Gene Summary

Gene:NCOA4; nuclear receptor coactivator 4
Aliases: RFG, ELE1, PTC3, ARA70
Summary:This gene encodes an androgen receptor coactivator. The encoded protein interacts with the androgen receptor in a ligand-dependent manner to enhance its transcriptional activity. Chromosomal translocations between this gene and the ret tyrosine kinase gene, also located on chromosome 10, have been associated with papillary thyroid carcinoma. Alternatively spliced transcript variants have been described. Pseudogenes are present on chromosomes 4, 5, 10, and 14. [provided by RefSeq, Feb 2009]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:nuclear receptor coactivator 4
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.

  • Cytoskeletal Proteins
  • Messenger RNA
  • Chromosome 10
  • Translocation
  • Neoplastic Cell Transformation
  • Gene Expression Profiling
  • Proto-Oncogene Proteins
  • Radioactive Hazard Release
  • Radiation-Induced Cancer
  • Polymerase Chain Reaction
  • Receptor Protein-Tyrosine Kinases
  • Oncogenes
  • FISH
  • Drosophila Proteins
  • Immunohistochemistry
  • Nuclear Receptor Coactivators
  • Molecular Sequence Data
  • Prostate Cancer
  • Thyroid Cancer
  • Androgen Receptors
  • Mutation
  • Childhood Cancer
  • Oncogene Fusion Proteins
  • Oncogene Proteins
  • Protein-Tyrosine Kinases
  • Gene Fusion
  • Cancer DNA
  • p300-CBP Transcription Factors
  • Proto-Oncogene Proteins c-ret
  • Papillary Carcinoma
  • Transfection
  • Single Nucleotide Polymorphism
  • Base Sequence
  • Genetic Predisposition
  • Gene Rearrangement
  • Cancer Gene Expression Regulation
  • Histone Acetyltransferases
  • NCOA4
  • Trans-Activators
Tag cloud generated 14 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

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

Entity Topic PubMed Papers
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
Prostate CancerNCOA4 and Prostate Cancer View Publications19

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

Latest Publications: NCOA4 (cancer-related)

Bongiovanni M, Uccella S, Giovanella L, et al.
Hürthle Cells Adenoma of the Thyroid with Post-surgical Implants in the Neck: Clinical, Morphological, and Molecular Analysis of Three Cases.
Endocr Pathol. 2016; 27(4):338-345 [PubMed] Related Publications
Thyroid implants in the soft tissue of the neck are very rare findings of traumatic, iatrogenic, or neoplastic origins. We describe the clinico-pathological and molecular analysis of three cases with an initial diagnosis of follicular adenoma, Hürthle cell variant (FA-HCT), which developed cervical thyroid implants at 60, 59, and 36 months after thyroid surgery, followed by further neck recurrences, and, eventually, by distant metastases. A systematic review of all histopathological samples of both the primary lesions and the neck implants was performed. Molecular study included the analysis of pan-RAS and BRAF mutations and RET/PTC1, RET/PTC3, and PAX8/PPARγ rearrangements. The review of the original slides and of additional re-cuts of each block of the thyroid lesions did not show any sign of capsular and/or vascular invasion; thus, the original diagnoses of FA-HCT were confirmed. When sampling adequacy was considered, it turned out that the capsule was completely evaluable in case #3, whereas 85 % was evaluable for case #1 and less than 50 % for case #2. We cannot exclude that cases #1 and #2 were carcinomas that had not been completely sampled. The first occurring neck implants showed neither histological signs of malignancy nor the presence of lymphoid tissue. However, further neck recurrences had different histological aspects, with a clear infiltrative growth. Moreover, a mesenchymal reaction forming a sort of capsule was observed around oncocytic cells along with signs of vascular invasion. Molecular analysis revealed no alterations in the genes and rearrangements studied. Oncocytic thyroid implants in the neck soft tissue should be regarded as metastasis, even in the absence of clear-cut signs of malignancy and in the case of a bona fide diagnosis of Hürthle cells adenoma of the thyroid.

Sjöblom L, Saramäki O, Annala M, et al.
Microseminoprotein-Beta Expression in Different Stages of Prostate Cancer.
PLoS One. 2016; 11(3):e0150241 [PubMed] Free Access to Full Article Related Publications
Microseminoprotein-beta (MSMB, MSMB) is an abundant secretory protein contributed by the prostate, and is implicated as a prostate cancer (PC) biomarker based on observations of its lower expression in cancerous cells compared with benign prostate epithelium. However, as the current literature on MSMB is inconsistent, we assessed the expression of MSMB at the protein and mRNA levels in a comprehensive set of different clinical stages of PC. Immunohistochemistry using monoclonal and polyclonal antibodies against MSMB was used to study protein expression in tissue specimens representing prostatectomies (n = 261) and in diagnostic needle biopsies from patients treated with androgen deprivation therapy (ADT) (n = 100), and in locally recurrent castration-resistant PC (CRPC) (n = 105) and CRPC metastases (n = 113). The transcript levels of MSMB, nuclear receptor co-activator 4 (NCOA4) and MSMB-NCOA4 fusion were examined by qRT-PCR in prostatectomy samples and by RNA-sequencing in benign prostatic hyperplasia, PC, and CRPC samples. We also measured serum MSMB levels and genotyped the single nucleotide polymorphism rs10993994 using DNA from the blood of 369 PC patients and 903 controls. MSMB expression in PC (29% of prostatectomies and 21% of needle biopsies) was more frequent than in CRPC (9% of locally recurrent CRPCs and 9% of CRPC metastases) (p<0.0001). Detection of MSMB protein was inversely correlated with the Gleason score in prostatectomy specimens (p = 0.024). The read-through MSMB-NCOA4 transcript was detected at very low levels in PC. MSMB levels in serum were similar in cases of PC and controls but were significantly associated with PC risk when adjusted for age at diagnosis and levels of free or total PSA (p<0.001). Serum levels of MSMB in both PC patients and controls were significantly associated with the rs10993994 genotype (p<0.0001). In conclusion, decreased expression of MSMB parallels the clinical progression of PC and adjusted serum MSMB levels are associated with PC risk.

