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1
Smith, Jenny L., Rhonda E. Ries, Yi-Cheng Wang, Amanda R. Leonti, Todd A. Alonzo, Alan S. Gamis, Richard Aplenc, et al. "ETS Family Transcription Factor Fusions in Childhood AML: Distinct Expression Networks and Clinical Implications." Blood 138, Supplement 1 (November 5, 2021): 2356. http://dx.doi.org/10.1182/blood-2021-148894.
Анотація:
Abstract The ETS family of genes encode transcription factors (TFs) containing the ETS DNA binding domain, which have roles in cellular growth and development, including embryonic hematopoiesis. Dysregulation of these genes is associated with malignant transformation and tumorigenesis. In childhood acute myeloid leukemia (AML), the MNX1-ETV6 t(7;12)(q36;p13) and FUS-ERG t(16;21)(p11;q22) fusions are associated with adverse outcome. However, the biological and clinical implications of other ETS oncofusions in pediatric AML remain unknown. We identified 62 ETS gene fusions in 1,473 primary diagnostic AML samples (4.2%) using whole transcriptome RNA-sequencing and karyotype data. Four ETS family genes were identified to be involved in fusions with various partner genes: ETV6, ERG, FEV, and FLI1. Fusions with ETV6 were the most abundant (58%, 36/62) while FEV and FLI1 were the least; 21 fusion partners were identified where many function as TFs and co-activators (Figure 1A). MNX1-ETV6 (N=16) is enriched in infants (87.5% < 3 years, p < 0.001, Figure 1B), consistent with previous reports. ETV6 fusions with various partners (ETV6-Other, N=20) were likewise enriched in infants (50% < 3 years) and were significantly younger than patients without ETS fusions (median age: 3.0 vs 9.6 years, p = 0.025). FUS-ERG (N=10), HNRNPH1-ERG (N=8), and ETS fusions with various partners (ETS-Other, N=8) were primarily identified in patients 5-18 years old. Outcomes for patients with ETS fusions was determined after censoring for stem cell transplantation. Patients with ETS fusions as a collective group had adverse outcome with an EFS of 17.7% vs 39.9% (p = 0.047, Figure 1C), similar to high-risk cases in the reference group (22%), suggesting that patients with any ETS fusion may be considered high risk. Evaluation of outcomes by individual fusion groups at 3 years from diagnosis demonstrated an EFS of 0% for HNRNPH1-ERG, 18.0% for FUS-ERG, 14.2% for ETV6-Other, 20.8% for ETS-Other, and 28.4% for those with MNX1-ETV6. Twenty-one patients (37.5%) with ETS family fusions received stem cell transplant (SCT) in first complete remission, including HNRNPH1-ERG (N=5), FUS-ERG (N=3), ETV6-Other (N=5), ETS-Other (N=2), and MNX1-ETV6 (N=6). For these SCT recipients, OS at 3 years after transplant was 60.2%. We investigated whether ETS family fusions might have similar transcriptome profiles. Unsupervised uniform manifold approximation and projection (UMAP) on RNA-seq gene expression data followed by Leiden clustering found that individual fusions clustered in the same 3D space. More importantly, ETS fusion groups clustered closely to one another, indicating a shared transcriptional profile (Figure 1D, circle). Next, ETS fusion groups were each independently compared to the reference cohort (N=1421) using differential expression (DE) analysis. Intersection of DE genes revealed 17 overexpressed genes common to ETS fusions and 9/17 (52%) were also dysregulated when contrasting ETS cohorts to healthy normal marrows' transcriptome (N=68, Figure 1E). The minimal set of dysregulated genes included an adhesion molecule EDIL3, a prostaglandin (PG) enzyme HPGD, and a tyrosine phosphatase PTP4A3, which is strongly associated with progression in lymphoblastic leukemia and multiple myeloma. EDIL3 was reported to be overexpressed in MNX1-ETV6 and we found this molecule is a common feature of ETS fusions and their cellular dysregulation. The minimal set of 9 genes were further investigated using protein interaction networks defined from Pathway Commons v11. FUS-ERG and HNRNPH1-ERG both had significantly (adj. p < 0.001) activated HPGD networks; PG-E synthase and > 10 PG metabolism genes were upregulated. PG metabolism has important roles in regulating hematopoietic stem and progenitor (HSPC) functions and PG-E2 was shown to increase HSPC survival. ETV6-MXN1, ETV6-Other, and FUS-ERG had activated PTP4A3 networks and its expression was associated with sensitivity to BET inhibitors (BETi) in myeloma. They also exhibited increased activity of an ERG network with the overexpression of upstream regulators CBFA2T3 and GATA, and downstream targets like VWF and ZBTB16. Overall, we show that ETS fusions are uniformly high risk and share dysregulated cell adhesion (EDIL3) and transcriptional networks for ERG, HPGD, and PTP4A3, which provide opportunities for further research into the metabolome and therapeutics (BETi) in these fusions. Figure 1 Figure 1. Disclosures Shaw: T-Cell and/or Gene Therapy for Cancer: Patents & Royalties.
2
Barbi de Moura, Michelle, Fadel S. Alyaqoub, Gargi D. Basu, David W. Hall, Jess R. Hoag, Janine R. LoBello, Frederick L. Baehner, Snehal Govind Thakkar, and Steven Canfield. "Erythroblast transformation-specific transcription factor fusions in prostate cancer." Journal of Clinical Oncology 41, no. 6_suppl (February 20, 2023): 224. http://dx.doi.org/10.1200/jco.2023.41.6_suppl.224.
