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:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:proto-oncogene tyrosine-protein kinase receptor Ret
Source:NCBIAccessed: 14 March, 2017


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 14 March 2017 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 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (14)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Multiple Endocrine Neoplasia Type 2aRET mutations in Multiple Endocrine Neoplasia - type 2A View Publications666
Pheochromocytoma and ParagangliomaRET and Pheochromocytoma and Paraganglioma View Publications388
Adrenocortical CancerRET and Adrenocortical Cancer View Publications312
Thyroid CancerRET mutations in Familial Medullary Thyroid Carcinoma View Publications287
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 Publications239
Multiple Endocrine Neoplasia Type 2bRET mutations in Multiple Endocrine Neoplasia Type 2b View Publications250
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 Publications164
Lung CancerRET and Lung Cancer View Publications167
Thyroid CancerRET Rearrangements Following Exposure to Ionizing Radiation View Publications64
Thyroid CancerRET-NTRK1 Rearangements in Papillary Thyroid Cancer View Publications38
Lung CancerRET-KIF5B fusion in Adenocarcinoma Lung Cancer View Publications36
Lung Cancer, Non-Small CellRET and Non-Small Cell Lung Cancer View Publications66
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).

Latest Publications: RET (cancer-related)

Liu Q, Tong D, Yuan W, et al.
Different RET gene mutation-induced multiple endocrine neoplasia type 2A in 3 Chinese families.
Medicine (Baltimore). 2017; 96(3):e5967 [PubMed] Free Access to Full Article Related Publications
BACKGROUD: Multiple endocrine neoplasia type 2A (MEN2A) is a condition with inherited autosomal dominant mutations in RET (rearranged during transfection) gene that predisposes the carrier to extremely high risk of medullary thyroid cancer (MTC) and other MEN2A-associated tumors such as parathyroid cancer and/or pheochromocytoma. Little is reported about MEN2A syndrome in the Chinese population.
METHODS: All members of the 3 families along with specific probands of MEN2A were analyzed for their clinical, laboratory, and genetic characteristics. Exome sequencing was performed on the 3 probands, and specific mutation in RET was further screened on each of the family members.
RESULTS: Different mutations in the RET gene were identified: C634S in Family 1, C611Y in Family 2, and C634Y in Family 3. Proband 1 mainly showed pheochromocytoma with MTC, both medullary thyroid carcinoma and pheochromocytoma were seen in proband 2, and proband 3 showed medullary thyroid carcinoma.
CONCLUSION: The genetic evaluation is strongly recommended for patients with a positive family history, early onset of age, or multiple sites of masses. If the results verified the mutations of RET gene, thyroidectomy should be undertaken as the guide for better prognosis.

Chang H, Sung JH, Moon SU, et al.
EGF Induced RET Inhibitor Resistance in CCDC6-RET Lung Cancer Cells.
Yonsei Med J. 2017; 58(1):9-18 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Rearrangement of the proto-oncogene rearranged during transfection (RET) has been newly identified potential driver mutation in lung adenocarcinoma. Clinically available tyrosine kinase inhibitors (TKIs) target RET kinase activity, which suggests that patients with RET fusion genes may be treatable with a kinase inhibitor. Nevertheless, the mechanisms of resistance to these agents remain largely unknown. Thus, the present study aimed to determine whether epidermal growth factor (EGF) and hepatocyte growth factor (HGF) trigger RET inhibitor resistance in LC-2/ad cells with CCDC6-RET fusion genes.
MATERIALS AND METHODS: The effects of EGF and HGF on the susceptibility of a CCDC6-RET lung cancer cell line to RET inhibitors (sunitinib, E7080, vandetanib, and sorafenib) were examined.
RESULTS: CCDC6-RET lung cancer cells were highly sensitive to RET inhibitors. EGF activated epidermal growth factor receptor (EGFR) and triggered resistance to sunitinib, E7080, vandetanib, and sorafenib by transducing bypass survival signaling through ERK and AKT. Reversible EGFR-TKI (gefitinib) resensitized cancer cells to RET inhibitors, even in the presence of EGF. Endothelial cells, which are known to produce EGF, decreased the sensitivity of CCDC6-RET lung cancer cells to RET inhibitors, an effect that was inhibited by EGFR small interfering RNA (siRNA), anti-EGFR antibody (cetuximab), and EGFR-TKI (Iressa). HGF had relatively little effect on the sensitivity to RET inhibitors.
CONCLUSION: EGF could trigger resistance to RET inhibition in CCDC6-RET lung cancer cells, and endothelial cells may confer resistance to RET inhibitors by EGF. E7080 and other RET inhibitors may provide therapeutic benefits in the treatment of RET-positive lung cancer patients.

Yoon H, Shin I, Nam Y, et al.
Identification of a novel 5-amino-3-(5-cyclopropylisoxazol-3-yl)-1-isopropyl-1H-pyrazole-4-carboxamide as a specific RET kinase inhibitor.
Eur J Med Chem. 2017; 125:1145-1155 [PubMed] Related Publications
Activating mutations of REarrange during Transfection (RET) kinase frequently occur in human thyroid and lung cancers. An enormous effort has been devoted to discover potent and selective inhibitors of RET. Selective and potent inhibitors against constitutively active RET mutants are rare to date as identification of selective RET inhibitors is challenging. In a recent effort we identified a novel and specific RET inhibitor of 5-aminopyrazole-4-carboxamide scaffold, which was designed to enhance the metabolic stability of the pyrazolopyrimidine scaffold. In the SAR study described in the current report, we identified the 5-aminopyrazole-4-carboxamide analog 15l, which displays high metabolic stability. Compound 15l is potent against gatekeeper mutant (IC50 = 252 nM) of RET as well as against wild-type RET (IC50 = 44 nM). This substance effectively suppresses growth of Ba/F3 cells transformed with wild-type RET and its gatekeeper mutant (V804M), and thyroid-cancer derived TT cells while it does not affect parental Ba/F3 cells and Nthy ori-3-1, normal thyroid cells. Also, the results of a global kinase profiling assay on a panel of 369 kinases, show that 15l exclusively inhibits RET. Based on its exceptional kinase selectivity, great potency and metabolic stability, 15l represents a promising lead for the discovery of RET directed therapeutic agent and should be a key tool in studies aimed at understanding RET biology.

