fusion in Adenocarcinoma Lung Cancer View Publications19
Thyroid Cancert(8,10) RET-HOOK Reaarangements in Papillary Thyroid Cancer View Publications2

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Related Links

Latest Publications: RET (cancer-related)

Zhang F, Tang JM, Wang L, et al.
Immunohistochemical detection of RET proto-oncogene product in tumoral and nontumoral mucosae of gastric cancer.
Anal Quant Cytopathol Histpathol. 2014; 36(3):128-36 [PubMed] Related Publications
OBJECTIVE: To detect RET (REarranged during Transfection) protein by immunohistochemistry (IHC) in gastric cancer.
STUDY DESIGN: A total of 210 samples were employed, of which 197 specimens were from 91 surgical pieces of gastric adenocarcinoma, comprising 91 tumoral, 91 nontumoral, and 15 intramucosal dysplastic samples. Another 13 gastric mucosae were from cancer-free patients. Two RET antibodies (clones Ret01 and 3F8) were used separately for IHC.
RESULTS: Of the nontumoral samples from gastric cancers, 28 were positive (31%) with either antibody Ret01 or 3F8. The positive stains were often located in deep pyloric glands and associated with chronic inflammation patterns (p = 0.045). RET positivity correlated with phosphorylated epidermal growth factor receptor, which had been previously tested (p = 0.021). In tumoral samples RET was positive in 7 cases with antibody Ret01 (8%) and 9 cases with 3F8 (10%). In 15 intramucosal dysplastic samples RET was detected in 6 cases with antibody Ret01 and 8 cases with 3F8. There was an accordance between the IHC using antibodies Ret01 and 3F8 in tumoral, nontumoral, and intramucosal dysplastic samples (p = 0.500, 1.000, and 0.500). The 13 samples from cancer-free patients were always negative.
CONCLUSION: Activation of RET proto-oncogene may be one of the molecular pathogeneses in gastric inflammatory and tumoral diseases.

Related: Stomach Cancer Gastric Cancer

Liu S, Gao A, Zhang B, et al.
Assessment of molecular testing in fine-needle aspiration biopsy samples: an experience in a Chinese population.
Exp Mol Pathol. 2014; 97(2):292-7 [PubMed] Related Publications
Fine-needle aspiration biopsy remains the mainstay for preoperative examination of thyroid nodules; however, it does not provide a definite diagnosis in up to 25% of nodules. Considerable studies have been performed to identify molecular markers to resolve this diagnostic dilemma. The aim of this study was to establish the distribution and frequency of common genetic alterations in a comprehensive set of benign and malignant thyroid nodules, and to determine the feasibility and role of testing for a panel of genetic alterations in improving the accuracy of cytology diagnosis in a Chinese population. This study was conducted in 314 thyroid nodules comprising 104 papillary thyroid carcinomas, 13 suspicious nodules, 52 indeterminate nodules, and 145 benign nodules. Point mutations and RET/PTC rearrangements, were evaluated by pyrosequencing and TaqMan real-time PCR, respectively. After surgery, 115 nodules were confirmed as conventional papillary thyroid carcinoma and 102 (88.70%) of these nodules harbored either the BRAF(V600E) mutation (76.52%) or RET/PTC rearrangements (12.17%). RAS mutation was found in 1 (33.33%) follicular thyroid carcinoma, 1 (14.29%) follicular thyroid adenoma and 4 (10%) goiter nodules. With cytology and molecular testing, the diagnostic accuracy was further increased to 98.82% in papillary thyroid carcinoma diagnosis, and was preoperatively increased to 76.92% and 84.00%, respectively, in nodules with suspicious and indeterminate cytology. In conclusion, molecular testing of a panel of genetic alterations in fine-needle aspiration biopsy can be effectively performed in clinical practice. It enhances the accuracy of cytology and is of particular value for indeterminate nodules in the Chinese population.

Related: BRAF gene Thyroid Cancer KRAS gene NRAS

Iwama E, Takayama K, Baba E, Nakanishi Y
[Personalized medicine in non-small-cell carcinoma].
Fukuoka Igaku Zasshi. 2014; 105(3):57-66 [PubMed] Related Publications

Styring E, Seinen J, Dominguez-Valentin M, et al.
Key roles for MYC, KIT and RET signaling in secondary angiosarcomas.
Br J Cancer. 2014; 111(2):407-12 [PubMed] Article available free on PMC after 15/07/2015 Related Publications
BACKGROUND: Angiosarcomas may develop as primary tumours of unknown cause or as secondary tumours, most commonly following radiotherapy to the involved field. The different causative agents may be linked to alternate tumorigenesis, which led us to investigate the genetic profiles of morphologically indistinguishable primary and secondary angiosarcomas.
METHODS: Whole-genome (18k) c-DNA-mediated annealing, selection, extension and ligation analysis was used to genetically profile 26 primary and 29 secondary angiosarcomas. Key findings were thereafter validated using RT-qPCR, immunohistochemistry and validation of the gene signature to an external data set.
RESULTS: In total, 103 genes were significantly deregulated between primary and secondary angiosarcomas. Secondary angiosarcomas showed upregulation of MYC, KIT and RET and downregulation of CDKN2C. Functional annotation analysis identified multiple target genes in the receptor protein tyrosine kinase pathway. The results were validated using RT-qPCR and immunohistochemistry. Further, the gene signature was applied to an external data set and, herein, distinguished primary from secondary angiosarcomas.
CONCLUSIONS: Upregulation of MYC, KIT and RET and downregulation of CDKN2C characterise secondary angiosarcoma, which implies possibilities for diagnostic application and a mechanistic basis for therapeutic evaluation of RET-kinase-inhibitors in these highly aggressive tumours.

Chen Z, Qi X, Fei J, et al.
[Multiple endocrine neoplasia type 2A caused by a p.C618R RET proto-oncogene mutation in a Chinese pedigree].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2014; 31(3):348-51 [PubMed] Related Publications
OBJECTIVE: To explore the clinical characteristics and significance of RET proto-oncogene screening in multiple endocrine neoplasia type 2A (MEN2A).
METHODS: Comprehensive medical history was obtained for 5 members from a 3-generation family from southern China. Clinical investigations have included biochemical testing, imaging, and screening of germline RET proto-oncogene mutations.
RESULTS: Genetic screening has revealed a missense mutation at codon 618(TGC>CGC) of exon 10 in 3 patients(p.C618R), which was consistent with their clinical manifestations. For the 3 individuals, the age at diagnosis was 21, 26 and 36 yr, and the maximum diameter of medullary thyroid carcinoma was 22, 25 and 39 cm, respectively. The 36-year-old female patient initially underwent right total thyroidectomy plus right neck lymph node dissection. Four years later, she again underwent left adrenal tumorectomy and left total thyroidectomy plus left neck lymph node dissection. The 21-year-old male patient underwent right total thyroidectomy plus right modified neck dissection. The follow-up was respectively 146 and 26 months following the initial operation. Two patients still presented elevated calcitonin and had bilateral neck lymph node masses and/or left thyroid masses on imaging examination. The 26-year-old female patient, who presented bilateral thyroid masses and elevated calcitonin, has refused thyroidectomy.
CONCLUSION: Combined family survey and RET gene screening can facilitate early diagnosis and surgical treatment to improve the prognosis.