Анотація:
224 Background: Common drivers in advanced prostate cancer (PC) involve fusions of the 3’ DNA binding domain-containing region of an Erythroblast Transformation Specific (ETS) transcription factor gene with a 5’ region of another gene, often one that is androgen-regulated. Previous work indicates that PCs harboring TMPRSS2:ERG fusions are more dependent on androgen signaling, and men with such tumors may, therefore, be more responsive to the effects of androgen deprivation therapy than men lacking this fusion. In this study, we examined the frequency of fusions involving ETS-family genes, including TMPRSS2:ERG, and determined how often such fusions would be missed if detection relied solely on DNA sequencing. Methods: To identify fusions and compare DNA-only versus DNA plus RNA sequencing, we utilized the Oncomap ExTra genomic profiling assay. This assay performs whole-exome, whole-transcriptome DNA and RNA sequencing of tumor and matched normal samples to identify somatic alterations in tumors. Single-nucleotide variants, indels, copy number alterations, alternative transcripts, and gene fusions are all detected. We specifically searched for fusions involving ETS transcription factor genes ERG and ETV1- 7. Results: A total of 512 PC patient samples assayed between April 2018 and July 2022 were included in the analysis; 226 ETS fusions were present in 223 (43.6%) patients; 3 patients carried two fusions. There were 196 ERG fusions including 185 (36.1%) patients having the familiar TMPRSS2: ERG fusion and 8 (1.6%) patients with a SLC45A3: ERG fusion, which is known to be associated with particularly poor prognosis. ETV1, 4, and 5 fusions were found in 29 (5.7%) patients and involved 12 different 5’ partner genes, the most common of which were SLC45A3 (6 fusions) and CANT1 (4 fusions). The two partner genes were on the same chromosome in 192 fusions, with 190 requiring a single deletion to create the fusion and 2 requiring a single inversion. For the 34 fusions involving genes on different chromosomes, a single translocation would be sufficient to produce the fusion gene in 23 cases; in 11 cases more than one structural rearrangement would be required. A total of 66 (29.6%) fusions were not detected in the DNA sequencing data, including 40 (21.6%) TMPRSS2: ERG fusions. In addition, 16 fusions were detected only in the DNA data, as RNA could not be sequenced, including 13 TMPRSS2: ERG fusions. Conclusions: In addition to TMPRSS2: ERG, the Oncomap ExTra assay identified several low frequency ETS fusions, all of which could be used to assist patients and physicians to select appropriate treatments. The identification of ETS fusions appears to be limited when using only DNA sequencing. Oncomap ExTra RNA analysis identified 66 additional fusions, representing almost 30% of those present, not identified by whole-exome DNA sequencing, suggesting RNA plus DNA assays detect fusions more reliably than DNA-only assays.
3
Staege, Martin S., and Daniela Max. "Genetics and Epigenetics of the TET-ETS Translocation Network." Genetics & Epigenetics 2 (January 2009): GEG.S2815. http://dx.doi.org/10.4137/geg.s2815.
Анотація:
In the present paper we review the translocation network involving TET and ETS family members with special focus on the Ewing family of tumors. FUS (fusion, involved in t(12;16) in malignant liposarcoma = TLS, Translocated in liposarcoma), EWSR1 (Ewing sarcoma breakpoint region 1) and TAF15 (TATA box-binding protein-associated factor, 68-KD) are the three human members of the TET family of RNA binding proteins. In addition, two EWSR1 pseudogenes are present in the human genome. TET family members are involved in several oncogenic gene fusions. Five of the 18 known fusion partners belong to the E26 (E twenty-six, ETS) family of transcription factors. Gene fusions between TET or ETS family members and other fusion partners link these gene fusions to a large network of oncogenic gene rearrangements.
4
Wei, Ting, Ji Lu, Tao Ma, Haojie Huang, Jean-Pierre Kocher, and Liguo Wang. "Re-Evaluate Fusion Genes in Prostate Cancer." Cancer Informatics 20 (January 2021): 117693512110275. http://dx.doi.org/10.1177/11769351211027592.
Анотація:
Background: Thousands of gene fusions have been reported in prostate cancer, but their authenticity, incidence, and tumor specificity have not been thoroughly evaluated, nor have their genomic characteristics been carefully explored. Methods: We developed FusionVet to dedicatedly validate known fusion genes using RNA-seq alignments. Using FusionVet, we re-assessed 2727 gene fusions reported from 36 studies using the RNA-seq data generated by The Cancer Genome Atlas (TCGA). We also explored their genomic characteristics and interrogated the transcriptomic and DNA methylomic consequences of the E26 transformation-specific (ETS) fusions. Results: We found that nearly two-thirds of reported fusions are intra-chromosomal, and 80% of them were formed between 2 protein-coding genes. Although most (76%) genes were fused to only 1 partner, we observed many fusion hub genes that have multiple fusion partners, including ETS family genes, androgen receptor signaling pathway genes, tumor suppressor genes, and proto-oncogenes. More than 90% of the reported fusions cannot be validated by TCGA RNA-seq data. For those fusions that can be validated, 5% were detected from tumor and normal samples with similar frequencies, and only 4% (120 fusions) were tumor-specific. The occurrences of ERG, ETV1, and ETV4 fusions were mutually exclusive, and their fusion statuses were tightly associated with overexpressions. Besides, we found ERG fusions were significantly co-occurred with PTEN deletion but mutually exclusive with common genomic alterations such as SPOP mutation and FOXA1 mutation. Conclusions: Most of the reported fusion genes cannot be validated by TCGA samples. The ETS family and androgen response genes were significantly enriched in prostate cancer–specific fusion genes. Transcription activity was significantly repressed, and the DNA methylation was significantly increased in samples carrying ERG fusion.