Grey W, Hulse R, Yakovleva A, et al.
The RET E616Q Variant is a Gain of Function Mutation Present in a Family with Features of Multiple Endocrine Neoplasia 2A.
Endocr Pathol. 2017; 28(1):41-48 [PubMed] Related Publications
The REarranged during Transfection (RET) proto-oncogene is a receptor tyrosine kinase involved in growth and differentiation during embryogenesis and maintenance of the urogenital and nervous systems in mammals. Distinct mutations across hotspot RET exons can cause Multiple Endocrine Neoplasia Type 2A (MEN2A) characterised by development of medullary thyroid cancer (MTC), phaeochromocytoma (PCC) and primary hyperparathyroidism (PHPT), with a strong correlation between genotype and phenotype. Here, we report a 42-year-old man presented in the clinic with a unilateral PCC, with subsequent investigations revealing a nodular and cystic thyroid gland. He proceeded to thyroidectomy, which showed bilateral C-cell hyperplasia (CCH) without evidence of MTC. His brother had neonatal Hirschsprung disease (HSCR). Genetic testing revealed the presence of a heterozygous variant of unknown significance (VUS) in the cysteine-rich region of exon 10 in the RET gene (c.1846G>C, p.E616Q), in both affected siblings and their unaffected mother. Exon 10 RET mutations are known to be associated with HSCR and MEN2. Variants in the cysteine-rich region of the RET gene, outside of the key cysteine residues, may contribute to the development of MEN2 in a less aggressive manner, with a lower penetrance of MTC. Currently, a VUS in RET cannot be used to inform clinical management and direct future care. Analysis of RET(E616Q) reveals a gain of function mutant phenotype for this variant, which has not previously been reported, indicating that this VUS should be considered at risk for future clinical management.

Ernani V, Kumar M, Chen AY, Owonikoko TK
Systemic treatment and management approaches for medullary thyroid cancer.
Cancer Treat Rev. 2016; 50:89-98 [PubMed] Related Publications
Although rare, medullary thyroid cancer (MTC) exemplifies the value that ever-expanding knowledge of molecular pathways and mechanisms brings to managing challenging cancers. Although surgery can be curative for MTC in many patients, a substantial proportion of patients present with locoregional or distant metastatic disease. Once distant disease occurs, treatment options are limited, and conventional cancer treatments such as cytotoxic chemotherapy are of minimal benefit. Biomarkers such as calcitonin and carcinoembryonic antigen are important correlates of disease burden as well as predictors of disease progress, including recurrence and survival. MTC is either sporadic (∼75%) or inherited (∼25%) as an autosomal dominant disease. Regardless, germline and somatic mutations, particularly in the rearranged during transfection (RET) proto-oncogene, are key factors in the neoplastic process. Gain-of-function RET mutations result in overactive proteins that lead to abnormal activation of downstream signal transduction pathways, resulting in ligand-independent growth and resistance to apoptotic stimuli. Specific RET mutation variants have been found to correlate with phenotype and natural history of MTC with some defects portending a more aggressive clinical course. Greater understanding of the consequence of the aberrant signaling pathway has fostered the development of targeted therapies. Two small-molecule tyrosine kinase inhibitors, vandetanib and cabozantinib, are currently available as approved agents for the treatment of advanced or progressive MTC and provide significant increases in progression-free survival. Since there have been no head-to-head comparisons, clinicians often select between these agents on the basis of familiarity, patient characteristics, comorbidities, and toxicity profile.

Chu YH, Lloyd RV
Medullary Thyroid Carcinoma: Recent Advances Including MicroRNA Expression.
Endocr Pathol. 2016; 27(4):312-324 [PubMed] Related Publications
Medullary thyroid carcinoma (MTC) is an uncommon neuroendocrine tumor arising from the C cells in the thyroid and accounts for about 5 % of all thyroid cancers. MTC exhibits more aggressive behavior than follicular tumors, with the majority of cases presenting with lymph node metastasis. It is particularly common among patients carrying germline RET mutations with almost 100 % penetrance. Because activating RET mutations occur in over 90 % of hereditary and 40 % of sporadic MTC, clinical trials of several RET-targeting multikinase inhibitors (MKIs) have resulted in FDA approval of vandetanib and cabozantinib for the treatment of MTC. Nevertheless, in light of significant individual differences in tumor behavior and treatment responses, there has been a persistent need for research efforts to decipher the molecular events within RET-driven or non-RET-driven tumors. Recently, the gene regulatory roles of microRNAs (miRNAs) in MTC have been studied extensively. Multiple miRNA deregulations have been discovered in MTC with potential prognostic and therapeutic implications. This review provides an overview of the basic pathology of MTC and an update on recent investigational progress.

Pandit R, Khadilkar K, Sarathi V, et al.
Germline mutations and genotype-phenotype correlation in Asian Indian patients with pheochromocytoma and paraganglioma.
Eur J Endocrinol. 2016; 175(4):311-23 [PubMed] Related Publications
BACKGROUND: Genetic aetiology of pheochromocytoma (PCC) and paraganglioma (PGL) is increasingly being studied; however, Asian Indian data on this aspect are scarce.
OBJECTIVE: To study the prevalence of germline mutations and genotype-phenotype correlation in Asian Indian PCC/PGL patients.
DESIGN: In this study, 150 index patients (M:F, 73:77) with PCC/PGL were evaluated. Phenotypic data were collected. Germline mutations in five susceptibility genes (RET, VHL, SDHB, SDHD and SDHC) were tested by sequencing and NF1 was diagnosed according to phenotype.
RESULT: Of the total population, 49 (32.7%) PCC/PGL patients had germline mutations (VHL: 23 (15.3%), RET: 13 (8.7%), SDHB: 9 (6%), SDHD: 2 (1.3%) and NF1: 2 (1.3%)). Amongst the 30 patients with familial and/or syndromic presentation, all had germline mutations (VHL: 14 (46.7%), RET: 13 (43.3%), SDHB: 1 (3.3%) and NF1: 2 (6.7%)). Out of 120 patients with apparently sporadic presentation, 19 (15.8%) had a germline mutation (VHL: 9 (7.5%), SDHB: 8 (6.7%) and SDHD: 2 (1.7%)). Mutation carriers were younger (29.9 ± 14.5 years vs 36.8 ± 14.9; P = 0.01) and had a higher prevalence of bilateral PCC (26.5% vs 2.9%, P < 0.001) and multifocal tumours (12.2% vs 0.96%, P = 0.06). Based on syndromic features, metastasis, location and number of tumours, around 96% mutations in our cohort could be detected by appropriately selected single gene testing.
CONCLUSION: Asian Indians with PCC/PGL differ from Western cohorts in having preponderance of VHL mutations in multifocal tumours and apparently sporadic unilateral PCC. Syndromic presentation, metastasis, location and number of PCC/PGL can be effectively used for guiding genetic prioritisation.