Gertz RJ, Nikiforov Y, Rehrauer W, et al.
Mutation in BRAF and Other Members of the MAPK Pathway in Papillary Thyroid Carcinoma in the Pediatric Population.
Arch Pathol Lab Med. 2016; 140(2):134-9 [PubMed] Related Publications
CONTEXT: Papillary thyroid carcinoma (PTC) is an uncommon tumor in the pediatric population. A limited number of studies have examined genetic mutations affecting the mitogen-activated protein kinase (MAPK) pathway in the pediatric population.
OBJECTIVE: To examine mutations affecting this pathway in PTC in our pediatric population and compare the BRAF V600E mutation rates in pediatric and adult tumors.
DESIGN: Eighty-four patients, including 14 pediatric and 70 adult, with PTC were tested for the BRAF V600E mutation by using real-time polymerase chain reaction and sequencing. Additionally, we examined the rate of RAS point mutations with real-time polymerase chain reaction and rearrangements of RET/PTC1 and RET/PTC3 in the pediatric group with fluorescence in situ hybridization. Clinical and histologic data were compared as well.
RESULTS: Of 77 tumors that had an interpretable result, the BRAF V600E mutant was identified in 4 of 13 pediatric patients (31%) and 43 of 64 adult patients (67%), which was a significant difference (using Fisher exact test, P = .03). One pediatric and 6 adult cases did not reveal an interpretable result with melting curve analysis. One of these cases harbored a rare 3-base pair deletion mutation (c.1799_1801delTGA). Mutations in RAS genes were not seen in any pediatric tumors. One tumor with a RET/PTC1 rearrangement and another with RET/PTC3 were identified in the pediatric population (15%).
CONCLUSIONS: The rate of the BRAF V600E mutation in the pediatric population is significantly lower than that seen in the adult population. Mutations in RAS do not contribute significantly to pediatric PTC. This experience from our institution adds to the growing body of knowledge regarding tumor genetics in pediatric PTC.

Shi K, Xu D, Yang C, et al.
Contactin 1 as a potential biomarker promotes cell proliferation and invasion in thyroid cancer.
Int J Clin Exp Pathol. 2015; 8(10):12473-81 [PubMed] Free Access to Full Article Related Publications
Contactin 1 (CNTN1) as a member of the immunoglobulin superfamily plays important role in the development of nervous system. Recent studies find that elevated CNTN1 can promote the metastasis of cancer. However, the expression and function of CNTN1 in thyroid cancer are still unknown. Here, we firstly find CNTN1 is a new gene which can be regulated by RET/PTC3 (Ret proto-oncogene and Ret-activating protein ELE1) rearrangement gene and the protein level of CNTN1 is increasing in thyroid cancer. Besides this change is positively associated with the TNM stage and tumor size. Moreover, we confirm that knockdown of CNTN1 significantly inhibits the tumor proliferation, invasiveness and represses the expression of cyclin D1 (CCND1). In conclusion, CNTN1 will be a potential diagnosis biomarker and therapy target for thyroid cancer.

Hechtman JF, Zehir A, Yaeger R, et al.
Identification of Targetable Kinase Alterations in Patients with Colorectal Carcinoma That are Preferentially Associated with Wild-Type RAS/RAF.
Mol Cancer Res. 2016; 14(3):296-301 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Targeted therapy for metastatic colorectal carcinoma consists of anti-EGFR therapy for patients with RAS/RAF wild-type tumors. However, the response rate remains low, suggesting the presence of alternative drivers possibly also representing potential therapeutic targets. We investigated receptor tyrosine kinase (RTK) alterations and MAP2K1 (MEK1) mutations in a large cohort of colorectal carcinoma patients studied by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and The Cancer Genome Atlas, focusing on amplifications, fusions, and hotspot mutations in RTK genes and MAP2K1. RTK gene amplifications were confirmed with FISH and immunohistochemical (IHC) staining. Among 751 colorectal carcinoma cases with next-generation sequencing data, 7% and 1% of colorectal carcinoma harbored RTK alterations and MAP2K1 hotspot mutations (n = 7), respectively. RTK-altered cases had fewer concurrent RAS/RAF mutations (P = 0.003) than RTK/MAP2K1 wild-type colorectal carcinoma. MAP2K1-mutated colorectal carcinoma showed no RAS/RAF mutations. ERBB2 (n = 32) and EGFR (n = 13) were the most frequently altered RTKs, both activated by amplification and/or hotspot mutations. Three RTK fusions were identified: NCOA4-RET, ERBB2-GRB7, and ETV6-NTRK3. Only 1 of 6 patients with an RTK or MAP2K1 alteration who received anti-EGFR and/or anti-ERBB2 therapy demonstrated stable disease; the rest progressed immediately. Overall, RTK alterations and MAP2K1 mutations occur in approximately 8% of colorectal carcinoma. In spite of the usual absence of RAS/RAF mutations, response to anti-EGFR and/or anti-ERBB2 therapy was poor in this limited group. Larger studies are warranted to further define these kinase alterations as novel therapeutic targets in colorectal carcinoma and as negative predictors of response to anti-EGFR therapy.
IMPLICATIONS: Targetable kinase alterations were identified in a subset of advanced colorectal carcinoma patients, preferentially associated with wild-type RAS/RAF, and may predict poor response to standard anti-EGFR therapy.

Mitsutake N, Fukushima T, Matsuse M, et al.
BRAF(V600E) mutation is highly prevalent in thyroid carcinomas in the young population in Fukushima: a different oncogenic profile from Chernobyl.
Sci Rep. 2015; 5:16976 [PubMed] Free Access to Full Article Related Publications
After the accident at the Fukushima Daiichi Nuclear Power Plant, the thyroid ultrasound screening program for children aged 0-18 at the time of the accident was started from October 2011. The prevalence of thyroid carcinomas in that population has appeared to be very high (84 cases per 296,253). To clarify the pathogenesis, we investigated the presence of driver mutations in these tumours. 61 classic papillary thyroid carcinomas (PTCs), two follicular variant PTCs, four cribriform-morular variant PTCs and one poorly-differentiated thyroid carcinoma were analysed. We detected BRAF(V600E) in 43 cases (63.2%), RET/PTC1 in six (8.8%), RET/PTC3 in one (1.5%) and ETV6/NTRK3 in four (5.9%). Among classic and follicular variant PTCs, BRAF(V600E) was significantly associated with the smaller size. The genetic pattern was completely different from post-Chernobyl PTCs, suggesting non-radiogenic etiology of these cancers. This is the first study demonstrating the oncogene profile in the thyroid cancers discovered by large mass screening, which probably reflects genetic status of all sporadic and latent tumours in the young Japanese population. It is assumed that BRAF(V600E) may not confer growth advantage on paediatric PTCs, and many of these cases grow slowly, suggesting that additional factors may be important for tumour progression in paediatric PTCs.