5
Gasi Tandefelt, Delila, Joost Boormans, Karin Hermans, and Jan Trapman. "ETS fusion genes in prostate cancer." Endocrine-Related Cancer 21, no. 3 (March 20, 2014): R143—R152. http://dx.doi.org/10.1530/erc-13-0390.
Анотація:
Prostate cancer is very common in elderly men in developed countries. Unravelling the molecular and biological processes that contribute to tumor development and progressive growth, including its heterogeneity, is a challenging task. The fusion of the genes ERG and TMPRSS2 is the most frequent genomic alteration in prostate cancer. ERG is an oncogene that encodes a member of the family of ETS transcription factors. At lower frequency, other members of this gene family are also rearranged and overexpressed in prostate cancer. TMPRSS2 is an androgen-regulated gene that is preferentially expressed in the prostate. Most of the less frequent ETS fusion partners are also androgen-regulated and prostate-specific. During the last few years, novel concepts of the process of gene fusion have emerged, and initial experimental results explaining the function of the ETS genes ERG and ETV1 in prostate cancer have been published. In this review, we focus on the most relevant ETS gene fusions and summarize the current knowledge of the role of ETS transcription factors in prostate cancer. Finally, we discuss the clinical relevance of TMRPSS2–ERG and other ETS gene fusions in prostate cancer.
6
Anderson, Nathaniel D., Richard de Borja, Matthew D. Young, Fabio Fuligni, Andrej Rosic, Nicola D. Roberts, Simon Hajjar, et al. "Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors." Science 361, no. 6405 (August 30, 2018): eaam8419. http://dx.doi.org/10.1126/science.aam8419.
Анотація:
Sarcomas are cancers of the bone and soft tissue often defined by gene fusions. Ewing sarcoma involves fusions between EWSR1, a gene encoding an RNA binding protein, and E26 transformation-specific (ETS) transcription factors. We explored how and when EWSR1-ETS fusions arise by studying the whole genomes of Ewing sarcomas. In 52 of 124 (42%) of tumors, the fusion gene arises by a sudden burst of complex, loop-like rearrangements, a process called chromoplexy, rather than by simple reciprocal translocations. These loops always contained the disease-defining fusion at the center, but they disrupted multiple additional genes. The loops occurred preferentially in early replicating and transcriptionally active genomic regions. Similar loops forming canonical fusions were found in three other sarcoma types. Chromoplexy-generated fusions appear to be associated with an aggressive form of Ewing sarcoma. These loops arise early, giving rise to both primary and relapse Ewing sarcoma tumors, which can continue to evolve in parallel.
7
Buteyn, Nathaniel J., Connor Burke, Eve Gardner, Vincent J. Sartori, Rhonda E. Ries, Todd A. Alonzo, Soheil Meshinchi, and Timothy Triche. "Reclassification of ETS Family Transcription Factor Fusions in Pediatric AML Based on Molecular Drivers." Blood 142, Supplement 1 (November 28, 2023): 4298. http://dx.doi.org/10.1182/blood-2023-189474.
Анотація:
Pediatric Acute Myeloid Leukemia (pAML) patients with a fusion involving an E26 transformation-specific (ETS) transcription factor have traditionally been considered high-risk. The most common fusions include ETV6::MNX1 t(7;12)(q36;p13) and FUS::ERG t(16;21)(p11;q22), yet primary fusion alone has proven incapable of predicting response to treatment. Indeed, within the 60 pAML patients with ETS fusions from the Children's Oncology Group (COG) trials AAML0531 and AAML1031, there were 25 unique fusions and diverse outcomes between patients who did share a primary fusion. A molecular based reclassification of ETS fused pAML could prove beneficial in the development of novel therapeutic additions to standard induction. Here, using genetic and RNAseq data from over 1,400 pediatric patients from AAML0531 and AAML1031, we reclassified ETS patients based on oncogenic transcriptional profiles as well as access to hematopoietic stem cell transplant (HSCT) ( Figure 1A). (19/60) patients presented with an enhanced MYC transcriptional signature (p-val < 0.00) independent of fusion partners [EP300::ETV6, ETV6::CCND3, ETV6::FAM133B, ETV6::FOXO1, ETV6::INO80D, ETV6::LMBR1, ETV6::MNX1, EWSR1::FEV, FLI1::IFIT2, FUS::ERG, FUS::FEV, FUS::FLI1]. Median event-free survival (EFS) was 293.5 days; median overall survival (OS) was 620.5 days. Notably, 100% (19/19) of patients with a MYC-driven signature relapsed; of the six patients who received HCST, five died within 3 years of diagnosis. Preliminary in vitro data in ETS cell lines with an enhanced MYC transcriptional signature (YNH-1, TSU-1621) suggests that the BET bromodomain inhibitor JQ1 may dampen MYC and induce anti-proliferative effects. (7/60) patients were defined by an EZH2-driven “immune-cold” signature characterized by global loss of immune receptors. Patients presented at diagnosis with significantly elevated EZH2 and low levels of MHC I and II receptors typically observed at relapse; additionally, there was significant downregulation in T cell and natural killer cell ligands and a 100% failure rate for HSCT. Median EFS was 255 days and median OS was 339 days. We have previously discussed the mechanism of leukemogenesis as well as proposed therapeutic interventions for this subset (Buteyn, ASH 2021). (34/60) patients did not possess either a MYC-driven or EZH2-driven signature. These “other” ETS were instead defined by whether or not the patient underwent HCST. (21/34) patients did not receive HCST and had median EFS and OS of 429 and 1194 days, respectively. The relapsed or refractory rate in this population was still 75%; (8/14) of R/R patients were deceased within three years. The remaining (13/60) ETS patients did receive HSCT in first remission. (11/13) are still alive and at a rate higher than the general pAML population post-HSCT (62.6%). Despite a survival rate at approximately 85%, ‘Other ETS +HSCT’ patients were all still categorized as ‘High Risk’ at the end of AAML1031. Overall, reclassification based on molecular drivers appears to not only be more accurate in predicting relapse and final outcome, but also in proposing novel agents for pAML patients who overwhelmingly do not respond to standard regimens. Reinvigoration of immune recognition by inhibition of EZH2 and/or inhibition of MYC-driven proliferation via BET inhibitors may prove an essential step in setting the stage for successful HSCT for a significant portion of pAML ETS patients.