Zhang XW, Wang JY, Zhang YB, et al.
[Genotype-phenotype correlations in multiple endocrine neoplasia type 2].
Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2016; 51(7):538-41 [PubMed] Related Publications
OBJECTIVE: To evaluate the relationship between different RET mutations and the aggressiveness of hereditary medullary thyroid cancer (HMTC) or the presentation of other endocrine disorders in patients with multiple endocrine neoplasia type 2 (MEN2).
METHODS: A total of 73 thyroid medullary carcinoma patients from 22 Chinese kindreds who were treated in our center from 2010 to 2015 were enrolled. RET genes in the patients and their relatives were screened.
RESULTS: According to the clinical data and 2015 American Thyroid Association (ATA) guidelines, patients were classified into 3 RET mutation risk groups: Modest, 24 cases; High, 48 cases; and Highest, 1 case. Multivariate analysis showed an increased likelihood of MTC stage III or IV at diagnosis with increasing of age and risk. The likelihood increased 11.6% per year of age at surgery (95% confidence interval, 1.040-1.198; P=0.002). The likelihood in patients with high risk was 7.9 times higher than patients with modest risk (95% confidence interval, 1.607-38.717; P=0.003). Aside from one patient with MEN2B, other 72 patients were MEN2A, of them, 28 cases from 7 kindreds with classical MEN2A (codon 634 & 618), 14 cases from 3 kindreds with cutaneous lichen amyloidosis (codon 634), 4 cases from 1 kindred with Hirschsprung's disease (codon 620), and 26 cases from 10 kindreds with familial MTC.
CONCLUSION: The aggressiveness of HMTC and the presentation of other endocrine diseases are related to specific RET mutations. For RET mutation carriers, MTC and other endocrine diseases should be diagnosed and treated early based on the RET genotypes.

Wei S, LiVolsi VA, Montone KT, et al.
Detection of Molecular Alterations in Medullary Thyroid Carcinoma Using Next-Generation Sequencing: an Institutional Experience.
Endocr Pathol. 2016; 27(4):359-362 [PubMed] Related Publications
Medullary thyroid carcinoma (MTC) harbors rearranged during transfection (RET) gene and rarely RAS gene mutations. The knowledge of the type of gene mutation in MTC is important to determine the treatment of the patients and the management of their family members. Targeted next-generation sequencing with a panel of 47 genes was performed in a total of 12 cases of sporadic (9/12) and hereditary MTC (3/12). Two of three hereditary MTCs had RET/C634R mutation, while the other one harbored two RET mutations (L790F and S649L). All the sporadic MTC had RET/M918T mutation except one case with HRAS mutation. Next-generation sequencing (NGS) can provide comprehensive analysis of molecular alterations in MTC in a routine clinical setting, which facilitate the management of the patient and the family members.

Kheiroddin P, Rasihashemi SZ, Estiar MA, et al.
RET Gene Analysis in Patients with Medullary Thyroid Carcinoma.
Clin Lab. 2016; 62(5):871-6 [PubMed] Related Publications
BACKGROUND: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor from the para follicular C cells of the thyroid gland. It occurs either sporadically or as part of an inherited syndrome. It is caused by an autosomal dominant mutation in the RET (Rearranged during Transfection) proto-oncogene.
METHODS: The studied population consisted of 47 patients diagnosed with MTC in a specific population of northwest Iran along with their three children. Blood samples were collected from all subjects, genomic DNA was extracted and RET exons 10, 11, 13, 14, 15, and 16 were analyzed using PCR and direct sequencing.
RESULTS: 32 missense mutations were identified in exons 10 (6.25%) and 11 (84.4%). Moreover, two novel mutations in codon 595 in exon 10 (E595D and E595A) and a new mutation in codon 689 exon 11 (S689T) were detected, and a new nucleotide change was found in exon 11 (T675T). Four different polymorphisms were also identified in exons 11, 13, 14, and 15. Based on our data, the frequency profile of RET mutations in the Azari population of Iran with MTC is 61.7%. The most frequent mutation in our population was C364G, whereas in most populations it is C634R.
CONCLUSIONS: These results underline the importance of the genetic background of family members of any patient with MTC.

Tiedje V, Ting S, Walter RF, et al.
Prognostic markers and response to vandetanib therapy in sporadic medullary thyroid cancer patients.
Eur J Endocrinol. 2016; 175(3):173-80 [PubMed] Related Publications
OBJECTIVE: Medullary thyroid carcinoma (MTC) occurs sporadically in 75% of patients. Metastatic disease is associated with significantly poorer survival. The aim of this study was to identify prognostic markers for progressive MTC and oncogenic factors associated with response to vandetanib therapy.
DESIGN AND METHODS: Clinical courses of 32 patients with sporadic MTC (n=10 pN0cM0, n=8 pN1cM0, n=14 pN1cM1) were compared with genetic profiles of the patients' primary tumour tissue. Analysis for RET proto-oncogene mutations was performed by Sanger sequencing and next-generation sequencing (NGS). The mRNA expression (mRNA count) of 33 targets was measured by nCounter NanoString analysis.
RESULTS: Somatic RET mutations occurred in 21/32 patients. The RET918 mutation was found in 8/14 pN1cM1 patients. BRAF (P=0.019), FGFR2 (P=0.007), FGFR3 (P=0.044) and VEGFC (P=0.042) mRNA expression was significantly lower in pN1cM0/pN1cM1 compared with pN0cM0 patients, whereas PDGFRA (P=0.026) mRNA expression was significantly higher in pN1cM0/pN1cM1 when compared with pN0cM0 patients. Among the 10/32 vandetanib-treated patients, 5 showed partial response (PR), all harbouring the RET918 mutation. mRNA expression of FLT1 (P=0.039), FLT4 (P=0.025) and VEGFB (P=0.042) was significantly higher in therapy responders.
CONCLUSIONS: In this study, we identified molecular markers in primary tumour tissue of sporadic MTC associated with the development of metastasis (both lymph node and organ metastasis) as well as response to vandetanib therapy.