Aydin K, Aydin C, Dagdelen S, et al.
Genetic Alterations in Differentiated Thyroid Cancer Patients with Acromegaly.
Exp Clin Endocrinol Diabetes. 2016; 124(3):198-202 [PubMed] Related Publications
AIM: Acromegaly is associated with increased thyroid cancer risk. We aimed to analyze the frequency of point mutations of BRAF and RAS genes, and RET/PTC, PAX8/PPARγ gene rearrangements in patients with acromegaly having differentiated thyroid cancers (DTC) and their relation with clinical and histological features.
MATERIALS AND METHODS: 14 acromegalic patients (8 male, 6 female) with DTC were included. BRAF V600E and NRAS codon 61 point mutations, RET/PTC1, RET/PTC3, and PAX8/PPARγ gene rearrangements were analyzed in thyroidectomy specimens. We selected 14 non-acromegalic patients with DTC as a control group.
RESULTS: 2 patients (14.3%) were detected to have positive BRAF V600E and 3 patients (21.4%) were detected to have NRAS codon 61 mutation. NRAS codon 61 was the most frequent genetic alteration. Patients with positive mutation had aggressive histologic features more frequently than patients without mutations. Comparison of the acromegalic and non-acromegalic patients with DTC revealed that BRAF V600E mutation was more frequent in non-acromegalic patients with DTC (14.2% vs. 64.3%, p=0.02). RET/PTC 1/ 3, PAX8/PPARγ gene rearrangements were not detected in any patient. None of the patients including the patients with positive point mutations had recurrence, and local and/or distant metastasis.
CONCLUSION: NRAS codon 61 is the most frequent genetic alteration in this acromegaly series with DTC. Since acromegalic patients have lower prevalance of BRAF V600E mutation, BRAF V600E mutation may not be a causative factor in development of DTC in acromegaly. Despite the relation of BRAF V600E and NRAS codon 61 mutations with aggresive histopathologic features, their impact on tumor prognosis remains to be defined in acromegaly in further studies.

Picarsic JL, Buryk MA, Ozolek J, et al.
Molecular Characterization of Sporadic Pediatric Thyroid Carcinoma with the DNA/RNA ThyroSeq v2 Next-Generation Sequencing Assay.
Pediatr Dev Pathol. 2016 Mar-Apr; 19(2):115-22 [PubMed] Related Publications
The aim of this study was to test the hypothesis that our 60-gene DNA/RNA ThyroSeq v2 next-generation sequence (NGS) assay would identify additional genetic markers, including gene fusions in sporadic pediatric differentiated thyroid carcinomas (DTC) that had no known molecular alterations. Sporadic pediatric DTCs with informative molecular testing (n=18) were studied. We previously tested 15 cases by our standard 7-gene (BRAF, NRAS, HRAS, KRAS, RET/PTC1, RET/PTC3, PAX8/PPARg) mutation panel. Three cases were not tested previously. The standard 7-gene panel identified molecular alterations in 9 of 15 tumors (60%). Cases analyzed by ThyroSeq v2 NGS included the six previously negative cases by the standard 7-gene panel and three cases not previously tested. The NGS assay revealed new gene fusions in four of six previously negative cases (67%). These gene fusions included ETV6/NTRK3 (n=3) and TPR/NTRK1 (n=1). A point mutation (BRAF-V600E) was detected in one of three untested cases. While standard testing could identify only molecular alterations in 60% of cases, with the addition of the ThyroSeq v2 NGS, this increased to 87% (n=13/15). Some cases with chromosomal rearrangements, including ETV6/NTRK3, appear to be associated with an aggressive histopathologic phenotype, but had no documented history of radiation exposure. Additional work is needed to investigate if pediatric DTCs could benefit from a reclassification based on molecular subtypes, which may better reflect their underlying biologic potential. Our data support the use of broad gene panels for the molecular diagnostics of pediatric thyroid nodules to aid future classification, treatment, and clinical management recommendations.

Tobiás B, Halászlaki C, Balla B, et al.
Genetic Alterations in Hungarian Patients with Papillary Thyroid Cancer.
Pathol Oncol Res. 2016; 22(1):27-33 [PubMed] Related Publications
The incidence of thyroid cancers is increasing worldwide. Some somatic oncogene mutations (BRAF, NRAS, HRAS, KRAS) as well as gene translocations (RET/PTC, PAX8/PPAR-gamma) have been associated with the development of thyroid cancer. In our study, we analyzed these genetic alterations in 394 thyroid tissue samples (197 papillary carcinomas and 197 healthy). The somatic mutations and translocations were detected by Light Cycler melting method and Real-Time Polymerase Chain Reaction techniques, respectively. In tumorous samples, 86 BRAF (44.2%), 5 NRAS (3.1%), 2 HRAS (1.0%) and 1 KRAS (0.5%) mutations were found, as well as 9 RET/PTC1 (4.6%) and 1 RET/PTC3 (0.5%) translocations. No genetic alteration was seen in the non tumorous control thyroid tissues. No correlation was detected between the genetic variants and the pathological subtypes of papillary cancer as well as the severity of the disease. Our results are only partly concordant with the data found in the literature.

Klempner SJ, Bazhenova LA, Braiteh FS, et al.
Emergence of RET rearrangement co-existing with activated EGFR mutation in EGFR-mutated NSCLC patients who had progressed on first- or second-generation EGFR TKI.
Lung Cancer. 2015; 89(3):357-9 [PubMed] Related Publications
OBJECTIVES: The gatekeeper mutation T790M mutation is the responsible for the majority of the resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with EGFR-mutated non-small cell lung cancer (NSCLC). Other previously described resistance mechanisms include HER2 amplification, MET amplification, PIK3CA mutation, epithelial-mesenchymal transition (EMT), small cell transformation have also been identified. However other resistance mechanisms remains to be discovered.
MATERIALS AND METHODS: Hybrid-capture based comprehensive genomic profiling (CGP) was performed on pre- and post-EGFR TKI progression EGFR-mutated NSCLC tumor samples during routine clinical care. We identify two paired pre- and post-EGFR TKI progression EGFR-mutated NSCLC patient tumor samples where both post EGFR TKI samples harbored in-frame CCDC6-RET rearrangements but not in the pre-EGFR TKI tumor samples. Furthermore analysis of the clinical database revealed one additional NCOA4-RET rearrangement co-existing with activated EGFR mutation in an EGFR-mutated NSCLC patient who had progressed on afatinib. None of the known resistance mechanisms to EGFR TKI including EGFR T790M, EGFR amplification, HER2 amplification, MET amplification, PIK3CA mutation, BRAF mutation, EMT or small cell transformation was identified in the three post progression samples that now harbored RET rearrangements.
RESULTS AND CONCLUSIONS: This is the first report of RET rearrangement co-existing with activated EGFR mutations in EGFR-mutated patients who had progressed on either first- or second generation EGFR TKI. As such, RET rearrangement may serve as a potential resistance mechanism to EGFR TKI in EGFR-mutated NSCLC.