8
Lawlor, E. R., J. A. Mathers, T. Bainbridge, D. E. Horsman, A. Kawai, J. H. Healey, A. G. Huvos, J. A. Bridge, M. Ladanyi, and P. H. Sorensen. "Peripheral primitive neuroectodermal tumors in adults: documentation by molecular analysis." Journal of Clinical Oncology 16, no. 3 (March 1998): 1150–57. http://dx.doi.org/10.1200/jco.1998.16.3.1150.
Анотація:
PURPOSE The Ewing tumor (ET) family of peripheral primitive neuroectodermal tumors (pPNETs) are primitive small round-cell tumors (SRCTs) of the bone and soft tissue that occur predominantly in children and adolescents. However, pPNETs only rarely enter the differential diagnosis of bone and soft tissue SRCTs in adults. Recently, gene fusions between the EWS gene and different members of the ETS transcription factor family have been shown to occur in virtually all pPNETs and thus constitute a pathognomonic marker for this tumor subclass. The aim of the present study was to document EWS/ETS fusion gene expression in suspected pPNETs of adults as objective evidence for the existence of this tumor family in older patients. PATIENTS AND METHODS The three contributing molecular diagnostic laboratories retrospectively compiled a cohort of all SRCT cases in which EWS/ETS gene fusions had been shown by molecular analysis. This cohort was surveyed for cases that occurred in patients aged 40 years or older, which were then analyzed for their clinical and pathologic features. RESULTS Nine patients between 40 and 65 years of age were found to have tumors positive for EWS/ETS gene fusions. Standard histopathologic and clinical features of these cases, other than age, were similar to those of childhood pPNETs. Patients were initiated on appropriate therapy after molecular analysis confirmed the diagnosis of pPNET. CONCLUSION Identification of an EWS/ETS gene fusion is useful in providing objective evidence of the diagnosis of pPNET in patients over the age of 40 years. This diagnosis should be considered in adults who present with bone and soft tissue SRCTs and appropriate biopsy specimens should be collected for molecular analysis at the time of diagnosis.
9
Downing, Nicholas F., Kaitlyn M. Mills, and Peter C. Hollenhorst. "Abstract 3033: Oncogenic ETS transcription factors avoid repression by EZH2 and FOXO1 in prostate cancer and Ewing sarcoma." Cancer Research 84, no. 6_Supplement (March 22, 2024): 3033. http://dx.doi.org/10.1158/1538-7445.am2024-3033.
Анотація:
Abstract ETS transcription factors play roles throughout development, aiding in hematopoiesis, blood vessel formation and cell fate. The ETS family is composed of 28 members, all of which share an ETS DNA-binding domain. Chromosomal rearrangements that lead to the overexpression of specific ETS promote oncogenic transformation and tumor development. More than half of prostate tumors are driven by aberrant expression of an ETS protein. Our lab has demonstrated that oncogenic ETS form essential interactions with a ubiquitous RNA-binding protein, EWS, to promote prostate tumorigenesis. A similar mechanism exists in Ewing sarcoma (ES). ES tumors are driven by the expression EWS/ETS fusion proteins. This project focuses on the similarities and differences between oncogenic ETS in prostate cancer and EWS/ETS fusions in Ewing sarcoma. We compared biological functions of the most common oncogenic ETS in prostate cancer, ERG, and the most common fusion in ES, EWS/FLI1. Both ERG and EWS/FLI1 promoted migration and clonogenic survival in normal prostate epithelial cell lines, RWPE1 and PNT2. These data suggest that the EWS-ERG complex and EWS/FLI1 fusion protein can function similarly in prostate cells. Knockdown of endogenous EWS/FLI1 in the ES cell line, A673, reduced anchorage-independent colony formation in soft agar. Rescue with exogenous EWS/FLI1 or EWS/ERG restored colony formation relative to control. Wildtype ERG was unable to rescue colony formation in A673. This suggests that ERG and EWS/FLI1 function differently in A673 cells. Pulldown assays from A673 lysates reveal that ERG interacts with EZH2 and FOXO1. Our lab has established that ERG acts as a transcriptional repressor through the formation of an ERG-EZH2-PRC2 complex. Others demonstrate that FOXO1 represses ERG activity by reducing its recruitment to the target sites. Both the N-terminal truncation of ERG and phosphorylation of ERG at S96 disrupted these interactions and rescued anchorage independent growth in A673 ES cells. These data suggest that EWS/ETS fusions avoid transcriptional repression in Ewing tumors due to loss of the N-terminus of the ETS protein. Citation Format: Nicholas F. Downing, Kaitlyn M. Mills, Peter C. Hollenhorst. Oncogenic ETS transcription factors avoid repression by EZH2 and FOXO1 in prostate cancer and Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3033.
10
Clark, Jeremy P., and Colin S. Cooper. "ETS gene fusions in prostate cancer." Nature Reviews Urology 6, no. 8 (August 2009): 429–39. http://dx.doi.org/10.1038/nrurol.2009.127.