Related: Thyroid Cancer

Rettew AN, Getty PJ, Greenfield EM
Receptor tyrosine kinases in osteosarcoma: not just the usual suspects.
Adv Exp Med Biol. 2014; 804:47-66 [PubMed] Related Publications
Despite aggressive surgical and chemotherapy protocols, survival rates for osteosarcoma patients have not improved over the last 30 years. Therefore, novel therapeutic agents are needed. Receptor tyrosine kinases have emerged as targets for the development of new cancer therapies since their activation leads to enhanced proliferation, survival, and metastasis. In fact, aberrant expression and activation of RTKs have been associated with the progression of many cancers. Studies from our lab using phosphoproteomic screening identified RTKs that are activated and thus may contribute to the signaling within metastatic human osteosarcoma cells. Functional genomic screening using siRNA was performed to distinguish which of the activated RTKs contribute to in vitro phenotypes associated with metastatic potential (motility, invasion, colony formation, and cell growth). The resulting RTK hits were then validated using independent validation experiments. From these results, we identified four RTKs (Axl, EphB2, FGFR2, and Ret) that have not been previously studied in osteosarcoma and provide targets for the development of novel therapeutics.

Related: Bone Cancers EPHB2 FGFR2 gene Signal Transduction AXL

Seib CD, Harari A, Conte FA, et al.
Utility of serum thyroglobulin measurements after prophylactic thyroidectomy in patients with hereditary medullary thyroid cancer.
Surgery. 2014; 156(2):394-8 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
INTRODUCTION: Prophylactic thyroidectomy can be curative for patients with hereditary medullary thyroid cancer (MTC) caused by RET proto-oncogene mutations. Calcitonin is a sensitive tumor marker used to follow patients. We suggest that thyroglobulin (Tg) levels should also be monitored postoperatively in these patients.
METHODS: We reviewed patients with RET mutations who underwent prophylactic thyroidectomy between 1981 and 2011 at an academic endocrine surgery center. Patients were excluded if they had no postoperative Tg levels recorded.
RESULTS: Of the 22 patients who underwent prophylactic thyroidectomy, 14 were included in the final analysis. The average age at thyroidectomy was 9.8 years (range, 4-29). Tg levels were detectable 1.5 months to 31 years postoperatively in 11 patients (79%), all of whom were <15 years old at thyroidectomy. Median thyroid-stimulating hormone (TSH) was 2.5 mIU/L and 13.4 mIU/L in patients with undetectable and detectable Tg, respectively. Of those with detectable Tg, 5 had cervical ultrasonographic examination: Two showed no residual tissue in the thyroid bed, and 3 showed remnant thyroid tissue.
CONCLUSION: Tg levels can identify patients with remnant thyroid tissue after prophylactic thyroidectomy. Ultrasonography can determine whether thyroid tissue remains posterolaterally that is at risk of MTC recurrence. Maintaining normal TSH may prevent growth of remaining thyroid follicular cells.

Related: Thyroid Cancer

Simbolo M, Mian C, Barollo S, et al.
High-throughput mutation profiling improves diagnostic stratification of sporadic medullary thyroid carcinomas.
Virchows Arch. 2014; 465(1):73-8 [PubMed] Related Publications
Sporadic medullary thyroid carcinoma (MTC) harbors RET gene somatic mutations in up to 50 % of cases, and RAS family gene mutations occur in about 10 %. A timely and comprehensive characterization of molecular alterations is needed to improve MTC diagnostic stratification and design-tailored therapeutic approaches. Twenty surgically resected sporadic MTCs, previously analyzed for RET mutations by Sanger sequencing using DNA from formalin-fixed paraffin-embedded samples, were investigated for intragenic mutations in 50 cancer-associated genes applying a multigene Ion AmpliSeq next-generation sequencing (NGS) technology. Thirteen (65 %) MTCs harbored a RET mutation; 10 were detected at both Sanger and NGS sequencing, while 3 undetected by Sanger were revealed by NGS. One of the 13 RET-mutated cases also showed an F354L germline mutation in STK11. Of the seven RET wild-type MTCs, four cases (57.1 %) harbored a RAS mutation: three in HRAS (all Q61R) and one in KRAS (G12R). The three remaining MTCs (15 %) resulted as wild-type for all the 50 cancer-related genes. Follow-up was available in all but one RET-mutated case. At the end of follow-up, 7 of 12 (58 %) RET-mutated patients had relapsed, while the 4 RAS-mutated MTC patients were disease-free. Two of the three patients with MTC wild-type for all 50 genes relapsed during the follow-up period. Detection of mutations by NGS has the potential to improve the diagnostic stratification of sporadic MTC.

Related: Thyroid Cancer

He S, Chen CH, Chernichenko N, et al.
GFRα1 released by nerves enhances cancer cell perineural invasion through GDNF-RET signaling.
Proc Natl Acad Sci U S A. 2014; 111(19):E2008-17 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
The ability of cancer cells to invade along nerves is associated with aggressive disease and diminished patient survival rates. Perineural invasion (PNI) may be mediated by nerve secretion of glial cell line-derived neurotrophic factor (GDNF) attracting cancer cell migration through activation of cell surface Ret proto-oncogene (RET) receptors. GDNF family receptor (GFR)α1 acts as coreceptor with RET, with both required for response to GDNF. We demonstrate that GFRα1 released by nerves enhances PNI, even in the absence of cancer cell GFRα1 expression. Cancer cell migration toward GDNF, RET phosphorylation, and MAPK pathway activity are increased with exposure to soluble GFRα1 in a dose-dependent fashion. Dorsal root ganglia (DRG) release soluble GFRα1, which potentiates RET activation and cancer cell migration. In vitro DRG coculture assays of PNI show diminished PNI with DRG from GFRα1(+/-) mice compared with GFRα1(+/+) mice. An in vivo murine model of PNI demonstrates that cancer cells lacking GFRα1 maintain an ability to invade nerves and impair nerve function, whereas those lacking RET lose this ability. A tissue microarray of human pancreatic ductal adenocarcinomas demonstrates wide variance of cancer cell GFRα1 expression, suggesting an alternate source of GFRα1 in PNI. These findings collectively demonstrate that GFRα1 released by nerves enhances PNI through GDNF-RET signaling and that GFRα1 expression by cancer cells enhances but is not required for PNI. These results advance a mechanistic understanding of PNI and implicate the nerve itself as a key facilitator of this adverse cancer cell behavior.