Le Rolle AF, Klempner SJ, Garrett CR, et al.
Identification and characterization of RET fusions in advanced colorectal cancer.
Oncotarget. 2015; 6(30):28929-37 [PubMed] Free Access to Full Article Related Publications
There is an unmet clinical need for molecularly directed therapies available for metastatic colorectal cancer. Comprehensive genomic profiling has the potential to identify actionable genomic alterations in colorectal cancer. Through comprehensive genomic profiling we prospectively identified 6 RET fusion kinases, including two novel fusions of CCDC6-RET and NCOA4-RET, in metastatic colorectal cancer (CRC) patients. RET fusion kinases represent a novel class of oncogenic driver in CRC and occurred at a 0.2% frequency without concurrent driver mutations, including KRAS, NRAS, BRAF, PIK3CA or other fusion tyrosine kinases. Multiple RET kinase inhibitors were cytotoxic to RET fusion kinase positive cancer cells and not RET fusion kinase negative CRC cells. The presence of a RET fusion kinase may identify a subset of metastatic CRC patients with a high response rate to RET kinase inhibition. This is the first characterization of RET fusions in CRC patients and highlights the therapeutic significance of prospective comprehensive genomic profiling in advanced CRC.

Lin C, Wang S, Xie W, et al.
The RET fusion gene and its correlation with demographic and clinicopathological features of non-small cell lung cancer: a meta-analysis.
Cancer Biol Ther. 2015; 16(7):1019-28 [PubMed] Free Access to Full Article Related Publications
PURPOSE: The RET fusion gene is a novel oncogene observed in a subset of NSCLC in recent years. Nevertheless, the results of epidemiological studies concerning the gene remain unclear. Thus, a meta-analysis was conducted to evaluate the correlation of RET fusion gene with demographic and clinicopathological features of NSCLC.
METHODS: PubMed, Embase, and Web of Science databases were searched to identify eligible studies. The association of RET fusion gene occurrence with gender, age, smoking status, histology type and tumor stage were analyzed in meta-analysis. Subgroup analysis according to patients' location (Asian and non-Asian) was also conducted. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated to assess the correlation.
RESULTS: Nine studies with a total of 6,899 NSCLC patients met the inclusion criteria. A total of 84 patients with RET fusion gene were detected. The RET fusion gene was identified at significantly higher frequencies in female (OR = 0.55, 95%CI = 0.35-0.85) than male patients and in young (<60) patients (OR = 0.43, 95%CI = 0.19-0.99) than old patients (≤60), particularly in patients from Asian. A significant higher frequency was also identified in non-smokers (OR = 0.28, 95% CI = 0.16-0.49), and in patients with lung adenocarcinomas (OR = 3.59, 95%CI = 1.50-8.56). Additionally, no association between RET fusion gene and the TNM stage of tumor was observed.
CONCLUSION: RET fusion gene occurred predominantly in Asian females with younger age, in non-smokers, and in lung adenocarcinomas patients. This subset of NSCLC patients might be good candidates for personalized diagnostic and therapeutic approaches.

Zhang T, Lu Y, Ye Q, et al.
An evaluation and recommendation of the optimal methodologies to detect RET gene rearrangements in papillary thyroid carcinoma.
Genes Chromosomes Cancer. 2015; 54(3):168-76 [PubMed] Related Publications
To recommend a reliable and clinically realistic RET/PTC rearrangement detection assay for papillary thyroid carcinoma (PTC), we compared multiplex quantitative polymerase chain reaction (qPCR), fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC). RET/PTC rearrangement was detected using either RET break-apart FISH followed by multicolor FISH to confirm CCDC6/RET or NCOA4/RET fusions, or by multiplex qPCR to detect 14 RET/PTC subtypes with simultaneous RET mRNA expression. RET protein expression was detected by IHC. The specificity and sensitivity of multiplex qPCR and IHC were calculated using break-apart FISH as a reference. Among 73 PTC patients with sufficient tissue available for FISH and multiplex qPCR, 10 cases were defined as RET/PTC positive by both assays, including eight CCDC6/RET and two NCOA4/RET fusions with relatively high RET mRNA. In addition, multiplex qPCR identified another two CCDC6/RET fusion positive cases, but with low RET mRNA expression. IHC staining identified 11 RET positive cases among 39 patients with available samples. In comparison to FISH, multiplex qPCR displayed 100% sensitivity and 97% specificity to detect RET/PTC fusions, while IHC was neither sensitive nor specific. Our data reveal that both multiplex qPCR and FISH assays are equally applicable for detection of RET/PTC rearrangements. Break-apart FISH methodology is highly recommended for the wider screening of RET rearrangements (regardless of partner genes), while multiplex qPCR is preferred to identify all known fusion types using one assay, provided mRNA expression is also measured. IHC analysis could potentially provide an additional method of fusion detection dependent on further optimization of assay conditions and scoring cutoffs.

Rossi M, Buratto M, Tagliati F, et al.
Relevance of BRAF(V600E) mutation testing versus RAS point mutations and RET/PTC rearrangements evaluation in the diagnosis of thyroid cancer.
Thyroid. 2015; 25(2):221-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A molecular profile including BRAF and RAS mutations as well as RET/PTC rearrangement evaluation has been proposed to provide an accurate presurgical assessment of thyroid nodules and to reduce the number of unnecessary diagnostic surgeries, sparing patients' health and saving healthcare resources. However, the application of such molecular analyses may provide different results among different centers and populations in real-life settings. Our aims were to evaluate the diagnostic utility of assessing the presence of BRAF and RAS mutations and RET/PTC1 and RET/PTC3 rearrangements in all cytological categories in an Italian group of thyroid nodule patients assessed prospectively, and to understand whether and which mutation testing might be helpful in cytologically indeterminate nodules.
METHODS: A total of 911 patients were submitted to ultrasound and fine-needle aspiration biopsy examination. Cytological evaluation was performed in parallel with molecular testing and compared to pathological results in 940 thyroid nodules, including 140 indeterminate lesions.
RESULTS: BRAF mutation testing provided the best contribution to cancer diagnosis, allowing the disease to be detected at an early stage, and identifying indeterminate nodules in which diagnostic lobectomy could be spared. On the contrary, RAS and RET/PTC analysis did not further increase diagnostic sensitivity for thyroid cancer. In addition, we found RET/PTC rearrangements in benign lesions, indicating that this molecular marker might not be useful for the detection of thyroid cancer.
CONCLUSION: BRAF(V600E) mutation analysis is superior to RAS point mutations and evaluation of RET/PTC rearrangements in the diagnosis of thyroid cancer, even in indeterminate lesions.