11
Deneen, Benjamin, Scott M. Welford, Thu Ho, Felicia Hernandez, Irwin Kurland, and Christopher T. Denny. "PIM3 Proto-Oncogene Kinase Is a Common Transcriptional Target of Divergent EWS/ETS Oncoproteins." Molecular and Cellular Biology 23, no. 11 (June 1, 2003): 3897–908. http://dx.doi.org/10.1128/mcb.23.11.3897-3908.2003.
Анотація:
ABSTRACT Despite significant structural diversity, present evidence suggests that EWS/ETS fusion proteins promote oncogenesis by transcriptionally modulating a common set of target genes. In order to identify these genes, microarray expression analyses were performed on NIH 3T3 polyclonal populations expressing one of three EWS/ETS fusion genes. The majority of these genes can be grouped into seven functional categories, including cellular metabolism and signal transduction. The biologic significance of these target genes was pursued. The effects of modulating genes involved in metabolism were assessed by flux studies and demonstrated shifts in glucose utilization and lactate production as a result of EWS/FLI1 expression. The proto-oncogene coding for serine/threonine kinase PIM3 was found to one of several genes encoding signal transduction proteins that were up-regulated by EWS/ETS fusions. PIM3 was found to be expressed in a panel of human Ewing's family tumor cell lines. Forced expression of PIM3 promoted anchorage-independent growth. Coexpression of a kinase-deficient PIM3 mutant attenuated EWS/FLI1-mediated NIH 3T3 tumorigenesis in immunodeficent mice.
12
Mani, Ram-Shankar, Scott A. Tomlins, Kaitlin Callahan, Aparna Ghosh, Mukesh K. Nyati, Sooryanarayana Varambally, Nallasivam Palanisamy, and Arul M. Chinnaiyan. "Induced Chromosomal Proximity and Gene Fusions in Prostate Cancer." Science 326, no. 5957 (October 29, 2009): 1230. http://dx.doi.org/10.1126/science.1178124.
Анотація:
Gene fusions play a critical role in cancer progression. The mechanisms underlying their genesis and cell type specificity are not well understood. About 50% of human prostate cancers display a gene fusion involving the 5′ untranslated region of TMPRSS2, an androgen-regulated gene, and the protein-coding sequences of ERG, which encodes an erythroblast transformation–specific (ETS) transcription factor. By studying human prostate cancer cells with fluorescence in situ hybridization, we show that androgen signaling induces proximity of the TMPRSS2 and ERG genomic loci, both located on chromosome 21q22.2. Subsequent exposure of the cells to gamma irradiation, which causes DNA double-strand breaks, facilitates the formation of the TMPRSS2-ERG gene fusion. These results may help explain why TMPRSS2-ERG fusions are restricted to the prostate, which is dependent on androgen signaling.
13
Hussain, Maha, Stephanie Daignault-Newton, Przemyslaw W. Twardowski, Costantine Albany, Mark N. Stein, Lakshmi P. Kunju, Javed Siddiqui, et al. "Targeting Androgen Receptor and DNA Repair in Metastatic Castration-Resistant Prostate Cancer: Results From NCI 9012." Journal of Clinical Oncology 36, no. 10 (April 1, 2018): 991–99. http://dx.doi.org/10.1200/jco.2017.75.7310.
Анотація:
Purpose To determine whether cotargeting poly (ADP-ribose) polymerase-1 plus androgen receptor is superior to androgen receptor inhibition in metastatic castration-resistant prostate cancer (mCRPC) and whether ETS fusions predict response. Patients and Methods Patients underwent metastatic site biopsy and were stratified by ETS status and randomly assigned to abiraterone plus prednisone without (arm A) or with veliparib (arm B). Primary objectives were: confirmed prostate-specific antigen (PSA) response rate (RR) and whether ETS fusions predicted response. Secondary objectives were: safety, measurable disease RR (mRR), progression-free survival (PFS), and molecular biomarker analysis. A total of 148 patients were randomly assigned to detect a 20% PSA RR improvement. Results A total of 148 patients with mCRPC were randomly assigned: arm A, n = 72; arm B, n = 76. There were no differences in PSA RR (63.9% v 72.4%; P = .27), mRR (45.0% v 52.2%; P = .51), or median PFS (10.1 v 11 months; P = .99). ETS fusions did not predict response. Exploratory analysis of tumor sequencing (80 patients) revealed: 41 patients (51%) were ETS positive, 20 (25%) had DNA-damage repair defect (DRD), 41 (51%) had AR amplification or copy gain, 34 (43%) had PTEN mutation, 33 (41%) had TP53 mutation, 39 (49%) had PIK3CA pathway activation, and 12 (15%) had WNT pathway alteration. Patients with DRD had significantly higher PSA RR (90% v 56.7%; P = .007) and mRR (87.5% v 38.6%; P = .001), PSA decline ≥ 90% (75% v 25%; P = .001), and longer median PFS (14.5 v 8.1 months; P = .025) versus those with wild-type tumors. Median PFS was longer in patients with normal PTEN (13.5 v 6.7 months; P = .02), TP53 (13.5 v 7.7 months; P = .01), and PIK3CA (13.8 v 8.3 months; P = .03) versus those with mutation or activation. In multivariable analysis adjusting for clinical covariates, DRD association with PFS remained significant. Conclusion Veliparib and ETS status did not affect response. Exploratory analysis identified a novel DRD association with mCRPC outcomes.
14
Zhang, Yue. "Article Commentary: ETS-FUSions Networking, Triggering and Beyond." Genetics & Epigenetics 3 (January 2010): GEG.S4166. http://dx.doi.org/10.4137/geg.s4166.