Related: Cancer of the Pancreas Pancreatic Cancer

Rusmini M, Griseri P, Matera I, et al.
Expression variability and function of the RET gene in adult peripheral blood mononuclear cells.
J Cell Physiol. 2014; 229(12):2027-37 [PubMed] Related Publications
RET is a gene playing a key role during embryogenesis and in particular during the enteric nervous system development. High levels of RET gene expression are maintained in different human tissues also in adulthood, although their physiological role remains unclear. In particular, collected evidences of a RET contribution in the development and maintenance of the immune system prompted us to investigate its levels of surface expression on peripheral blood mononuclear cells (PBMCs) from adult healthy donors. Despite variability among samples, RET expression was conserved at similar levels in the different immune cell subsets, with higher correlations in similar lymphocyte populations (i.e. CD4(+) and CD8(+) T cells). Conversely, no correlation was found between the amount of RET receptor, the expression of its putative ligands and co-receptors and the genotypes at the RET locus. Moreover, we investigated the RET-associated inflammatory pathways in PBMCs from healthy donors both in resting conditions and upon glial cell derived neurotrophic factor (GDNF) and GPI-linked co-receptors alpha 1 (GFRα1) mediated RET activation. RET mRNA levels positively correlated with the transcript amount of interleukin-8 (IL-8), a cytokine produced by monocytes and macrophages, though we could not demonstrate its direct effect on RET expression by in vitro experiments on THP1 human monocytic cells. These results imply that RET expression might be influenced by either cis- and/or trans-factors, which together would account for its high variability within the general population, and suggest a putative functional role of the RET gene in modulating immune cell responses during inflammation and carcinogenesis.

Wang N, Xu D, Sofiadis A, et al.
Telomerase-dependent and independent telomere maintenance and its clinical implications in medullary thyroid carcinoma.
J Clin Endocrinol Metab. 2014; 99(8):E1571-9 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
CONTEXT: Telomere maintenance via telomerase activation and the alternative lengthening of telomeres (ALT) mechanism was assessed in medullary thyroid carcinoma.
SETTING AND DESIGN: In total, 42 medullary thyroid carcinomas (MTC) were studied including 24 rearranged during transfection (RET)- mutated cases. Relative telomerase reverse transcriptase (TERT) expression, splice forms, and telomere length were determined by PCR-based methods, and telomerase activity by ELISA. The ALT mechanism was detected by Southern blot analysis and immunofluorescence.
RESULTS: TERT expression and telomerase activity were detected in 21/42 tumors (50%), and was independent of the common somatic M918T RET mutation. Mean telomere length was shorter in MTCs compared with thyroids. Telomerase activation was associated with large tumor size (P = .027), advanced clinical stage (P = .0001), and short survival (P = .0001). Full-length TERT and the α(-) and β(-)-deletion forms were revealed, and the full-length form was associated with short survival (P = .04). A subset of cases without telomerase activation showed involvement of the ALT mechanism, which was associated with a low MIB-1 proliferation index (P = .024).
CONCLUSIONS: Stabilization of telomeres by telomerase activation occurs in half of the MTCs and by the ALT mechanism in a subset of cases. Telomerase activation may be used as an additional prognostic marker in medullary thyroid carcinoma.

Related: Thyroid Cancer

Grüllich C
Cabozantinib: a MET, RET, and VEGFR2 tyrosine kinase inhibitor.
Recent Results Cancer Res. 2014; 201:207-14 [PubMed] Related Publications
Cabozantinib is a receptor tyrosine kinase inhibitor with activity against MET, VEGFR2, FLT3, c-KIT, and RET. Activity of cabozantinib toward a broad range of tumor models could be detected in several preclinical studies. Of note, cabozantinib decreases metastasis potential and tumor invasiveness when compared with placebo or agents that target VEGFR and have no activity against MET. Clinical phase I and II studies with cabozantinib have been conducted in various malignancies including medullary thyroid cancer (MTC), NSCLC, breast, ovarian, pancreatic, and prostate cancer. In MTC, gain of function mutations of RET are central for tumorigenesis. Hereditary forms of MTC (MEN II) are caused by germline mutations of RET, in sporadic MTC in up to 50% of cases RET mutations occur. Additionally, activating molecular changes in VEGFR and MET pathways have also been implicated in MTC progression. Clinical responses with cabozantinib in MTC could be observed in early clinical trials, and following confirmation of clinical benefit in a randomized phase III trial, cabozantinib gained FDA approval for first-line treatment of advanced MTC in 2012. In prostate cancer models, MET expression increases with androgen ablation and clinical progression of bone and lymph node metastasis. A phase II trial with cabozantinib also showed very promising response rates in patients with metastatic prostate cancer. Therefore, randomized phase III studies are currently ongoing to validate the efficacy of cabozantinib in heavily pretreated prostate cancer patients.

Related: Cancer Prevention and Risk Reduction MET gene

Stacchiotti S, Pantaleo MA, Astolfi A, et al.
Activity of sunitinib in extraskeletal myxoid chondrosarcoma.
Eur J Cancer. 2014; 50(9):1657-64 [PubMed] Related Publications
BACKGROUND: Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft tissue sarcoma, marked by NR4A3 rearrangement. Herein we report on the activity of sunitinib in a series of 10 patients, strengthening what initially observed in two cases.
PATIENTS AND METHODS: From July 2011, 10 patients with progressive metastatic translocated EMC have been consecutively treated with sunitinib 37.5mg/day, on a named-use basis. In an attempt to interpret the activity of sunitinib in EMC, genotype/phenotype correlations were carried out by fluorescence in situ hybridization (FISH) analyses. Moreover, transcriptome, immunohistochemical and biochemical analyses of a limited set of samples were performed focusing on some putative targets of sunitinib.
RESULTS: Eight of 10 patients are still on therapy. Six patients had a Response Evaluation Criteria in Solid Tumours (RECIST) partial response (PR), two were stable, two progressed. Positron emission tomography (PET) was consistent in 6/6 evaluable cases. One patient underwent surgery after sunitinib, with evidence of a pathologic response. At a median follow-up of 8.5 months (range 2-28), no secondary resistance was detected. Median progression free survival (PFS) has not been reached. Interestingly, all responsive cases turned out to express the typical EWSR1-NR4A3 fusion, while refractory cases carried the alternative TAF15-NR4A3 fusion. Among putative sunitinib targets, only RET was expressed and activated in analysed samples.
CONCLUSIONS: This report confirms the therapeutic activity of sunitinib in EMC. Genotype/phenotype analyses support a correlation between response and EWSR1-NR4A3 fusion. Involvement of RET deserves further investigation.

Related: Angiogenesis Inhibitors Bone Cancers Secondary Bone Cancer (bone metastasis) EWSR1 gene TAF15 gene Sunitinib (Sutent) FLT3 gene

Zhang Y, Wang S, Chen X, et al.
Quantitative assessment of the association between L769L and S836S polymorphisms at RET gene and medullary thyroid carcinoma risk.
Tumour Biol. 2014; 35(7):6641-7 [PubMed] Related Publications
RET single nucleotide polymorphisms (SNPs) have been implicated in the pathogenesis and progression of medullary thyroid carcinoma (MTC). Epidemiologic studies have evaluated the association between RET L769L and S836S polymorphisms and predisposition to MTC. However, the results were inconclusive. A literature search was performed using the PubMed database for relevant studies published through October 31, 2013. A total of 13 eligible studies were selected for this meta-analysis, including 1,117 cases and 1,916 controls for L769L and 1,230 cases and 2,246 controls for S836S. The carrier frequency of the variant alleles was 26.3 % in patients with MTC and 24.6 % in controls for L769L polymorphism, and 6.6 % in patients with MTC and 5.0 % in controls for S836S polymorphism. In our pooled analysis of all these studies, the results of our meta-analysis suggested that the RET L769L variant was not significantly associated with an elevated MTC risk (odds ratio (OR) 1.06, 95 % confidence interval (CI) 0.94-1.19). And there was no evidence for the association between the S836S variant and MTC risk (OR 1.20, 95 % CI 0.97-1.49). Moreover, no significant differences were found when considering patients or controls heterozygous or homozygous for RET L769L and S836S polymorphisms. In conclusion, this meta-analysis suggests that RET L769L and S836S polymorphisms may not be associated with MTC development.