Malaguarnera R, Chen KY, Kim TY, et al.
Switch in signaling control of mTORC1 activity after oncoprotein expression in thyroid cancer cell lines.
J Clin Endocrinol Metab. 2014; 99(10):E1976-87 [PubMed] Free Access to Full Article Related Publications
CONTEXT: Thyroid growth is regulated by TSH and requires mammalian target of rapamycin (mTOR). Thyroid cancers frequently exhibit mutations in MAPK and/or phosphoinositol-3-kinase-related kinase effectors.
OBJECTIVE: The objective of the study was to explore the contribution of RET/PTC, RAS, and BRAF to mTOR regulation and response to mTOR inhibitors.
METHODS: PCCL3 cells conditionally expressing RET/PTC3, HRAS(G12V), or BRAF(V600E) and human thyroid cancer cells harboring mutations of these genes were used to test pathways controlling mTOR and its requirement for growth.
RESULTS: TSH/cAMP-induced growth of PCCL3 cells requires mTOR, which is stimulated via protein kinase A in a MAPK kinase (MEK)- and AKT-independent manner. Expression of RET/PTC3, HRAS(G12V), or BRAF(V600E) in PCCL3 cells induces mTOR but does not entirely abrogate the cAMP-mediated control of its activity. Acute oncoprotein-induced mTOR activity is regulated by MEK and AKT, albeit to differing degrees. By contrast, mTOR was not activated by TSH/cAMP in human thyroid cancer cells. Tumor genotype did not predict the effects of rapamycin or the mTOR kinase inhibitor AZD8055 on growth, with the exception of a PTEN-null cell line. Selective blockade of MEK did not influence mTOR activity of BRAF or RAS mutant cells. Combined MEK and mTOR kinase inhibition was synergistic on growth of BRAF- and RAS-mutant thyroid cancer cells in vitro and in vivo.
CONCLUSION: Thyroid cancer cells lose TSH/cAMP dependency of mTOR signaling and cell growth. mTOR activity is not decreased by the MEK or AKT inhibitors in the RAS or BRAF human thyroid cancer cell lines. This may account for the augmented effects of combining the mTOR inhibitors with selective antagonists of these oncogenic drivers.

Rao PJ, Vardhini NV, Parvathi MV, et al.
Prevalence of RET/PTC1 and RET/PTC3 gene rearrangements in Chennai population and its correlation with clinical parameters.
Tumour Biol. 2014; 35(10):9539-48 [PubMed] Related Publications
Thyroid cancer is one of the most common endocrine disorders in the world. In India, about 42 million people suffer from various thyroid disorders. However, based on population-based cancer registry (PBCR) and Chennai cancer registry, thyroid cancer is emerging as a common cancer particularly in Chennai. Papillary thyroid carcinoma is considered as the most prevalent cancer constituting about 80-85 % of thyroid malignancies. Rearranged during transfection (RET)/papillary thyroid carcinoma (PTC) gene rearrangements are one of the major genetic alterations found in papillary thyroid carcinoma. This present study aims at estimating the frequency of RET/PTC1 and RET/PTC3 gene rearrangements in Chennai population and investigating the correlation between RET/PTC gene expressions with clinical parameters. Formalin-fixed paraffin-embedded (FFPE) tumor tissues obtained from 30 patients with papillary thyroid carcinoma were analyzed. Initially, to differentiate classic and follicular variants of papillary thyroid carcinoma samples, immunohistochemistry was performed. Thereafter, total RNA was isolated, and quantitative evaluation of RET/PTC1 and RET/PTC3 gene rearrangements by real-time PCR was performed. Chi-square test was performed to understand the correlation between positive and negative mutations of RET/PTC messenger RNA (mRNA) expression with clinical parameters. RET/PTC3 gene rearrangements were identified in 26/30 (86.67 %) cases, and none of the patient in our series had RET/PTC1 gene rearrangements. There was no statistically significant difference observed between positive and negative mutations of RET/PTC3 mRNA expression with clinic pathological parameters. Our results indicate that RET/PTC3 gene rearrangements are the most prevalent form of rearrangements in PTCs of Chennai population.

Ali HM, Urbinati G, Chapuis H, et al.
Effects of siRNA on RET/PTC3 junction oncogene in papillary thyroid carcinoma: from molecular and cellular studies to preclinical investigations.
PLoS One. 2014; 9(4):e95964 [PubMed] Free Access to Full Article Related Publications
RET/PTC3 junction oncogene is typical of radiation-induced childhood papillary thyroid carcinoma (PTC) with a short latency period. Since, RET/PTC3 is only present in the tumour cells, thus represents an interesting target for specific therapy by small interfering RNA (siRNA). Our aim is to demonstrate in vitro and in vivo molecular and cellular effects of siRNA on RET/PTC3 knockdown for therapeutic application.First, we established a novel cell line stably expressing RET/PTC3 junction oncogene, named RP3 which was found tumorigenic in nude mice compared to NIH/3T3 mouse fibroblasts. Among four siRNAs and five concentrations tested against RET/PTC3, an efficient siRNA RET/PTC3 and an appropriate dose (50 nM) were selected which showed significant inhibition (p<0.001) of gene (RT-qPCR) and protein (Western blot) expressions. This siRNA was found efficient in RP3 cells (harbouring RET/PTC3) but non-efficient in BHP10-3 SCmice cell line (harbouring RET/PTC1) showing that a specific siRNA against fusion sequence is required to target the junction oncogene. In vitro siRNA RET/PTC3 showed significant (p<0.001) inhibitory effects on RP3 cell viability (MTT assay) and on invasion/migration (IncuCyte scratch test) with blockage of cell cycle at G0/G1 phase (flow cytometry) and induced apoptosis by caspase-3 and PARP1 cleavage (WB). After intravenous injection in nude mice, respective squalene (SQ) nanoparticles (NPs) of siRNA RET/PTC3 significantly (p<0.001) reduced RP3 tumour growth, oncogene and oncoprotein expressions, induced apoptosis and partially restored differentiation (decrease in Ki67). Hence, our findings highly support the use of siRNA RET/PTC3-SQ NPs as a new promising treatment for patients affected by PTC expressing RET/PTC3.