Анотація:
Gene fusion is a hallmark of cancer development with the mechanisms underlying their genesis emerging. The Staege and Max paper together with another recent paper have provided a comprehensive first view on current TET-ETS translocation studies. This significance, the trigering of gene fusion and beyond will be discussed in this article.
15
Feng, Felix Y., J. Chad Brenner, Maha Hussain, and Arul M. Chinnaiyan. "Molecular Pathways: Targeting ETS Gene Fusions in Cancer." Clinical Cancer Research 20, no. 17 (June 23, 2014): 4442–48. http://dx.doi.org/10.1158/1078-0432.ccr-13-0275.
16
Zou, Ying S., Laura Morsberger, Melanie Hardy, Jen Ghabrial, Victoria Stinnett, Jaclyn B. Murry, Patty Long, et al. "Complex/cryptic EWSR1::FLI1/ERG Gene Fusions and 1q Jumping Translocation in Pediatric Ewing Sarcomas." Genes 14, no. 6 (May 24, 2023): 1139. http://dx.doi.org/10.3390/genes14061139.
Анотація:
Ewing sarcomas (ES) are rare small round cell sarcomas often affecting children and characterized by gene fusions involving one member of the FET family of genes (usually EWSR1) and a member of the ETS family of transcription factors (usually FLI1 or ERG). The detection of EWSR1 rearrangements has important diagnostic value. Here, we conducted a retrospective review of 218 consecutive pediatric ES at diagnosis and found eight patients having data from chromosome analysis, FISH/microarray, and gene-fusion assay. Three of these eight ES had novel complex/cryptic EWSR1 rearrangements/fusions by chromosome analysis. One case had a t(9;11;22)(q22;q24;q12) three-way translocation involving EWSR1::FLI1 fusion and 1q jumping translocation. Two cases had cryptic EWSR1 rearrangements/fusions, including one case with a cryptic t(4;11;22)(q35;q24;q12) three-way translocation involving EWSR1::FLI1 fusion, and the other had a cryptic EWSR1::ERG rearrangement/fusion on an abnormal chromosome 22. All patients in this study had various aneuploidies with a gain of chromosome 8 (75%), the most common, followed by a gain of chromosomes 20 (50%) and 4 (37.5%), respectively. Recognition of complex and/or cryptic EWSR1 gene rearrangements/fusions and other chromosome abnormalities (such as jumping translocation and aneuploidies) using a combination of various genetic methods is important for accurate diagnosis, prognosis, and treatment outcomes of pediatric ES.
17
Yoshimoto, M., A. M. Joshua, S. Chilton-Macneill, J. Bayani, M. Prasad, N. Fleshner, A. Finelli, et al. "Detection of novel variant TMPRSS2 /ERG fusion transcripts suggests independent genomic alterations may underlie origin of multi-centric prostate cancer." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 10029. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.10029.
Анотація:
10029 Background: Most of the early successes in identifying chromosomal translocations in neoplasias came from the study of hematological malignancies and sarcomas, with limited evidence that consistent genomic rearrangements were present in epithelial malignancies. Recently it was reported that ∼75% of prostate cancers carry a genomic rearrangement leading to fusion of the TMPRSS2 locus to either the ERG or ETV1 genes (both ETS transcription factors). In the fusion gene, the androgen-sensitive promoter elements of TMPRSS2 are thought to mediate over-expression of these ETS transcription factors. Over-activity of the ETS family of transcription factors has been suggested to be involved in the transition from pre-neoplasia to carcinoma as they regulate genes involved in processes such as adhesion, motility, invasion and angiogenesis. Methods: Using both RT-PCR and FISH with published primers and BACs respectively we analyzed 15 samples of prostatic carcinoma from radical prostatectomies and sequenced a subset of the TMPRSS2/ERG fusions. Results: We have found ERG-TMPRSS2 fusion transcripts in 6 samples and no ETV1-TMPRSS2 fusions. Of the 6 fusion tumours, 5 were Gleason 7 and 1 was Gleason 9. Tumour stages ranged from T2a-T3b. One sample with multi-centric carcinoma exhibited 2 distinct in-frame rearrangements generating novel TMPRSS2 /ERG fusion transcripts. Variant I TMPRSS2/ERG transcript was 430 bp and it led to fusion of exons 1 and 2 of the TMPRSS2 gene with exons 5 and 6 of the ERG gene. Variant II TMPRSS2/ERG fusion transcript was slightly smaller at 350 bp and it led to fusion of exon 1 of the TMPRSS2 gene to exons 5 and 6 of the ERG gene. These novel transcripts appear to be smaller than the published fusion proteins but preliminary analysis suggests that all known regulatory and functional protein domains are maintained. Conclusions: The demonstration of two new TMPRSS2/ERG variant fusion transcripts in prostate cancer deserves further study to evaluate their functional impact and prognostic and pathological importance. Moreover the presence of two distinct transcripts within a single multi-centric tumor provides genomic evidence that independent clonal neoplasms can arise synchronously in prostate cancer. No significant financial relationships to disclose.
18
He, Wei, Fukang Sun, Juping Zhao, Dai Jun, Le Xu, Chenghe Wang, Chen Fang, et al. "Prevalence and genetic features of TMPRSS2-ERG fusion in Chinese patients with prostate cancer." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e17529-e17529. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e17529.