Related: Thyroid Cancer

Krampitz GW, Norton JA
RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma.
Cancer. 2014; 120(13):1920-31 [PubMed] Related Publications
The rapid technical advances in molecular biology and accelerating improvements in genomic and proteomic diagnostics have led to increasingly personalized strategies for cancer therapy. Such an approach integrates the genomic, proteomic, and molecular information unique to the individual to provide an accurate genetic diagnosis, molecular risk assessment, informed family counseling, therapeutic profiling, and early preventative management that best fits the particular needs of each patient. The discovery of mutations in the RET proto-oncogene resulting in variable onset and severity of multiple endocrine neoplasia type 2 (MEN2) was the first step in developing direct genetic testing for at-risk individuals. Patients with germline RET mutations may undergo risk assessment and appropriate intervention based on specific mutations. Moreover, family members of affected individuals receive counseling based on understanding of the genetic transmission of the disease. Increasingly, clinicians are able to make therapeutic choices guided by an informative biomarker code. Improvements in detection and management of patients with MEN2 resulting from understanding of the RET proto-oncogene are evidence of the benefits of personalized cancer medicine. This review describes the discovery of the RET proto-oncogene, the association between genotype and phenotype, and the role of mutation analysis on diagnosis and treatment of MEN2.

Related: Thyroid Cancer

Duan L, Hao X, Liu Z, et al.
MiR-129-5p is down-regulated and involved in the growth, apoptosis and migration of medullary thyroid carcinoma cells through targeting RET.
FEBS Lett. 2014; 588(9):1644-51 [PubMed] Related Publications
Dysregulation of the REarranged during Transfection proto-oncogene (RET) pathway and microRNA (miRNAs) are crucial for the development of medullary thyroid carcinomas (MTC). Here we demonstrate that miR-129-5p is down-regulated in MTC tissues and cell lines and inhibits RET expression by directly binding its 3' untranslated regions. Ectopic expression of miR-129-5p significantly decreases cell growth, induces apoptosis and suppresses migration ability in MTC cells through decreasing the phosphorylated AKT, thus functioning as a tumor suppressor. These findings give new clues for understanding MTC carcinogenesis and may help in developing a therapeutic approach for the treatment of RET-activated MTC.

Related: Apoptosis Thyroid Cancer

Siqueira DR, Ceolin L, Ferreira CV, et al.
Role of RET genetic variants in MEN2-associated pheochromocytoma.
Eur J Endocrinol. 2014; 170(6):821-8 [PubMed] Related Publications
BACKGROUND: RET polymorphisms have been involved in the clinical presentation and prognosis of multiple endocrine neoplasia type 2 (MEN2)-associated medullary thyroid carcinoma.
OBJECTIVE: To investigate the effect of RET variants on the penetrance of pheochromocytoma (PHEO) in MEN2 patients.
METHODS: The RET variants L769L, S836S, and G691S/S904S were evaluated in a cohort of 153 MEN2 patients attending a tertiary teaching hospital. A comparison of RET variant frequencies between patients with and without PHEO was performed. Kaplan-Meier curves and Cox regression analysis were used to estimate the effect of RET variants on the age-dependent penetrance.
RESULTS: A total of 48 (31.4%) patients presented with MEN2-associated PHEOs. The mean age at diagnosis was 35.5±13.4 years, 60.4% of patients were women, and 92.8% had RET mutations at codon 634. The frequencies of RET polymorphisms were as follows: 20.1% L769L, 4.75% S836S, and 17.3% S904S/G691S. We did not observe any association between the frequencies of L769L, S836S, or S904S/G691S variants and PHEO development (all P>0.05). However, individuals carrying two RET polymorphic alleles had an increased estimated risk of PHEO (2.63; 95% CI, 1.4-5.0; P=0.004) and were younger at diagnosis when compared with those with one or no polymorphism (29.6±6.3 and 39.3±14.4 years respectively; P=0.006). Accordingly, additional analysis using Cox proportional hazard models demonstrated that the presence of two RET variants was associated with an increased risk for early PHEO development (hazard ratio, 5.99 (95% CI, 2.24-16.03); P<0.001).
CONCLUSIONS: RET polymorphic alleles have an additive effect on the estimated risk of age-related PHEO penetrance in MEN2 patients.

Araujo AN, Moraes L, França MI, et al.
Genome-wide copy number analysis in a family with p.G533C RET mutation and medullary thyroid carcinoma identified regions potentially associated with a higher predisposition to lymph node metastasis.
J Clin Endocrinol Metab. 2014; 99(6):E1104-12 [PubMed] Related Publications
CONTEXT: Our group described a p.G533C RET gene mutation in a large family with multiple endocrine neoplasia type 2 syndrome. Clinical heterogeneity, primarily associated with the presence of lymph node metastases, was observed among the p.G533C carriers.
OBJECTIVE: The aim of this study was to use single-nucleotide polymorphism-array technology to identify copy number variations (CNVs), which are present in the constitutional DNA and associated with the established clinical and pathological features of aggressive medullary thyroid carcinoma (MTC), primarily the presence of lymph node metastasis.
DESIGN: Fifteen p.G533C carriers with MTC were chosen for the initial screening. The subjects were divided into two groups according the presence (n = 8) or absence (n = 7) of lymph node metastasis. Peripheral blood DNA was independently hybridized using a genome-wide single-nucleotide polymorphism Array 6.0 platform. The results were analyzed using both Genotyping Console and PennCNV software. To identify the possible candidate regions associated with the presence of lymph node metastasis, cases (metastatic MTC) were compared with controls (nonmetastatic MTC). The identified CNVs were validated by quantitative PCR in an extended cohort (n = 32).
RESULTS: Using two different algorithms, we identified nine CNV regions that may contribute to susceptibility to lymph node metastasis. The validation step confirmed that a CNV loss impacting the FMN2 gene was potentially associated with a greater predisposition to lymph node metastasis in this family (P = .0179). Finally, we sought to investigate whether the development of lymph node metastasis might not depend on a single CNV but rather a combination of various CNVs. These analyses defined a CNV pattern related to a more aggressive phenotype in this family, with CNV deletions being enriched in the metastatic group (P = .0057).
CONCLUSION: Although hereditable specific RET mutations are important to determine cancer risk, germline CNVs in disease-affected individuals may predispose them to MTC aggressiveness.

Related: CGH Thyroid Cancer

Mulligan LM
RET revisited: expanding the oncogenic portfolio.
Nat Rev Cancer. 2014; 14(3):173-86 [PubMed] Related Publications
The RET receptor tyrosine kinase is crucial for normal development but also contributes to pathologies that reflect both the loss and the gain of RET function. Activation of RET occurs via oncogenic mutations in familial and sporadic cancers - most notably, those of the thyroid and the lung. RET has also recently been implicated in the progression of breast and pancreatic tumours, among others, which makes it an attractive target for small-molecule kinase inhibitors as therapeutics. However, the complex roles of RET in homeostasis and survival of neural lineages and in tumour-associated inflammation might also suggest potential long-term pitfalls of broadly targeting RET.