Dacic S, Luvison A, Evdokimova V, et al.
RET rearrangements in lung adenocarcinoma and radiation.
J Thorac Oncol. 2014; 9(1):118-20 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: RET rearrangement, a hallmark of radiation-induced thyroid cancer, has been reported to occur in 1% of lung adenocarcinoma patients. Patients with this rearrangement tend to be younger and never smokers, raising a possibility of other causes, such as radiation. We hypothesized that RET chromosomal rearrangement may represent a genetic mechanism of radiation-induced lung cancer.
METHODS: Two hundred forty-five consecutive primary lung adenocarcinomas without history of radiation and 38 lung adenocarcinoma patients with a history of therapeutic radiation for breast carcinoma or mediastinal Hodkgin lymphoma were tested for RET rearrangement by fluorescence in situ hybridization. Human lung adenocarcinoma cells (201T) were subjected to γ radiation and tested for RET gene fusions by reverse transcriptase-polymerase chain reaction and Southern blot hybridization.
RESULTS: We identified one case with RET rearrangement in the group without history of radiation (1 of 240; 0.4%) and two cases in the group with history of radiation (2 of 37; 5.4%; P=0.0436). Both these patients were women, who were former smokers with a history of breast carcinoma treated with surgery and radiation. Furthermore, we found that RET fusions could be directly induced in 201T human lung cells by exposure to 1 Gy of γ radiation. All fusions identified were between RET and KIF5B genes, and no RET fusions to CCDC6 or NCOA4 genes, characteristic for thyroid cancer, were identified in the irradiated lung cells.
CONCLUSION: RET fusions may represent a genetic mechanism of radiation-induced lung adenocarcinoma.

Shang Z, Niu Y, Cai Q, et al.
Human kallikrein 2 (KLK2) promotes prostate cancer cell growth via function as a modulator to promote the ARA70-enhanced androgen receptor transactivation.
Tumour Biol. 2014; 35(3):1881-90 [PubMed] Related Publications
Recent data suggested that tissue human kallikrein 2 (KLK2) might be involved in the carcinogenesis and tumor metastasis of prostate cancer (PCa). However, the detailed pathophysiological roles of KLK2 in PCa remain unclear. We report here that KLK2 may be treated as a potential therapeutic target in castration-resistant PCa (CRPC). Histologic analyses show that the increased KLK2 expression is correlated with higher cell proliferation rate and lower cell apoptosis index in CRPC specimens. Adding functional KLK2 cDNA into high passage LNCaP cells led to increased cell growth, and knockdown of KLK2 expression with KLK2-siRNA in LNCaP cells resulted in increased cell apoptosis with cell growth arrest at the G1 phase. Results from in vitro colony formation assay and in vivo xenografted PCa tissues also demonstrated that targeting KLK2 led to suppressed growth of PCa in the castration-resistant stage. Further mechanism dissection shows that KLK2 may cooperate with the AR coregulator, ARA70, to enhance AR transactivation that may result in alteration of PCa formation. Together, these results suggested KLK2 might become a new therapeutic target to battle the CRPC and KLK2-siRNA may be developed as an alternative approach to suppress PCa growth.

Proietti A, Sartori C, Borrelli N, et al.
Follicular-derived neoplasms: morphometric and genetic differences.
J Endocrinol Invest. 2013; 36(11):1055-61 [PubMed] Related Publications
BACKGROUND: The distinction between follicular adenomas (FAs) and well differentiated follicular and papillary carcinomas is often a demanding task and sometimes only intuitive.
AIM: We report an histomorphological evaluation of follicular neoplasms [FAs, follicular carcinomas (FCs), and follicular variant of papillary carcinomas (FVPTCs)], supported by a qualitative and quantitative image analysis and by a molecular characterization.
MATERIAL AND METHODS: Tumor fibrosis and haemorrhage, neoplastic capsule thickness, follicle diameter, number of neoplastic cells, nuclear diameter of neoplastic cells, vessels density, vessels area and intratumoral distribution were evaluated. Ras and BRAF mutations, RET/PTC1, RET/PTC3, and PAX8/PPARγ rearrangements were analyzed. Correlations with clinico-pathological features have been studied.
RESULTS: We found that FAs had a more extensive intratumoral haemorrhage, while malignant neoplasms were characterized by an evident fibrosis, higher cellularity and larger size. FVPTCs had higher nuclear diameter; cells count was higher in the minimally invasive follicular thyroid carcinomas, as well as a thickener neoplastic capsule. The CD34 stain showed a higher microvessel density in the FVPTCs group. A higher peripheral vessels distribution was observed only in malignant neoplasms. We observed overall Ras mutations in 2.4% of adenomas, in 41.5% of FVPTCs, and in 44.8% of FCs. It is outstanding that there is a marked difference in the Ras mutation distribution between the benign and malignant tumors in our series.
CONCLUSIONS: We found that genotyping of Ras gene family together with an accurate analysis of selected morphological features could help in the differential diagnosis of follicular-derived thyroid neoplasms.

Okamoto K, Kodama K, Takase K, et al.
Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models.
Cancer Lett. 2013; 340(1):97-103 [PubMed] Related Publications
RET gene fusions are recurrent oncogenes identified in thyroid and lung carcinomas. Lenvatinib is a multi-tyrosine kinase inhibitor currently under evaluation in several clinical trials. Here we evaluated lenvatinib in RET gene fusion-driven preclinical models. In cellular assays, lenvatinib inhibited auto-phosphorylation of KIF5B-RET, CCDC6-RET, and NcoA4-RET. Lenvatinib suppressed the growth of CCDC6-RET human thyroid and lung cancer cell lines, and as well, suppressed anchorage-independent growth and tumorigenicity of RET gene fusion-transformed NIH3T3 cells. These results demonstrate that lenvatinib can exert antitumor activity against RET gene fusion-driven tumor models by inhibiting oncogenic RET gene fusion signaling.

Bansal M, Gandhi M, Ferris RL, et al.
Molecular and histopathologic characteristics of multifocal papillary thyroid carcinoma.
Am J Surg Pathol. 2013; 37(10):1586-91 [PubMed] Related Publications
Papillary thyroid carcinoma (PTC) is frequently multifocal, which can represent either intraglandular spread from a single primary tumor or multiple synchronous primary tumors (MSPTs). To distinguish and characterize these entities, we investigated whether multifocal PTCs contain genetically similar or different mutations and have particular histopathologic characteristics. In 60 cases of PTC with 2 to 4 discrete tumor foci, each focus was tested for BRAF, NRAS, HRAS, and KRAS point mutations and RET/PTC1 and RET/PTC3 rearrangements and analyzed for various histopathologic features. Overall, BRAF mutations were found in 43% of tumors, RAS in 27%, and RET/PTC in 2%. Four different patterns of mutation occurrence were identified: (i) 2 foci containing different mutations (30%); (ii) 1 tumor containing a mutation and another carrying no mutations (32%); (iii) both/all tumors containing the same mutation (25%); (iv) all tumors having no mutations (13%). The 30% of cases with 2 different mutations represent a group of tumors that are unequivocally MSPT. These tumors more commonly occurred in different lobes, although they could be located as close as 0.6 cm from each other. Moreover, MSPTs typically demonstrated distinct histologic variants/microscopic features, were encapsulated or had a smooth border, and showed no microscopic peritumoral dissemination. In conclusion, we demonstrate that at least 30% of multifocal PTCs represent unequivocal MSPTs that develop through distinct molecular alterations and that as many as 60% of multifocal PTCs are likely MSPTs. Histopathologically, MSPTs are typically located in different lobes, have distinct growth patterns, and do not show microscopic peritumoral dissemination.