Анотація:
e17529 Background: Prostate cancer (PCa) is one of the most common malignancies, with rising incidence rate in China. The Cancer Genome Atlas (TCGA) revealed 53% of patients with PCa had ETS family gene fusions. The most frequent fusion type of ETS fusions is TMPRSS2-ERG, which may predicts resistance to taxane and androgen-deprivation therapies. The prevalence of TMPRSS2-ERG fusion in Chinese PCa patients evaluated by fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) varied from 7.5% to 78.0%. However, the sample sizes were small. In the present study, we investigated the prevalence and genetic features of TMPRSS2-ERG fusion by next generation sequencing (NGS) in a larger Chinese PCa cohort. Methods: Genomic profiling was performed through NGS from Chinese patients with PCa between January, 2017 and November, 2019. Formalin fixed paraffin-embedded (FFPE) tumor specimens or blood samples from participants were collected for NGS. IHC staining for PD-L1 expression was performed using PD-L1 IHC 22C3 pharmDx assay or Ventana PD-L1 SP263 assay. Data analyses were performed using SPSS and R 3.6.1. Results: A total of 526 Chinese PCa patients were included in this study. The median age was 70 (range, 29-90) years old. We observed 13.1% patients with a positive PD-L1 expression, 3.0% patients with MSI-H, and a median TMB of 4.0 muts/Mb (range: 0-72.9). TMPRSS2 fusions were detected in 47 (8.9%) PCa patients, and 6.8% of patients had TMPRSS2-ERG fusion, which is significantly lower than that of Caucasian patients. The PD-L1 expression pattern and TMB distribution of the TMPRSS2-ERG fusion-positive patients were similar with TMPRSS2-ERG fusion-negative patients, however no fusion-positive patients were identified as MSI-H. Among these 36 TMPRSS2-ERG fusion-positive patients, the most frequently somatic mutations were detected in TP53 (38.9%), AR (11.1%), ATM (11.1%), and PTEN (11.1%). 9 (22.2%) patients harbored somatic mutations in PI3K/ AKT/mTOR pathway that has been previously demonstrated to collaborate with ERG to promote prostate cancer progression. Conclusions: This study revealed the prevalence and genetic features of TMPRSS2-ERG fusion in Chinese PCa patients by NGS in the first time. Our results provide a better understanding of molecular features in Chinese TMPRSS2-ERG fusion-positive PCa patients.
19
Arvand, Afsane, and Christopher T. Denny. "Biology of EWS/ETS fusions in Ewing's family tumors." Oncogene 20, no. 40 (September 2001): 5747–54. http://dx.doi.org/10.1038/sj.onc.1204598.
20
Khosh Kish, Ealia, Muhammad Choudhry, Yaser Gamallat, Sabrina Marsha Buharideen, Dhananjaya D, and Tarek A. Bismar. "The Expression of Proto-Oncogene ETS-Related Gene (ERG) Plays a Central Role in the Oncogenic Mechanism Involved in the Development and Progression of Prostate Cancer." International Journal of Molecular Sciences 23, no. 9 (April 26, 2022): 4772. http://dx.doi.org/10.3390/ijms23094772.
Анотація:
The ETS-related gene (ERG) is proto-oncogene that is classified as a member of the ETS transcription factor family, which has been found to be consistently overexpressed in about half of the patients with clinically significant prostate cancer (PCa). The overexpression of ERG can mostly be attributed to the fusion of the ERG and transmembrane serine protease 2 (TMPRSS2) genes, and this fusion is estimated to represent about 85% of all gene fusions observed in prostate cancer. Clinically, individuals with ERG gene fusion are mostly documented to have advanced tumor stages, increased mortality, and higher rates of metastasis in non-surgical cohorts. In the current review, we elucidate ERG’s molecular interaction with downstream genes and the pathways associated with PCa. Studies have documented that ERG plays a central role in PCa progression due to its ability to enhance tumor growth by promoting inflammatory and angiogenic responses. ERG has also been implicated in the epithelial–mesenchymal transition (EMT) in PCa cells, which increases the ability of cancer cells to metastasize. In vivo, research has demonstrated that higher levels of ERG expression are involved with nuclear pleomorphism that prompts hyperplasia and the loss of cell polarity.
21
Khosh Kish, Ealia, Muhammad Choudhry, Yaser Gamallat, Sabrina Marsha Buharideen, Dhananjaya D, and Tarek A. Bismar. "The Expression of Proto-Oncogene ETS-Related Gene (ERG) Plays a Central Role in the Oncogenic Mechanism Involved in the Development and Progression of Prostate Cancer." International Journal of Molecular Sciences 23, no. 9 (April 26, 2022): 4772. http://dx.doi.org/10.3390/ijms23094772.
Анотація:
The ETS-related gene (ERG) is proto-oncogene that is classified as a member of the ETS transcription factor family, which has been found to be consistently overexpressed in about half of the patients with clinically significant prostate cancer (PCa). The overexpression of ERG can mostly be attributed to the fusion of the ERG and transmembrane serine protease 2 (TMPRSS2) genes, and this fusion is estimated to represent about 85% of all gene fusions observed in prostate cancer. Clinically, individuals with ERG gene fusion are mostly documented to have advanced tumor stages, increased mortality, and higher rates of metastasis in non-surgical cohorts. In the current review, we elucidate ERG’s molecular interaction with downstream genes and the pathways associated with PCa. Studies have documented that ERG plays a central role in PCa progression due to its ability to enhance tumor growth by promoting inflammatory and angiogenic responses. ERG has also been implicated in the epithelial–mesenchymal transition (EMT) in PCa cells, which increases the ability of cancer cells to metastasize. In vivo, research has demonstrated that higher levels of ERG expression are involved with nuclear pleomorphism that prompts hyperplasia and the loss of cell polarity.
22
Zhang, Zhusheng, Qiyuan Bao, Junxiang Wen, Zhuochao Liu, Qi Liu, Yuhui Shen, Lin Shao, Bing Li, Song-An Chen, and Weibin Zhang. "Abstract 4545: Integrative immune-genomic comparison of canonical Ewing sarcoma with Ewing-like mimics identifies potential targets for personalized therapies." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4545. http://dx.doi.org/10.1158/1538-7445.am2023-4545.