Related: Cancer Prevention and Risk Reduction

Birner P, Bartsch R, Schreiber M, et al.
New approaches for breast cancer: should Ret kinase be considered as a novel therapeutic target?
Future Oncol. 2014; 10(3):333-6 [PubMed] Related Publications

Related: Breast Cancer

Caria P, Frau DV, Dettori T, et al.
Optimizing detection of RET and PPARg rearrangements in thyroid neoplastic cells using a home-brew tetracolor probe.
Cancer Cytopathol. 2014; 122(5):377-85 [PubMed] Related Publications
BACKGROUND: Fluorescence in situ hybridization (FISH) to identify specific DNA target sequences in the nuclei of nondividing cells of numerous solid neoplasms has contributed to the introduction of molecular cytogenetics as a useful adjunct to cytology, leading recently to the "marriage" of the 2 disciplines. Numerous cancer molecular markers can now be investigated using different technical approaches, at both the gene and expression levels, in biopsies of various suspected cancers, including differentiated thyroid carcinoma. The limited amount of bioptic material is often insufficient to carry out multiple tests, and optimizing handling of the biopsy is desirable.
METHODS: We have developed a home-brew tetracolor break-apart probe able to simultaneously identify the 2 most common genetic alterations in differentiated thyroid carcinoma: RET/PTC variants in papillary thyroid carcinoma and PAX8/PPARg fusion and variants in follicular thyroid carcinoma.
RESULTS: The probe had 100% specificity, 99.5% sensitivity, and ≥ 3% cutoff. The probe was tested on RET/PTC and PAX8/PPARg RT-PCR positive controls, and feasibility was assessed in 368 thyroid nodule fine-needle aspirations (FNA). In the latter analysis, 24 FNAs had split RET signal, and 9 had split PPARg signal. FISH analysis of available surgically removed nodules confirmed the sensitivity of FISH in detecting abnormal clones and oligoclones.
CONCLUSIONS: The home-brew tetracolor probe showed high feasibility, optimizing the use of the biological material in relation to the available molecular tests and maximizing the FISH experimental and slide-scoring times. This probe may be considered an alternative to RT-PCR when recovery and quality of RNA amplification from FNA are insufficient.

Related: FISH PPARG gene Thyroid Cancer

Tsuta K, Kohno T, Yoshida A, et al.
RET-rearranged non-small-cell lung carcinoma: a clinicopathological and molecular analysis.
Br J Cancer. 2014; 110(6):1571-8 [PubMed] Article available free on PMC after 18/03/2015 Related Publications
BACKGROUND: To elucidate clinicopathological characteristics of non-small-cell lung carcinoma (NSCLC) cases carrying RET rearrangements causing oncogenic fusions to identify responders to therapy with RET tyrosine kinase inhibitors.
METHODS: We investigated 1874 patients with carcinomas, including 1620 adenocarcinomas (ADCs), 203 squamous cell carcinomas (SCCs), 8 large cell carcinomas, and 43 sarcomatoid carcinomas (SACs). Fluorescence in situ hybridisation (FISH) and/or reverse transcription-PCR (RT-PCR) were performed to detect RET gene rearrangement.
RESULTS: In all, 22 cases (1.2%) showed RET rearrangements; all cases were of ADC histology. Of the 22 patients, 19 possessed KIF5B-RET fusion genes, whereas 3 possessed CCDC6-RET fusion genes. The RET-rearranged tumours were significantly more common in younger patients (P=0.038) and tended to occur in patients with no history of smoking (P=0.051). In addition, RET rearrangements were not associated with gender, occupational history (particularly radioactive exposure), tumour size, lymph node status, tumour stage, or patient survival. The predominant growth pattern in RET-rearranged ADCs was lepidic in 6 cases, papillary in 9 cases, acinar in 2 cases, micropapillary in 1 case, and solid in 4 cases. Cells with cytoplasmic mucin production were at least focally present in 12 of the 22 (54.5%) RET-rearranged ADC cases. Among the 21 analysed RET-rearranged tumours, RET immunopositivity was observed in 15 cases (71.4%), and was significantly associated with RET rearrangement (P<0.001).
CONCLUSIONS: The RET rearrangements were observed in 1.2% of NSCLCs. All cases of RET rearrangement were ADCs. The RET rearrangements were more likely to be observed in younger patients. Although cytoplasmic mucin production was at least focally present in 54.5% of RET-rearranged ADCs, specific histological features were not detected.

Related: Non-Small Cell Lung Cancer FISH Lung Cancer

Gori S, Foglietta J, Rossi M, et al.
Sunitinib therapy in metastatic papillary thyroid cancer.
Tumori. 2013 Nov-Dec; 99(6):285e-7e [PubMed] Related Publications
We present the case of a 51-year-old woman with a follicular variant of papillary thyroid carcinoma. After surgery she experienced a relapse. Chemotherapy treatment led only to disease stabilization. In August 2009, we decided to start therapy with sunitinib 50 mg daily in an intermittent schedule (4 weeks on/2 weeks off). A CT scan after 3 months of treatment showed partial remission of disease according to the RECIST criteria. The patient continued sunitinib until January 2011, when CT evidenced progression in the mediastinal lymph nodes and pleura. Genetic analyses were carried out to determine if the clinical response in our patient was correlated with the presence of RET or BRAF mutations. No RET/PTC rearrangements or BRAF-V600E mutation, which are the two most common genetic alterations detected in papillary thyroid carcinoma, were found. It can be hypothesized that the activity of sunitinib in this patient was due to its antiangiogenic properties.

Related: Angiogenesis Inhibitors Carboplatin Cisplatin Doxorubicin Etoposide Lung Cancer BRAF gene Thyroid Cancer Sunitinib (Sutent)