Koterov AN, Ushenkova LN, Biryukov AP
[Dose-Response Dependences for Frequency of RET/PTC Gene Rearrangements in Papillary Thyroid Carcinoma after Irradiation. Simple Pooling Analysis of Molecular Epidemiological Data].
Radiats Biol Radioecol. 2016 Jan-Feb; 56(1):5-25 [PubMed] Related Publications
On the basis of all possible publications on the theme included in the previously formed base of sources on molecular epidemiology of RET/PTC rearrangements in thyroid papillary carcinoma a pooled analysis ("simple pooling data") on determination of the dose-effect dependences for RET/PTC frequency in radiogenic carcinomas of various irradiated groups was performed. (They are groups subjected to radiotherapeutic exposure, residents near the Chernobyl nuclear power plant (CNPP) and victims of nuclear bombing). The tendency to Pearson linear correlation (r = 0.746; p = 0.148) between the frequency of RET/PTC and the estimated dose on thyroid in the regions affected by the CNPP accident was revealed. But this tendency was recognized to be random owing to abnormally low values of the indicator for the most contaminated Gomel region. The method tentatively called "case-control" showed reliable differences in thyroid dose values for carcinomas with RET/PTC and without those. The versatility of changes was found: the lack of RET/PTC for radiotherapeutic impacts was associated with higher doses, whereas in case of the CNPP accident and for nuclear bombing victims it was the opposite. Probably, in the first case the "cellular cleaning" phenomenon after exposure to very high doses took place. Search of direct Pearson correlations between average/median thyroid doses on groups and RET/PTC frequency in carcinomas of these groups showed a high reliability for the dose-effect dependences- at the continuous dose scale (for RET/PTC in total and RET/PTC1 respectively: r = 0.830; p = 0.002 and r = 0.906; p = 0.0003); while there was no significant correlation received for RET/PTC3. When using the weighting least square regression analysis (proceeding from the number of carcinomas in samples), the specified regularities remained. Attempts to influence the strength of correlation by exception ofthe data of all the samples connected with the accident on the CNPP did not significantly reduce the strength of associations for RET/PTC in total. On the basis of ordinal scale doses (background, "low" (0.1 Gy), "middle" (0.1-1 Gy) and "large" (1-10 Gy) dose) also found was a significant correlation (Spearman) with the dose for the frequency RET/PTC in total (r = 0.736; p = 0.0098), but for certain types of rearrangements the results were reverse to the previous analysis (the effect was significant only for the RET/PTC3: r = 0.731; p = 0.024). The linear dose-response trends of the Cochrane-Armitage-test for the frequency of RET/PTC in total, RET/PTC1 and RET/PTC3 depending on the dose to the thyroid in the ordinal scale were registered (p, respectively: < 0.0001 < 0.0001 and 0.007). Thus; after more than 20 years of the molecular and epidemiological research of RET/PTC in thyroid radiogenic carcinomas the comprehensive evidence of the dose-effect dependence existence indicating a real relationship between the studied parameters and a radiation factor was obtained for the first time.

Kaji H
[Pathophysiology of primary hyperparathyroidism].
Clin Calcium. 2016; 26(6):815-20 [PubMed] Related Publications
Primary hyperparathyroidism is a disease with increased cell proliferation and enhanced PTH secretion due to the escape from negative feedback by calcium ion in parathyroid cells for their tumorization. Involvements of several gene abnormalities have been demonstrated in the pathogenesis of parathyroid tumor. First, an activation of cyclin D1 gene by the translocation of 11 chromosome was found as one of the cause of parathyroid tumorigenesis. Moreover, mutation of multiple endocrine type 1 gene is the most frequent as a genetic cause of sporadic parathyroid tumor. Its related tumor is developed by an inactivation mutation of tumor suppressor gene. Parafibromin, calcium-sensing receptor, vitamin D receptor, Klotho and RET might be related to the tumorigeneis of parathyroid tumor.

Heilmann AM, Subbiah V, Wang K, et al.
Comprehensive Genomic Profiling of Clinically Advanced Medullary Thyroid Carcinoma.
Oncology. 2016; 90(6):339-46 [PubMed] Article available free on PMC after 21/05/2017 Related Publications
OBJECTIVE: The aim of this study was to determine the genomic alterations of cancer-related genes in advanced medullary thyroid carcinoma during the course of clinical care.
METHODS: Hybrid-capture-based comprehensive genomic profiling was performed on 34 consecutive medullary thyroid carcinoma cases to identify all four classes of genomic alterations, and outcome for an index patient was collected.
RESULTS: RET was mutated in 88% (30/34) of cases, with RET M918T being responsible for 70% (21/30) of the RET alterations. The other RET alterations were RET E632_L633del, C634R, C620R, C618G/R/S, V804M, and RET amplification. Two of the four RET wild-type patients harbored mutations in KRAS or HRAS (1/34 each). The next most frequent genomic alterations were amplifications of CCND1, FGF3, and FGF19 and alterations in CDKN2A (3/34 each). One case with a RET M918T mutation developed acquired resistance to progressively dose-escalated vandetanib. When the mTOR inhibitor everolimus was added to continued vandetanib treatment, the patient achieved a second 25% reduction of tumor volume (RECIST 1.1) for 8 months.
CONCLUSIONS: Comprehensive genomic profiling identified the full breadth of RET alterations in metastatic medullary thyroid carcinoma and possible cooperating oncogenic driver alterations. This approach may refine the use of targeted therapy for these patients.

Marchand L, Nozières C, Walter T, et al.
Combination chemotherapy with 5-fluorouracil and dacarbazine in advanced medullary thyroid cancer, a possible alternative?
Acta Oncol. 2016; 55(8):1064-6 [PubMed] Related Publications

Wang L, Ding Y, Wei L, et al.
Recurrent Olfactory Neuroblastoma Treated With Cetuximab and Sunitinib: A Case Report.
Medicine (Baltimore). 2016; 95(18):e3536 [PubMed] Article available free on PMC after 21/05/2017 Related Publications
Olfactory neuroblastoma (ONB) is a rare cancer originating in the olfactory epithelium of the nasal vault. The recurrence rate of ONB is high, as the standard treatment of surgery followed by radiotherapy and/or chemotherapy is usually unsuccessful. The use of targeted therapy based on individual genomic variations after cancer relapse has not been reported. Here, we present the case of a 44-year-old man who was diagnosed with recurrent ONB and treated with a regimen developed using whole exome sequencing. Potential targets were first identified and then matched to appropriate drugs. Gene mutations in the genes encoding EGFR, FGFR2, KDR, and RET were discovered in the patient's tumor tissue by whole exome sequencing and the patient was treated with a combination of the targeted drugs cetuximab and sunitinib. Five days after treatment, enhancement magnetic resonance imaging showed a 65% reduction in tumor size, and the Visual analog scale headache scores went down to 2/10 from 10/10. Repeat imaging at 1 month showed a complete response.This study represents the first demonstration of an effective personalized treatment of ONB by targeted drugs, and sheds light on how precision medicine can be used to treat recurrent ONB that fails to respond to routine tumor resection, radiotherapy, and/or chemotherapy.