Wang R, Hu H, Pan Y, et al.
RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer.
J Clin Oncol. 2012; 30(35):4352-9 [PubMed] Related Publications
PURPOSE: The RET fusion gene has been recently described in a subset of non-small-cell lung cancers (NSCLCs). Because we have limited knowledge about these tumors, this study was aimed at determining the clinicopathologic characteristics of patients with NSCLC harboring the RET fusion gene.
PATIENTS AND METHODS: We examined the RET fusion gene in 936 patients with surgically resected NSCLC using a reverse transcriptase polymerase chain reaction (PCR) plus quantitative real-time PCR strategy, with validation using immunohistochemical and fluorescent in situ hybridization assays. A subset of 633 lung adenocarcinomas was also studied for EGFR, KRAS, HER2, and BRAF mutations, as well as ALK rearrangements. Patient characteristics, including age, sex, smoking history, stage, grade, International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of subtypes of lung adenocarcinoma, and relapse-free survival, were collected.
RESULTS: Of 936 patients with NSCLC, the RET fusion gene was exclusively detected in 13 patients (11 of 633 patients with adenocarcinomas and two of 24 patients with adenosquamous cell carcinomas). Of the 13 patients, nine patients had KIF5B-RET, three patients had CCDC6-RET, and one patient had a novel NCOA4-RET fusion. Patients with lung adenocarcinomas with RET fusion gene had more poorly differentiated tumors (63.6%; P = .029 for RET v ALK, P = .007 for RET v EGFR), with a tendency to be younger (≤ 60 years; 72.7%) and never-smokers (81.8%) and to have solid subtype (63.6%) and a smaller tumor (≤ 3 cm) with N2 disease (54.4%). The median relapse-free survival was 20.9 months.
CONCLUSION: RET fusion occurs in 1.4% of NSCLCs and 1.7% of lung adenocarcinomas and has identifiable clinicopathologic characteristics, warranting further clinical consideration and targeted therapy investigation.

Celestino R, Sigstad E, Løvf M, et al.
Survey of 548 oncogenic fusion transcripts in thyroid tumors supports the importance of the already established thyroid fusions genes.
Genes Chromosomes Cancer. 2012; 51(12):1154-64 [PubMed] Related Publications
Neoplasms frequently present structural chromosomal aberrations that can alter the level of expression of a protein or to the expression of an aberrant chimeric protein. In the thyroid, the PAX8-PPARG fusion is present in the neoplastic lesions that have a follicular architecture-follicular thyroid carcinoma (FTC) and follicular variant of papillary thyroid carcinoma (FVPTC), and less frequently in follicular thyroid adenoma (FTA), while the presence of RET/PTC fusions are largely restricted to papillary thyroid carcinoma (PTC). The ability to detect fusion genes is relevant for a correct diagnosis and for therapy. We have developed a new fusion gene microarray-based approach for simultaneous analysis of all known and predicted fusion gene variants. We did a comprehensive screen for 548 known and putative fusion genes in 27 samples of thyroid tumors and three positive controls-one thyroid cancer cell line (TPC-1) and two PTCs with known CCDC6-RET (alias RET/PTC1) fusion gene, using this microarray. Within the thyroid tumors tested, only well known, previously reported fusion genes in thyroid oncology were identified. Our results reinforce the pathogenic role played by RET/PTC1, RET/PTC3, and PAX8-PPARG fusion genes in thyroid tumorigenesis.

Caria P, Dettori T, Frau DV, et al.
Simultaneous occurrence of PAX8-PPARg and RET-PTC3 rearrangements in a follicular variant of papillary thyroid carcinoma.
Am J Surg Pathol. 2012; 36(9):1415-20 [PubMed] Related Publications
Specific genotype-phenotype correlations have been identified in conventional-type papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC). In contrast, the genetic alterations underlying the pathogenesis of the follicular variant of PTC (FV-PTC), which shares some clinicopathologic and molecular features with both PTC and FTC, remain to be clarified. This entity shows a PAX8-PPARg fusion gene (associated with FTC), more frequently than BRAF or RET-PTC alterations (associated with PTC). Herein, we report, for the first time, an FV-PTC with the simultaneous occurrence of both RET-PTC and PAX8-PPARg alterations. Neoplastic cells were of the wild type for BRAF and H,K,N-RAS, had an apparently normal karyotype by conventional cytogenetics, and had a balanced genome by array comparative genomic hybridization analysis. In fact, submicroscopic chromosome rearrangements producing RET-PTC3 and PAX8-PPARg chimeric genes were found by interphase fluorescence in situ hybridization. We demonstrated that these 2 genetic alterations coexisted in the same tumor and were confined to 2 different clones. Our findings indicate that molecular heterogeneity, although an uncommon phenomenon, may occur in thyroid carcinoma and demonstrate the coexistence in a case of FV-PTC not only of the histologic but also of the molecular features of both PTC (RET-PTC) and FTC (PAX8-PPARg).

FitzGerald LM, Zhang X, Kolb S, et al.
Investigation of the relationship between prostate cancer and MSMB and NCOA4 genetic variants and protein expression.
Hum Mutat. 2013; 34(1):149-56 [PubMed] Free Access to Full Article Related Publications
Two genome-wide association studies (GWAS) identified the β-microseminoprotein (MSMB) promoter SNP, rs10993994:C>T, as significantly associated with prostate cancer (PC) risk. Follow-up studies demonstrate that the variant allele directly affects expression of the MSMB-encoded protein, PSP94, and also suggest that it affects mRNA expression levels of an adjacent gene, NCOA4, which is involved in androgen receptor transactivation. In a population-based study of 1,323 cases and 1,268 age-matched controls, we found the NCOA4 SNP, rs7350420:T>C, was associated with a 15% reduction in PC risk, but the association was not significant after adjustment for the rs10993994:C>T genotype. Tumor tissue microarrays of 519 radical prostatectomy patients were used to measure PSP94 and NCOA4 protein expression. Taken together, these data confirm that the rs10993994:C>T variant allele is associated with decreased PSP94 expression, and the association is stronger in tumor compared to normal prostate tissue. No association was observed between rs10993994:C>T and NCOA4 expression, and only moderate associations were seen between two NCOA4 SNPs, rs10761618:T>C and rs7085433:G>A, and NCOA4 protein expression. These data indicate that the increase in PC risk associated with rs10993994:C>T is likely mediated by the variant's effect on PSP94 expression; however, this effect does not extend to NCOA4 in the data presented here.