Kushchayeva Y, Jensen K, Recupero A, et al.
The HIV protease inhibitor nelfinavir down-regulates RET signaling and induces apoptosis in medullary thyroid cancer cells.
J Clin Endocrinol Metab. 2014; 99(5):E734-45 [PubMed] Related Publications
CONTEXT: Mutations of RET tyrosine kinase are associated with the development of medullary thyroid cancer (MTC). The heat shock protein (HSP) 90 chaperone is required for folding and stability of RET mutants. HSP90 is a molecular target for the HIV protease inhibitor nelfinavir (NFV).
OBJECTIVE: We hypothesized that treatment with NFV may lead to the inhibition of RET signaling and induction of apoptosis in MTC cells.
DESIGN: Two human MTC cell lines, TT and MZ-CRC-1, which harbor endogenous C634W or M918T RET mutations, respectively, were exposed to clinically achievable concentrations of NFV. JC-1 staining and caspase-3 cleavage assays were performed to measure mitochondrial membrane potential and apoptosis. Activation of RET signaling was examined by Western blot. Autophagy was monitored by the detection of the light-chain 3BII. Expression of HSP90 and LC3B were examined in 36 human MTCs.
RESULTS: At a therapeutic serum concentration (10 μM), NFV inhibited the viability of TT and MZ-CRC-1 cells by 55% and 10%, respectively. In a dose-dependent manner, NFV inhibited cyclin D1 and caused caspase-3 cleavage. NFV decreased the level of RET protein and blocked the activation of RET downstream targets (phosphorylated ERK, phosphorylated AKT, and p70S6K/pS6). NFV induced metabolic stress, activated AMP-activated protein kinase and increased autophagic flux. Pharmacological inhibition of autophagy (chloroquine) augmented NFV-inducible cytotoxicity, suggesting that autophagy was protective in NFV-treated cells. NFV led to mitochondrial membrane depolarization and induced both oxidative stress and DNA damage. An antioxidant (n-acetylcysteine) attenuated DNA damage and prevented NFV-inducible apoptosis. HSP90 overexpression was found in 17 of 36 human MTCs and correlated with metastases and RET mutations. LC3B was detected in 20 of 36 human MTCs.
CONCLUSIONS: NFV has a wide spectrum of activity against MTC cells, and its cytotoxicity can be augmented by inhibiting autophagy. Expression of NFV molecular targets in metastatic MTC suggests that NFV has a potential to become a thyroid cancer therapeutic agent.

Related: Apoptosis Signal Transduction Thyroid Cancer

Klein P, Müller-Rischart AK, Motori E, et al.
Ret rescues mitochondrial morphology and muscle degeneration of Drosophila Pink1 mutants.
EMBO J. 2014; 33(4):341-55 [PubMed] Article available free on PMC after 18/03/2015 Related Publications
Parkinson's disease (PD)-associated Pink1 and Parkin proteins are believed to function in a common pathway controlling mitochondrial clearance and trafficking. Glial cell line-derived neurotrophic factor (GDNF) and its signaling receptor Ret are neuroprotective in toxin-based animal models of PD. However, the mechanism by which GDNF/Ret protects cells from degenerating remains unclear. We investigated whether the Drosophila homolog of Ret can rescue Pink1 and park mutant phenotypes. We report that a signaling active version of Ret (Ret(MEN₂B) rescues muscle degeneration, disintegration of mitochondria and ATP content of Pink1 mutants. Interestingly, corresponding phenotypes of park mutants were not rescued, suggesting that the phenotypes of Pink1 and park mutants have partially different origins. In human neuroblastoma cells, GDNF treatment rescues morphological defects of PINK1 knockdown, without inducing mitophagy or Parkin recruitment. GDNF also rescues bioenergetic deficits of PINK knockdown cells. Furthermore, overexpression of Ret(MEN₂B) significantly improves electron transport chain complex I function in Pink1 mutant Drosophila. These results provide a novel mechanism underlying Ret-mediated cell protection in a situation relevant for human PD.

Related: Apoptosis Neuroblastoma Signal Transduction

Kales SC, Nau MM, Merchant AS, Lipkowitz S
Enigma prevents Cbl-c-mediated ubiquitination and degradation of RETMEN2A.
PLoS One. 2014; 9(1):e87116 [PubMed] Article available free on PMC after 18/03/2015 Related Publications
The Cbl proteins (Cbl, Cbl-b, and Cbl-c) are a highly conserved family of RING finger ubiquitin ligases (E3s) that function as negative regulators of tyrosine kinases in a wide variety of signal transduction pathways. In this study, we identify a new Cbl-c interacting protein, Enigma (PDLIM7). This interaction is specific to Cbl-c as Enigma fails to bind either of its closely related homologues, Cbl and Cbl-b. The binding between Enigma and Cbl-c is mediated through the LIM domains of Enigma as removal of all three LIM domains abrogates this interaction, while only LIM1 is sufficient for binding. Here we show that Cbl-c binds wild-type and MEN2A isoforms of the receptor tyrosine kinase, RET, and that Cbl-c enhances ubiquitination and degradation of activated RET. Enigma blocks Cbl-c-mediated RETMEN2A ubiquitination and degradation. Cbl-c decreased downstream ERK activation by RETMEN2A and co-expression of Enigma blocked the Cbl-c-mediated decrease in ERK activation. Enigma showed no detectable effect on Cbl-c-mediated ubiquitination of activated EGFR suggesting that this effect is specific to RET. Through mapping studies, we show that Cbl-c and Enigma bind RETMEN2A at different residues. However, binding of Enigma to RETMENA prevents Cbl-c recruitment to RETMEN2A. Consistent with these biochemical data, exploratory analyses of breast cancer patients with high expression of RET suggest that high expression of Cbl-c correlates with a good outcome, and high expression of Enigma correlates with a poor outcome. Together, these data demonstrate that Cbl-c can ubiquitinate and downregulate RETMEN2A and implicate Enigma as a positive regulator of RETMEN2A through blocking of Cbl-mediated ubiquitination and degradation.

Related: Breast Cancer Cancer of the Pancreas Pancreatic Cancer

Ellis RJ, Wang Y, Stevenson HS, et al.
Genome-wide methylation patterns in papillary thyroid cancer are distinct based on histological subtype and tumor genotype.
J Clin Endocrinol Metab. 2014; 99(2):E329-37 [PubMed] Article available free on PMC after 01/02/2015 Related Publications
CONTEXT: Aberrant DNA methylation is known to be a major factor in oncogenesis and cancer progression, but effects of methylation in papillary thyroid cancer (PTC) are not well defined.
OBJECTIVE: The objective of the study was to identify altered methylation patterns, which may be associated with PTC disease behavior.
DESIGN: This study was a genome-wide methylation analysis of PTC.
SETTING: The study was conducted at the National Institutes of Health Clinical Center.
PATIENTS: PTC tissue from 51 patients were analyzed and compared with normal thyroid tissue from seven patients.
INTERVENTIONS: CpG methylation status was assessed using advanced genome-wide methylation bead chips.
OUTCOME MEASURES: Altered methylation patterns in PTC were analyzed by stage, recurrence, histological subtype of tumor, and tumor genotype.
RESULTS: PTC is globally hypomethylated compared with normal thyroid with 2837 differentially methylated CpG sites. The follicular variant of PTC demonstrated less differential methylation with only 569 differentially methylated CpG sites. Tumors with mutations in BRAF, RET/PTC, and RAS demonstrated a 3.6-fold increase in the number of differentially methylated sites compared with wild-type tumors. The differentially methylated genes were associated with oncological pathways including cellular movement, growth, and proliferation.
CONCLUSION: PTC is epigenetically distinct from the follicular variant of PTC and by gene mutation status (BRAF, RET/PTC, and RAS).