Draht MX, Smits KM, Jooste V, et al.
Analysis of RET promoter CpG island methylation using methylation-specific PCR (MSP), pyrosequencing, and methylation-sensitive high-resolution melting (MS-HRM): impact on stage II colon cancer patient outcome.
Clin Epigenetics. 2016; 8:44 [PubMed] Article available free on PMC after 21/05/2017 Related Publications
BACKGROUND: Already since the 1990s, promoter CpG island methylation markers have been considered promising diagnostic, prognostic, and predictive cancer biomarkers. However, so far, only a limited number of DNA methylation markers have been introduced into clinical practice. One reason why the vast majority of methylation markers do not translate into clinical applications is lack of independent validation of methylation markers, often caused by differences in methylation analysis techniques. We recently described RET promoter CpG island methylation as a potential prognostic marker in stage II colorectal cancer (CRC) patients of two independent series.
METHODS: In the current study, we analyzed the RET promoter CpG island methylation of 241 stage II colon cancer patients by direct methylation-specific PCR (MSP), nested-MSP, pyrosequencing, and methylation-sensitive high-resolution melting (MS-HRM). All primers were designed as close as possible to the same genomic region. In order to investigate the effect of different DNA methylation assays on patient outcome, we assessed the clinical sensitivity and specificity as well as the association of RET methylation with overall survival for three and five years of follow-up.
RESULTS: Using direct-MSP and nested-MSP, 12.0 % (25/209) and 29.6 % (71/240) of the patients showed RET promoter CpG island methylation. Methylation frequencies detected by pyrosequencing were related to the threshold for positivity that defined RET methylation. Methylation frequencies obtained by pyrosequencing (threshold for positivity at 20 %) and MS-HRM were 13.3 % (32/240) and 13.8 % (33/239), respectively. The pyrosequencing threshold for positivity of 20 % showed the best correlation with MS-HRM and direct-MSP results. Nested-MSP detected RET promoter CpG island methylation in deceased patients with a higher sensitivity (33.1 %) compared to direct-MSP (10.7 %), pyrosequencing (14.4 %), and MS-HRM (15.4 %). While RET methylation frequencies detected by nested-MSP, pyrosequencing, and MS-HRM varied, the prognostic effect seemed similar (HR 1.74, 95 % CI 0.97-3.15; HR 1.85, 95 % CI 0.93-3.86; HR 1.83, 95 % CI 0.92-3.65, respectively).
CONCLUSIONS: Our results show that upon optimizing and aligning four RET methylation assays with regard to primer location and sensitivity, differences in methylation frequencies and clinical sensitivities are observed; however, the effect on the marker's prognostic outcome is minimal.

Wang L, Zhang Y, Gao Y, et al.
Prognostic and Predictive Values of Subcellular Localisation of RET in Renal Clear-Cell Carcinoma.
Dis Markers. 2016; 2016:6870470 [PubMed] Article available free on PMC after 21/05/2017 Related Publications
Metastatic renal cell carcinoma (RCC) presents a poor prognosis and an unpredictable course. To date, no validated biomarkers can predict the outcome of RCC. Ongoing efforts are conducted to identify the molecular markers of RCC progression, as well as the targets for novel therapeutic approaches. RET is a tyrosine kinase receptor which has been investigated as a possible target in other cancers because it is involved in oncogenic activation. To evaluate the predictive and prognostic functions of RET in ccRCC, a tissue microarray study was conducted on 273 ccRCC patients. Results showed that both RET cytoplasmic and nuclear expression were independently associated with PFS and OS, and the combined RET cytoplasmic and nuclear statuses demonstrated that the ratio of high nuclear RET and cytoplasmic RET was the strongest predictor of both PFS and OS. The high cytoplasmic RET expression retained its independent poor prognostic value in targeted drug treated patients. The RET nuclear expression was associated with distant metastasis. Moreover, the RET nuclear expression was an independent predictor of ccRCC postoperative metastasis. In conclusion, RET may be useful in prognostication and can be used at initial diagnosis to identify patients with high potential to develop metastasis.

Gong Y, Zhu J, Gong R, et al.
[Genetic testing and surgical treatment of two families with hereditary medullary thyroid carcinoma].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2016; 33(2):272-3 [PubMed] Related Publications

Chen LF, Chen XY, Yu XB
[Correlation of clinicopathologic features and driver gene mutation in non-small cell lung cancer].
Zhonghua Bing Li Xue Za Zhi. 2016; 45(4):221-5 [PubMed] Related Publications
OBJECTIVE: To study the relationship between mutations of well-known driver genes and clinicopathologic characteristics of non-small cell lung cancers (NSCLC).
METHODS: Scorpions amplification refractory mutation system (scorpions ARMS) fluorescence quantitative PCR was performed to investigate 205 driver gene mutation status in NSCLC in correlation with clinicopathological characteristics of the patients.
RESULTS: Driver gene mutations were detected in 146 of 205 (71.2%) patients with NSCLC, including 81.7%(138/169) adenocarcinomas, in which mutations of nine genes were found: EGFR (63.3%, 107/169), KRAS (5.9%, 10/169), PIK3CA (4.1%, 7/169), ALK (4.1%, 7/169), ROS1 (3.0%, 5/169), RET (3.6%, 6/169), HER2 (1.8%, 3/169), NRAS (0.6%, 1/169) and BRAF (0.6%, 1/169). The frequencies of driver gene mutations were higher in adenocarcinomas, female patients and non-smokers (P<0.01, P=0.003, P<0.01, respectively). Driver gene mutation status showed no correlation with either the age or the clinical stage (P=0.281, P=0.490, respectively). However, EGFR mutations tended to occur in adenocarcinoma, female, non-smokers, and patients of ≥62 years of age (P<0.01, P<0.01, P=0.002, P=0.012, respectively). The frequency of EGFR mutation was positively correlated with the tumor histology of lepidic, acinar, papillary and micropapillary predominant growth patterns. There was no relationship between EGFR mutation and the clinical stage (P=0.237). The frequency of KRAS mutation was higher in solid predominant and invasive mucinous adenocarcinomas (P=0.015); that of PIK3CA mutation was higher in patients of ≥62 years of age, invasive mucinous adenocarcinoma and fetal adenocarcinoma (P=0.015, P=0.006, respectively). ALK, ROS1 or RET mutation positive NSCLC tended to occur in nonsmokers and have solid predominant tumors and invasive mucinous adenocarcinoma (P=0.012, P=0.017 respectively). The frequency of EML4-ALK mutation was higher in the early stage patients with solid predominant tumors and invasive mucinous adenocarcinomas (P=0.025, P=0.014, respectively); that of ROS1 rearrangement was higher in invasive mucinous adenocarcinomas (P=0.049). NRAS, BRAF and HER2 gene mutations were infrequent and their clinical significance remained to be elucidated.
CONCLUSIONS: The relationship between mutations of well-known driver genes and clinicopathological characteristics in patients with NSCLC has diversity, the rate of mutations is higher in non-smoking female patients with adenocarcinoma.