Gandhi M, Evdokimova V, Nikiforov YE
Frequency of close positioning of chromosomal loci detected by FRET correlates with their participation in carcinogenic rearrangements in human cells.
Genes Chromosomes Cancer. 2012; 51(11):1037-44 [PubMed] Free Access to Full Article Related Publications
It has been well established that genes participating in oncogenic rearrangements are non-randomly positioned and frequently close to each other in human cell nuclei. However, the actual distance between these fusion partners has never been determined. The phenomenon of fluorescence resonance energy transfer (FRET) is observed when a donor fluorophore is close (<10 nm) to transfer some of it energy to an acceptor fluorophore. The aim of this study was to validate the use of FRET on directly labeled DNA molecules to assess the frequency of positioning at <10 nm distances between genes known to be involved in rearrangement and to correlate it with their probability to undergo rearrangement. In the validation experiments, the frequency of FRET-sensitized emission (SE) was found to be 93-96% between probes for the immediately adjacent chromosomal regions as compared to 0.1-0.2% between probes for the random loci located on large linear separation. Further, we found that the frequency of FRET-SE between four pairs of genes that form rearrangements in thyroid cancer was 5% for RET and CCDC6, 4% for RET and NCOA4, 2% for BRAF and AKAP9, and 2% for NTRK1 and TPR. Moreover, the frequency with which FRET was observed showed strong correlation (r = 0.9871) with the prevalence of respective rearrangements in thyroid cancer. Our findings demonstrate that FRET can be used as a technique to analyze proximity between specific DNA regions and that the frequency of gene positioning at distances allowing FRET correlates with their probability to undergo chromosomal rearrangements.

Grisanzio C, Werner L, Takeda D, et al.
Genetic and functional analyses implicate the NUDT11, HNF1B, and SLC22A3 genes in prostate cancer pathogenesis.
Proc Natl Acad Sci U S A. 2012; 109(28):11252-7 [PubMed] Free Access to Full Article Related Publications
One of the central goals of human genetics is to discover the genes and pathways driving human traits. To date, most of the common risk alleles discovered through genome-wide association studies (GWAS) map to nonprotein-coding regions. Because of our relatively poorer understanding of this part of the genome, the functional consequences of trait-associated variants pose a considerable challenge. To identify the genes through which risk loci act, we hypothesized that the risk variants are regulatory elements. For each of 12 known risk polymorphisms, we evaluated the correlation between risk allele status and transcript abundance for all annotated protein-coding transcripts within a 1-Mb interval. A total of 103 transcripts were evaluated in 662 prostate tissue samples [normal (n = 407) and tumor (n = 255)] from 483 individuals [European Americans (n = 233), Japanese (n = 127), and African Americans (n = 123)]. In a pooled analysis, 4 of the 12 risk variants were strongly associated with five transcripts (NUDT11, MSMB, NCOA4, SLC22A3, and HNF1B) in histologically normal tissue (P ≤ 0.001). Although associations were also observed in tumor tissue, they tended to be more attenuated. Previously, we showed that MSMB and NCOA4 participate in prostate cancer pathogenesis. Suppressing the expression of NUDT11, SLC22A3, and HNF1B influences cellular phenotypes associated with tumor-related properties in prostate cancer cells. Taken together, the data suggest that these transcripts contribute to prostate cancer pathogenesis.

Lou H, Li H, Yeager M, et al.
Promoter variants in the MSMB gene associated with prostate cancer regulate MSMB/NCOA4 fusion transcripts.
Hum Genet. 2012; 131(9):1453-66 [PubMed] Free Access to Full Article Related Publications
Beta-microseminoprotein (MSP)/MSMB is an immunoglobulin superfamily protein synthesized by prostate epithelial cells and secreted into seminal plasma. Variants in the promoter of the MSMB gene have been associated with the risk of prostate cancer (PCa) in several independent genome-wide association studies. Both MSMB and an adjacent gene, NCOA4, are subjected to transcriptional control via androgen response elements. The gene product of NCOA4 interacts directly with the androgen receptor as a co-activator to enhance AR transcriptional activity. Here, we provide evidence for the expression of full-length MSMB-NCOA4 fusion transcripts regulated by the MSMB promoter. The predominant MSMB-NCOA4 transcript arises by fusion of the 5'UTR and exons 1-2 of the MSMB pre-mRNA, with exons 2-10 of the NCOA4 pre-mRNA, producing a stable fusion protein, comprising the essential domains of NCOA4. Analysis of the splice sites of this transcript shows an unusually strong splice acceptor at NCOA4 exon 2 and the presence of Alu repeats flanking the exons potentially involved in the splicing event. Transfection experiments using deletion clones of the promoter coupled with luciferase reporter assays define a core MSMB promoter element located between -27 and -236 of the gene, and a negative regulatory element immediately upstream of the start codon. Computational network analysis reveals that the MSMB gene is functionally connected to NCOA4 and the androgen receptor signaling pathway. The data provide an example of how GWAS-associated variants may have multiple genetic and epigenetic effects.

Kollara A, Brown TJ
Expression and function of nuclear receptor co-activator 4: evidence of a potential role independent of co-activator activity.
Cell Mol Life Sci. 2012; 69(23):3895-909 [PubMed] Free Access to Full Article Related Publications
Nuclear receptor coactivator 4 (NcoA4), also known as androgen receptor-associated protein 70 (ARA70), was initially discovered as a component of Ret-Fused Gene expressed in a subset of papillary thyroid carcinomas. Subsequent studies have established NcoA4 as a coactivator for a variety of nuclear receptors, including peroxisome proliferator activated receptors α and γ, and receptors for steroid hormones, vitamins D and A, thyroid hormone, and aryl hydrocarbons. While human NcoA4 has both LXXLL and FXXLF motifs that mediate p160 coactivator nuclear receptor interactions, this ubiquitously expressed protein lacks clearly defined functional domains. Several studies indicate that NcoA4 localizes predominantly to the cytoplasm and affects ligand-binding specificity of the androgen receptor, which has important implications for androgen-independent prostate cancer. Two NcoA4 variants, which may exert differential activities, have been identified in humans. Recent studies suggest that NcoA4 may play a role in development, carcinogenesis, inflammation, erythrogenesis, and cell cycle progression that may be independent of its role as a receptor coactivator. This review summarizes what is currently known of the structure, expression, regulation, and potential functions of this unique protein in cancerous and non-cancerous pathologies.

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