Related: BRAF gene Thyroid Cancer

Lira ME, Choi YL, Lim SM, et al.
A single-tube multiplexed assay for detecting ALK, ROS1, and RET fusions in lung cancer.
J Mol Diagn. 2014; 16(2):229-43 [PubMed] Related Publications
Approximately 7% of non-small cell lung carcinomas (NSCLCs) harbor oncogenic fusions involving ALK, ROS1, and RET. Although tumors harboring ALK fusions are highly sensitive to crizotinib, emerging preclinical and clinical data demonstrate that patients with ROS1 or RET fusions may also benefit from inhibitors targeting these kinases. Using a transcript-based method, we designed a combination of 3' overexpression and fusion-specific detection strategies to detect ALK, ROS1 and RET fusion transcripts in NSCLC tumors. We validated the assay in 295 NSCLC specimens and showed that the assay is highly sensitive and specific. ALK results were 100% concordant with fluorescence in situ hybridization (FISH) (n = 52) and 97.8% concordant with IHC (n = 179) [sensitivity, 96.8% (95% CI 91.0%-98.9%); specificity, 98.8% (95% CI 93.6%-99.8%)]. For ROS1 and RET, we also observed 100% concordance with FISH (n = 46 and n = 15, respectively). We identified seven ROS1 and 14 RET fusion-positive tumors and confirmed the fusion status by RT-PCR and FISH. One RET fusion involved a novel partner, cutlike homeobox 1 gene (CUX1), yielding an in-frame CUX1-RET fusion. ROS1 and RET fusions were significantly enriched in tumors without KRAS/EGFR/ALK alterations. ALK/ROS1/RET/EGFR/KRAS alterations were mutually exclusive. As a single-tube assay, this test shows promise as a more practical and cost-effective screening modality for detecting rare but targetable fusions in NSCLC.

Related: Non-Small Cell Lung Cancer FISH Lung Cancer ROS1 gene

Piciu D
Thyroid cancer incidence 25 years after Chernobyl, in a Romanian cancer center: is it a public health problem?
Curr Radiopharm. 2013; 6(4):249-52 [PubMed] Related Publications
Incidence of thyroid cancer (TC) has increased over the last decade, in most parts of the world, possibly because of increased ionizing radiations. We therefore analyzed records of patients with TC who were treated at our hospital (Prof. Dr. Ion Chiricuta, Institute of Oncology Cluj-Napoca, Romania) since the nuclear accident at Chernobyl in 1986. We performed a comparative analysis of the database for 10, 20 and 25 years after the Chernobyl accident. Changes in histological profiles and tumor sizes imply that, in addition to nuclear fallout, highly sensitive thyroid diagnostic procedures are responsible for this increase in reported incidence, which appears to be driven by improved discovery of small (<1 cm) preclinical tumors. This invites a real public health question.

Related: Thyroid Cancer

Ding X, Xiang L, Wang N, et al.
Vandetanib-induced inhibition of neuroblastoma cell migration and invasion is associated with downregulation of the SDF-1/CXCR4 axis and matrix metalloproteinase 14.
Oncol Rep. 2014; 31(3):1165-74 [PubMed] Related Publications
Rearranged during transfection (RET) is widely expressed in neuroblastoma (NB) and partly contributes to high metastatic potential and survival of NB. The aim of the present study was to investigate whether vandetanib (a RET inhibitor) inhibits proliferation, migration and invasion of NB cells in vitro. The effects of vandetanib on the proliferation, apoptosis and cell cycle and on RET phosphorylation of SK-N-SH and SH-SY5Y cells were evaluated in vitro. The migration and invasion potential of vandetanib-treated NB cells were analyzed using Transwell cell migration and invasion assays, respectively. qPCR, western blotting and immunofluorescence were used to detect mRNA and protein levels in NB cells treated with vandetanib. Our data demonstrated that vandetanib inhibits the proliferation of SK-N-SH and SH-SY5Y cells and that this inhibition is mediated by the induction of G1 phase cell cycle arrest at lower concentrations and by apoptosis at higher concentrations. In the presence of vandetanib, the migration and invasion of two NB cell lines were markedly decreased compared with the control group (p<0.01). In addition, our data showed that the levels of C-X-C chemokine receptor type 4 (CXCR4) and matrix metalloproteinase 14 (MMP14) mRNA expression in NB cell lines treated with vandetanib were significantly lower than those in the cells that were treated with vehicle (p<0.01) and similar results were obtained for protein levels as determined by western blotting and immunofluorescence analysis. Vandetanib may inhibit the proliferation, migration and invasion of NB cells in vitro. The potential mechanisms for the inhibition of NB migration and invasion by vandetanib may partly be attributed to the ability of vandetanib to suppress the expression of CXCR4 and MMP14 in human NB cells.

Related: Apoptosis Neuroblastoma

Further References

Mulligan LM, Kwok JB, Healey CS, et al.
Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A.
Nature. 1993; 363(6428):458-60 [PubMed] Related Publications
Multiple endocrine neoplasia type 2A (MEN 2A) is a dominantly inherited cancer syndrome that affects tissues derived from neural ectoderm. It is characterized by medullary thyroid carcinoma (MTC) and phaeochromocytoma. The MEN2A gene has recently been localized by a combination of genetic and physical mapping techniques to a 480-kilobase region in chromosome 10q11.2 (refs 2,3). The DNA segment encompasses the RET proto-oncogene, a receptor tyrosine kinase gene expressed in MTC and phaeochromocytoma and at lower levels in normal human thyroid. This suggested RET as a candidate for the MEN2A gene. We have identified missense mutations of the RET proto-oncogene in 20 of 23 apparently distinct MEN 2A families, but not in 23 normal controls. Further, 19 of these 20 mutations affect the same conserved cysteine residue at the boundary of the RET extracellular and transmembrane domains.

Related: Multiple Endocrine Neoplasia Thyroid Cancer

Donis-Keller H, Dou S, Chi D, et al.
Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC.
Hum Mol Genet. 1993; 2(7):851-6 [PubMed] Related Publications
Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are dominantly inherited conditions which predispose to the development of endocrine neoplasia. Evidence is presented that sequence changes within the coding region of the RET proto-oncogene, a putative transmembrane tyrosine kinase, may be responsible for the development of neoplasia in these inherited disorders. Single strand conformational variants (SSCVs) in exons 7 and 8 of the RET proto-oncogene were identified in eight MEN 2A and four FMTC families. The variants were observed only in the DNA of individuals who were either affected or who had inherited the MEN2A or FMTC allele as determined by haplotyping experiments. The seven variants identified were sequenced directly. All involved point mutations within codons specifying cysteine residues, resulting in nonconservative amino acid changes. Six of the seven mutations are located in exon 7. A single mutation was found in exon 8. Variants were not detected in four MEN 2B families studied for all exon assays available, nor were they detectable in 16 cases of well documented sporadic medullary thyroid carcinoma or pheochromocytoma that were tested for exon 7 variants. Coinheritance of the mutations with disease and the physical and genetic proximity of the RET proto-oncogene provide evidence that RET is responsible for at least two of the three inherited forms of MEN 2. Neither the normal function, nor the ligand of RET are yet known. However, its apparent involvement in the development of these inherited forms of neoplasia as well as in papillary thyroid carcinoma suggest an important developmental or cell regulatory role for the protein.