Zhao W, Choi YL, Song JY, et al.
ALK, ROS1 and RET rearrangements in lung squamous cell carcinoma are very rare.
Lung Cancer. 2016; 94:22-7 [PubMed] Related Publications
OBJECTIVES: Chromosomal rearrangements of ALK and ROS1 genes in non-small cell lung carcinoma (NSCLC) define a molecular subgroup of lung adenocarcinoma (ADC) that is amenable to targeted therapy with tyrosine kinase inhibitors (TKIs) crizotinib. Emerging clinical studies have demonstrated that patients with RET-rearranged NSCLC may also benefit from existing RET TKIs, including cabozantinib and vandetanib. However, the reported cases of lung squamous cell carcinomas (SCC) harboring gene rearrangements have been detected via fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) from materials such as biopsy or resection. Fusion events identified in lung SCC raise the question of whether this histologic subtype should also be evaluated for merit molecular testing. This work was undertaken to study the prevalence of lung SCC harboring ALK, ROS1, and RET translocations.
MATERIALS AND METHODS: Squamous cell carcinomas were confirmed using both histological examination by pathologists and immunohistochemistry analysis with positive staining of P63 and CK5/6 combined with negative CK7 and TTF-1 staining. 214 samples from surgically resected patient tissues were used to search for ALK, ROS1, and RET rearrangements by a NanoString analysis method. Fusion events were detected in a single-tube, multiplex assay system that relied on a complementary strategy of interrogation of 3' gene overexpression and detection of specific fusion transcript variants.
RESULTS AND CONCLUSION: ALK, ROS1 or RET gene rearrangements appeared 0 times out of 214 cases of lung SCC. Our data revealed that these fusions may be very rare in lung squamous cancer. The molecular screening strategy should therefore be focused on lung adenocarcinoma as the current National Comprehensive Cancer Network (NCCN) guideline recommends.

Horiike A, Takeuchi K, Uenami T, et al.
Sorafenib treatment for patients with RET fusion-positive non-small cell lung cancer.
Lung Cancer. 2016; 93:43-6 [PubMed] Related Publications
BACKGROUND: RET fusions were recently identified in non-small cell lung cancer (NSCLC) and are considered as a potential therapeutic target of NSCLC. Sorafenib, a multi-kinase inhibitor, has potent anti-RET activity. We conducted a study to evaluate the efficacy of sorafenib in a small number of patients with RET fusion-positive NSCLC.
MATERIALS AND METHODS: Eligible patients had advanced or recurrent NSCLC, were more than 20 years old, had undergone treatment with one or more previous chemotherapy regimens, had an Eastern Cooperative Oncology Group performance status 0-2, had adequate organ function, and provided informed consent. The presence of the RET fusion gene was confirmed by a split FISH assay. The patients were treated twice daily with 400mg of sorafenib taken orally. The treatment was continued until either disease progression or unacceptable toxicity.
RESULTS: From March 2012 to April 2013, three patients were enrolled. The responses to sorafenib included one patient with stable disease (SD) and two patients with progressive disease (PD). One patient took sorafenib for twelve months. The most common toxicities were palmar-plantar erythrodysesthesia syndrome, hypertension, and diarrhea.
CONCLUSION: Since sorafenib did not show dramatic responses, we suggest testing other RET inhibitors for the treatment of RET fusion-positive NSCLC. This study was registered at UMIN as trial number 000007515.

Kotecka-Blicharz A, Hasse-Lazar K, Jurecka-Lubieniecka B, et al.
Occurrence of phaeochromocytoma tumours in RET mutation carriers - a single-centre study.
Endokrynol Pol. 2016; 67(1):54-8 [PubMed] Related Publications
INTRODUCTION: Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant genetic syndrome caused by germline mutation in RET proto-oncogene. The most common mutations are in a cysteine rich domain. Phaeochromocytoma will develop in approximately 50% of RET proto-oncogene carriers.
MATERIAL AND METHODS: The studied population consisted of 228 RET proto-oncogene mutation carriers. Monitoring for the diagnosis of phaeochromocytoma was carried out in all patients with established genetic status. Mean time of follow up was 138 months. Surveillance consisted of periodically performed clinical evaluation, 24-hour urinary determinations of total metanephrines complementary with imaging (CT, MR, MIBG scintigraphy).
RESULTS: Phaeochromocytoma developed in 41 patients (18% of all RET proto-oncogene mutations carriers). The mean age of diagnosis for the whole cohort was 43 years. In eight cases phaeochromocytoma was the first manifestation of the MEN 2 syndrome. Only eight (20%) patients were symptomatic at diagnosis of phaeochromocytoma. The mean size of the tumour was 4.3 cm. There was no extra-adrenal localisation. We observed one case of malignant phaeochromocytoma.
CONCLUSIONS: In patients with MEN 2 syndrome phaeochromocytomas are usually benign adrenal tumours with high risk of bilateral development. Taking to account the latter risk and non-specific clinical manifestation of the neoplasm it is mandatory to screen all RET proto-oncogene mutations carriers for phaeochromocytoma.