Related: Multiple Endocrine Neoplasia Polymorphisms Thyroid Cancer

Mulligan LM, Eng C, Healey CS, et al.
Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC.
Nat Genet. 1994; 6(1):70-4 [PubMed] Related Publications
We have analysed 118 families with inherited medullary thyroid carcinoma (MTC) for mutations of the RET proto-oncogene. These included cases of multiple endocrine neoplasia types 2A (MEN 2A) and 2B (MEN 2B) and familial MTC (FMTC). Mutations at one of 5 cysteines in the extracellular domain were found in 97% of patients with MEN 2A and 86% with FMTC but not in MEN 2B patients or normal controls. 84% of the MEN2A mutations affected codon 634. MEN 2A patients with a Cys634 to Arg substitution had a greater risk of developing parathyroid disease than those with other codon 634 mutations. Our data show a strong correlation between disease phenotype and the nature and position of the RET mutation, suggesting that a simple, constitutive activation of the RET tyrosine kinase is unlikely to explain the events leading to MEN 2A and FMTC.

Related: Multiple Endocrine Neoplasia Thyroid Cancer

Hofstra RM, Landsvater RM, Ceccherini I, et al.
A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma.
Nature. 1994; 367(6461):375-6 [PubMed] Related Publications
Multiple endocrine neoplasia type 2 (MEN 2) comprises three clinically distinct, dominantly inherited cancer syndromes. MEN 2A patients develop medullary thyroid carcinoma (MTC) and phaeochromocytoma. MEN 2B patients show in addition ganglioneuromas of the gastrointestinal tract and skeletal abnormalities. In familial MTC, only the thyroid is affected. Germ-line mutations of the RET proto-oncogene have recently been reported in association with MEN 2A and familial MTC. All mutations occurred within codons specifying cysteine residues in the transition point between the RET protein extracellular and transmembrane domains. We now show that MEN 2B is also associated with mutation of the RET proto-oncogene. A mutation in codon 664, causing the substitution of a threonine for a methionine in the tyrosine kinase domain of the protein, was found in all nine unrelated MEN 2B patients studied. The same mutation was found in six out of 18 sporadic tumours.

Related: Multiple Endocrine Neoplasia Polymorphisms Thyroid Cancer

Bounacer A, Wicker R, Caillou B, et al.
High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation.
Oncogene. 1997; 15(11):1263-73 [PubMed] Related Publications
A high frequency (about 60%) of ret rearrangements in papillary thyroid carcinomas of children exposed to radioactive fallout in Belarus after the Chernobyl accident, has been reported by three recent studies (Fugazzola et al., 1995; Ito et al., 1994; Klugbauer et al., 1995). These studies suggested that the radiation exposure may be a direct inducer of activating rearrangements in the ret gene. In order to confirm the postulated link between irradiation and the role of the ret proto-oncogene in thyroid tumorigenesis, we analysed for the presence of ret activating rearrangements using RT-PCR, XL-PCR, Southern blot and direct sequencing techniques, 39 human thyroid tumors (19 papillary carcinomas and 20 follicular adenomas), from patients who had received external radiation for benign or malignant conditions. As controls, we studied 39 'spontaneous' tumors (20 papillary carcinomas and 19 follicular adenomas). Our data concerning the radiation-associated tumors, showed that: (1) the overall frequency of ret rearrangements was 84% in papillary carcinomas (16/19) and 45% (9/20) in follicular adenomas; (2) in contrast with the results obtained in the Chernobyl tumors, the most frequently observed chimeric gene was RET/PTC1 instead of the RET/PTC3 and (3) all the tumors were negative for RET/PTC2. In the 'spontaneous' tumors, only the papillary carcinomas presented a ret rearrangement (15%:3/20): 1 RET/PTC1, 1 RET/ PTC3 and 1 uncharacterized. In conclusion, our results confirm the crucial role played by the ret proto-oncogene activating rearrangements in the development of radiation-associated thyroid tumors appearing after therapeutic or accidental ionizing irradiation, and show, for the first time, the presence of RET/PTC genes in follicular adenomas appeared after external irradiation.

Related: Thyroid Cancer

Nikiforov YE, Rowland JM, Bove KE, et al.
Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children.
Cancer Res. 1997; 57(9):1690-4 [PubMed] Related Publications
In this study, we compare the morphological and genetic characteristics of 38 post-Chernobyl thyroid papillary carcinomas from Belarussian children 5-18 years old with those of 23 sporadic papillary carcinomas from the same age children without history of radiation exposure from Los Angeles and Cincinnati. Among radiation-induced tumors, solid variant of papillary carcinoma was found in 37%, follicular in 29%, typical papillary in 18%, and mixed and diffuse sclerosing variants in 8% each. In the sporadic group, a typical papillary pattern was prevalent in 70%, follicular in 17%, diffuse sclerosing variant in 9%, and solid in 4%. In both groups, the prevalence of ret rearrangements was high, but the frequency of specific types of rearrangement was significantly different. Among radiation-induced tumors, ret/PTC3 was found in 58%, ret/PTC1 in 16%, and ret/PTC2 in 3%, whereas among sporadic tumors, ret/PTC1 was found in 47% (P < 0.05), and ret/PTC3 was found in 18% (P = 0.01). The morphological variants of papillary carcinoma showed different prevalence of the specific types of ret rearrangement. Seventy-nine % of solid variant tumors had ret/PTC3, whereas only 7% had ret/PTC1 (P = 0.0007). Among typical papillary tumors, ret/PTC1 was found in 38%, ret/PTC3 in 19%, and ret/PTC2 in 5%. Thus, ret rearrangements are highly prevalent in pediatric papillary carcinomas from children exposed to radiation and in those occurring sporadically. However, the types of ret/PTC vary between these two populations, with ret/PTC3 present more commonly in post-Chernobyl tumors. Furthermore, solid variants have a high prevalence of ret/PTC3, whereas typical papillary carcinomas do not, suggesting that the different types of ret rearrangement confer neoplastic thyroid cells with distinct phenotypic properties.

Related: Thyroid Cancer

Smida J, Salassidis K, Hieber L, et al.
Distinct frequency of ret rearrangements in papillary thyroid carcinomas of children and adults from Belarus.
Int J Cancer. 1999; 80(1):32-8 [PubMed] Related Publications
Rearrangements of the ret oncogene were investigated in papillary thyroid carcinomas (PTC) from 51 Belarussian children with a mean age of 3 years at the time of the Chernobyl radiation accident. For comparison, 16 PTC from exposed Belarussian adults and 16 PTC from German patients without radiation history were included in the study. ret rearrangements were detected and specified by RT-PCR and direct sequencing using specific primers for ret/PTC1, 2 and 3. Only ret/PTC1, and no ret/PTC3, was found in the adult patients, with a frequency of 69% for the Belarussian cases, but of only 19% in the German patients. In contrast, 13 ret/PTC3 (25.5%) and 12 ret/PTC1 (23.5%) rearrangements were present in PTC from Belarussian children. Thus, our study reveals about a 1:1 ratio of ret/PTC3 and ret/PTC1, in contrast to earlier studies with lower numbers of cases and exhibiting a high predominance of ret/PTC3 (ratio about 3:1). A ratio (2.5:1) similar to that in earlier investigations (diagnosed 1991-94) was obtained for cases included in our study that were diagnosed in 1993/94. The present data suggest that ret/PTC3 may be typical for radiation-associated childhood PTC with a short latency period, whereas ret/PTC1 may be a marker for later-occurring PTC of radiation-exposed adults and children.

Related: Thyroid Cancer


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