Romei C, Ciampi R, Elisei R
A comprehensive overview of the role of the RET proto-oncogene in thyroid carcinoma.
Nat Rev Endocrinol. 2016; 12(4):192-202 [PubMed] Related Publications
The rearranged during transfection (RET) proto-oncogene was identified in 1985 and, very soon thereafter, a rearrangement named RET/PTC was discovered in papillary thyroid carcinoma (PTC). After this discovery, other RET rearrangements were found in PTCs, particularly in those induced by radiation. For many years, it was thought that these genetic alterations only occurred in PTC, but, in the past couple of years, some RET/PTC rearrangements have been found in other human tumours. 5 years after the discovery of RET/PTC rearrangements in PTC, activating point mutations in the RET proto-oncogene were discovered in both hereditary and sporadic forms of medullary thyroid carcinoma (MTC). In contrast to the alterations found in PTC, the activation of RET in MTC is mainly due to activating point mutations. Interestingly, in the past year, RET rearrangements that were different to those described in PTC were observed in sporadic MTC. The identification of RET mutations is relevant to the early diagnosis of hereditary MTC and the prognosis of sporadic MTC. The diagnostic and prognostic role of the RET/PTC rearrangements in PTC is less relevant but still important in patient management, particularly for deciding if a targeted therapy should be initiated. In this Review, we discuss the pathogenic, diagnostic and prognostic roles of the RET proto-oncogene in both PTC and MTC.

Veldore VH, Patil S, Satheesh CT, et al.
Genomic profiling in a homogeneous molecular subtype of non-small cell lung cancer: An effort to explore new drug targets.
Indian J Cancer. 2015 Apr-Jun; 52(2):243-8 [PubMed] Related Publications
BACKGROUND: Patients' who are positive for kinase domain activating mutations in epidermal growth factor receptor (EGFR) gene, constitute 30-40% of non-small cell lung cancer (NSCLC), and are suitable candidates for Tyrosine Kinase Inhibitor based targeted/personalized therapy. In EGFR non-mutated subset, 8-10% that show molecular abnormalities such as EML4-ALK, ROS1-ALK, KIP4-ALK, may also derive the benefit of targeted therapy. However, 40% of NSCLC belong to a grey zone of tumours that are negative for the clinically approved biomarkers for personalized therapy. This pilot study aims to identify and classify molecular subtypes of this group to address the un-met need for new drug targets in this category. Here we screened for known/novel oncogenic driver mutations using a 46 gene Ampliseq Panel V1.0 that includes Ser/Thr/Tyr kinases, transcription factors and tumor suppressors.
METHODS: NSCLC with tumor burden of at least 40% on histopathology were screened for 29 somatic mutations in the EGFR kinase domain by real-time polymerase chain reaction methods. 20 cases which were EGFR non-mutated for TK domain mutations were included in this study. DNA Quality was verified from each of the 20 cases by fluorimeter, pooled and subjected to targeted re-sequencing in the Ion Torrent platform. Torrent Suite software was used for next generation sequencing raw data processing and variant calling.
RESULTS: The clinical relevance and pathological role of all the mutations/variants that include SNPs and Indels was assessed using polyphen-2/SIFT/PROVEAN/mutation assessor structure function prediction programs. There were 10 pathogenic mutations in six different oncogenes for which annotation was available in the COSMIC database; C420R mutation in PIK3CA, Q472H mutation in vascular endothelial growth factor receptor 2 (VEGFR2) (KDR), C630W and C634R in RET, K367M mutation in fibroblast growth factor receptor 2 (FGFR2), G12C in KRAS and 4 pathogenic mutations in TP53 in the DNA binding domain (E285K, R213L, R175H, V173G).
CONCLUSION: Results suggest, a potential role for PIK3CA, VEGFR2, RET and FGFR2 as therapeutic targets in EGFR non-mutated NSCLC that requires further clinical validation.

Kihara M, Miyauchi A, Yoshioka K, et al.
Germline RET mutation carriers in Japanese patients with apparently sporadic medullary thyroid carcinoma: A single institution experience.
Auris Nasus Larynx. 2016; 43(5):551-5 [PubMed] Related Publications
OBJECTIVE: Genetic testing for RET germline mutation can be useful to distinguish whether a patient with medullary thyroid carcinoma (MTC) is genuinely sporadic or hereditary. Conducting a routine preoperative germline RET genetic screening for all patients with MTC has the clinical benefit, i.e., avoidance of unnecessary total thyroidectomy in the selected patients. We sought to clarify the incidence of germline RET mutation carriers in Japanese patients with apparently sporadic MTC and to address the differences in clinicopathological characteristics between true sporadic MTC and hereditary MTC in these patients, all of whom were treated at Kuma Hospital.
METHODS: A total of 134 patients with apparently sporadic MTC who underwent surgery between 1996 and 2014 were enrolled. All patients underwent a germline RET gene mutation analysis preoperatively.
RESULTS: Germline mutations in RET proto-oncogene were identified in 20 of the 134 (14.9%) apparently sporadic MTC patients. No significant difference in clinicopathological characteristics was observed between the patients with sporadic MTC (n=114) and those with hereditary MTC (n=20) except for the RET gene carriers' younger age at diagnosis and presence of multifocal and bilateral lesions.
CONCLUSION: Germline RET mutations were identified in 14.9% of Japanese patients with apparently sporadic MTC. No clearly decisive clinicopathological characteristics was observed to distinguish whether an apparently sporadic MTC case was genuinely sporadic or unconsciously hereditary. For the treatment strategy decision, it is advantageous to conduct a routine preoperative germline RET genetic screening for all patients with MTC, even if their MTC is apparently sporadic.

De Andrade JP, Park JM, Gu VW, et al.
EGFR Is Regulated by TFAP2C in Luminal Breast Cancer and Is a Target for Vandetanib.
Mol Cancer Ther. 2016; 15(3):503-11 [PubMed] Free Access to Full Article Related Publications
Expression of TFAP2C in luminal breast cancer is associated with reduced survival and hormone resistance, partially explained through regulation of RET. TFAP2C also regulates EGFR in HER2 breast cancer. We sought to elucidate the regulation and functional role of EGFR in luminal breast cancer. We used gene knockdown (KD) and treatment with a tyrosine kinase inhibitor (TKI) in cell lines and primary cancer isolates to determine the role of RET and EGFR in regulation of p-ERK and tumorigenesis. KD of TFAP2C decreased expression of EGFR in a panel of luminal breast cancers, and chromatin immunoprecipitation sequencing (ChIP-seq) confirmed that TFAP2C targets the EGFR gene. Stable KD of TFAP2C significantly decreased cell proliferation and tumor growth, mediated in part through EGFR. While KD of RET or EGFR reduced proliferation (31% and 34%, P < 0.01), combined KD reduced proliferation greater than either alone (52% reduction, P < 0.01). The effect of the TKI vandetanib on proliferation and tumor growth response of MCF-7 cells was dependent upon expression of TFAP2C, and dual KD of RET and EGFR eliminated the effects of vandetanib. The response of primary luminal breast cancers to TKIs assessed by ERK activation established a correlation with expression of RET and EGFR. We conclude that TFAP2C regulates EGFR in luminal breast cancer. Response to vandetanib was mediated through the TFAP2C target genes EGFR and RET. Vandetanib may provide a therapeutic effect in luminal breast cancer, and RET and EGFR can serve as molecular markers for response.

Ceolin L, Romitti M, Siqueira DR, et al.
Effect of 3'UTR RET Variants on RET mRNA Secondary Structure and Disease Presentation in Medullary Thyroid Carcinoma.
PLoS One. 2016; 11(2):e0147840 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The RET S836S variant has been associated with early onset and increased risk for metastatic disease in medullary thyroid carcinoma (MTC). However, the mechanism by which this variant modulates MTC pathogenesis is still open to discuss. Of interest, strong linkage disequilibrium (LD) between RET S836S and 3'UTR variants has been reported in Hirschsprung's disease patients.
OBJECTIVE: To evaluate the frequency of the RET 3'UTR variants (rs76759170 and rs3026785) in MTC patients and to determine whether these variants are in LD with S836S polymorphism.
METHODS: Our sample comprised 152 patients with sporadic MTC. The RET S836S and 3'UTR (rs76759170 and rs3026785) variants were genotyped using Custom TaqMan Genotyping Assays. Haplotypes were inferred using the phase 2.1 program. RET mRNA structure was assessed by Vienna Package.
RESULTS: The mean age of MTC diagnosis was 48.5±15.5 years and 57.9% were women. The minor allele frequencies of RET polymorphisms were as follows: S836S, 5.6%; rs76759170, 5.6%; rs3026785, 6.2%. We observed a strong LD among S836S and 3'UTR variants (|D'| = -1, r2 = 1 and |D'| = -1, r2 = 0,967). Patients harboring the S836S/3'UTR variants presented a higher percentage of lymph node and distant metastasis (P = 0.013 and P<0.001, respectively). Accordingly, RNA folding analyses demonstrated different RNA secondary structure predictions for WT(TCCGT), S836S(TTCGT) or 3'UTR(GTCAC) haplotypes. The S836S/3'UTR haplotype presented a greater number of double helices sections and lower levels of minimal free energy when compared to the wild-type haplotype, suggesting that these variants provides the most thermodynamically stable mRNA structure, which may have functional consequences on the rate of mRNA degradation.
CONCLUSION: The RET S836S polymorphism is in LD with 3'UTR variants. In silico analysis indicate that the 3'UTR variants may affect the secondary structure of RET mRNA, suggesting that these variants might play a role in posttranscriptional control of the RET transcripts.

Kwon H, Kim WG, Sung TY, et al.
Changing trends in the clinicopathological features and clinical outcomes of medullary thyroid carcinoma.
J Surg Oncol. 2016; 113(2):152-8 [PubMed] Related Publications
BACKGROUND: The early detection of papillary thyroid cancer has contributed to the increase in the incidence and improved clinical outcomes. However, recent changes of medullary thyroid carcinoma (MTC) over time remain unclear. We evaluated changes of the clinicopathological characteristics and clinical outcomes in patients with MTC in recent years.
METHODS: A total of 109 MTC patients were classified based on the year of initial surgery: 1996-2000 (n = 14), 2001-2006 (n = 39), and 2007-2011 (n = 56).
RESULTS: The primary tumor size significantly decreased and the proportion of microMTCs (size ≤1 cm) increased over time (P = 0.002 and P < 0.001, respectively). The proportion of patients with cervical lymph node (LN) metastasis significantly decreased (P = 0.037), and the ratio of metastatic LNs significantly decreased (P = 0.011). Disease-free survival (DFS) rate of patients was significantly improved over time (P = 0.007). There was no significant difference in DFS between microMTC and macroMTC patients. However, more advanced LN stage patients demonstrated more recurrences (P < 0.001). Especially, there were significantly more recurrences in patients with N1b diseases in comparison with patients without cervical LN metastases (P < 0.001).
CONCLUSIONS: The prognosis of MTC patients has significantly improved in recent years. These changes could be associated with the early diagnosis before development of lateral and extensive cervical LN metastases. J. Surg. Oncol. 2016;113:152-158. © 2015 Wiley Periodicals, Inc.

Flynn A, Dwight T, Harris J, et al.
Pheo-Type: A Diagnostic Gene-expression Assay for the Classification of Pheochromocytoma and Paraganglioma.
J Clin Endocrinol Metab. 2016; 101(3):1034-43 [PubMed] Related Publications
CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) are heritable neoplasms that can be classified into gene-expression subtypes corresponding to their underlying specific genetic drivers.
OBJECTIVE: This study aimed to develop a diagnostic and research tool (Pheo-type) capable of classifying PPGL tumors into gene-expression subtypes that could be used to guide and interpret genetic testing, determine surveillance programs, and aid in elucidation of PPGL biology.
DESIGN: A compendium of published microarray data representing 205 PPGL tumors was used for the selection of subtype-specific genes that were then translated to the Nanostring gene-expression platform. A support vector machine was trained on the microarray dataset and then tested on an independent Nanostring dataset representing 38 familial and sporadic cases of PPGL of known genotype (RET, NF1, TMEM127, MAX, HRAS, VHL, and SDHx). Different classifier models involving between three and six subtypes were compared for their discrimination potential.
RESULTS: A gene set of 46 genes and six endogenous controls was selected representing six known PPGL subtypes; RTK1-3 (RET, NF1, TMEM127, and HRAS), MAX-like, VHL, and SDHx. Of 38 test cases, 34 (90%) were correctly predicted to six subtypes based on the known genotype to gene-expression subtype association. Removal of the RTK2 subtype from training, characterized by an admixture of tumor and normal adrenal cortex, improved the classification accuracy (35/38). Consolidation of RTK and pseudohypoxic PPGL subtypes to four- and then three-class architectures improved the classification accuracy for clinical application.
CONCLUSIONS: The Pheo-type gene-expression assay is a reliable method for predicting PPGL genotype using routine diagnostic tumor samples.

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.

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.

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.

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.

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.

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.

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.

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