Анотація:
Abstract Introduction: Ewing sarcoma (ES) is one of the most common types of small round cell sarcoma (SRCS) from the skeletal origin, characterized by small round blue cell morphology and FET-ETS fusions. However, recent NGS-based technology has dramatically increased the characterization of other SRCS entities that share morphological, pathological, and clinical similarity with canonical ES. Currently, these sarcomas are often treated with similar regimens derived from ES. Whether any subsets of these sarcomas might benefit from personalized anti-cancer strategies remains largely unknown. Methods: To explore potential therapeutic vulnerabilities, 51 FFPE samples from 49 patients (median age 31 years, 65.3% male) diagnosed as ES or its mimics by conventional pathology review were sent to DNA (OncoScreen®Plus) and RNA sequencing (OncoRNA, Burning Rock Biotech) for genomic and immune signature profiling. Tumor samples were classified into 5 groups based on their similarity with classic ES: (a) Canonical ES (n=12), defined as ES with EWSR1-FLI1fusion and a primary bone origin; (b) Non-canonical ES, which were found with either non-EWSR1-FLI1 FET-ETS fusion, or ES in extra-skeletal sites (n=11); (c) Non-FET-ETS fusion SRCS (n=10), defined as SRCS with gene fusions other than FET-ETS family; (d) Fusion-negative SRCS (n=4); and (e) non-SRCS, where the diagnosis was primarily suspected as ES but finally re-diagnosed as another histology (n=12). Results: The NGS-based diagnosis rectified the pathological diagnosis in 9/51 samples, including ES misdiagnosed as other (n=3), other misdiagnosed as ES (n=4), Non-FET-ETS fusion SRCS misdiagnosed as ES (n=1) and ALK fusion sarcoma misdiagnosed as SRCS (n=1). In the remaining 42 samples, 23 diagnoses were confirmed by both NGS and FISH, while 11 SRCS were negative in both NGS and FISH assay, yielding a concordance of 81.0% (34/42). In the 8 samples with discordant diagnosis, a definitive diagnosis was achieved by FISH but not NGS in 1 of 8 (12.5%), and vice versa in 7 of 8 (87.5%). Interestingly, genomic profiling revealed that Non-FET-ETS fusion SRCS had high frequencies of TP53 mutations (40%) and copy number loss (including 30% in CD274 and JAK2; 20% in PTCH1, CDKN2A/B, and MTAP) and featured higher levels of homologous recombination deficiency (HRD) (p=0.024) and chromosome instability (p=0.022) than other groups. Remarkably, non-canonical ES demonstrated upregulated PDCD1 expression (p=0.034). The distribution of immune hot and cold subtypes was comparable among all groups (p=0.334). Conclusion: Our study shows that NGS could efficiently facilitate the definitive diagnosis of ES and its mimics. We also revealed a diverse immune-genomic landscape of these SRCS, indicative of potential therapeutic opportunities targeting HRD and immune check-point in specific subtypes of these sarcoma entities. Citation Format: Zhusheng Zhang, Qiyuan Bao, Junxiang Wen, Zhuochao Liu, Qi Liu, Yuhui Shen, Lin Shao, Bing Li, Song-An Chen, Weibin Zhang. Integrative immune-genomic comparison of canonical Ewing sarcoma with Ewing-like mimics identifies potential targets for personalized therapies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4545.
23
Le Deley, Marie-Cecile, Olivier Delattre, Karl-Ludwig Schaefer, Sue A. Burchill, Gabriele Koehler, Pancras C. W. Hogendoorn, Thomas Lion, et al. "Impact of EWS-ETS Fusion Type on Disease Progression in Ewing's Sarcoma/Peripheral Primitive Neuroectodermal Tumor: Prospective Results From the Cooperative Euro-E.W.I.N.G. 99 Trial." Journal of Clinical Oncology 28, no. 12 (April 20, 2010): 1982–88. http://dx.doi.org/10.1200/jco.2009.23.3585.
Анотація:
Purpose EWS-ETS fusion genes are the driving force in Ewing's sarcoma pathogenesis. Because of the variable breakpoint locations in the involved genes, there is heterogeneity in fusion RNA and protein architecture. Since previous retrospective studies suggested prognostic differences among patients expressing different EWS-FLI1 fusion types, the impact of fusion RNA architecture on disease progression and relapse was studied prospectively within the Euro-E.W.I.N.G. 99 clinical trial. Patients and Methods Among 1,957 patients who registered before January 1, 2007, 703 primary tumors were accessible for the molecular biology study. Fusion type was assessed by polymerase chain reaction on frozen (n = 578) or paraffin-embedded materials (n = 125). The primary end point was the time to disease progression or relapse. Results After exclusion of noninformative patients, 565 patients were entered into the prognostic factor analysis comparing type 1 (n = 296), type 2 (n = 133), nontype 1/nontype 2 EWS-FLI1 (n = 91) and EWS-ERG fusions (n = 45). Median follow-up time was 4.5 years. The distribution of sex, age, tumor volume, tumor site, disease extension, or histologic response did not differ between the four fusion type groups. We did not observe any significant prognostic value of the fusion type on the risk of progression or relapse. The only slight difference was that the risk of progression or relapse associated with nontype 1/nontype 2 EWS-FLI1 fusions was 1.38 (95% CI, 0.96 to 2.0) times higher than risk associated with other fusion types, but it was not significant (P = .10). Conclusion In contrast to retrospective studies, the prospective evaluation did not confirm a prognostic benefit for type 1 EWS-FLI1 fusions.
24
Anderson, Peter Meade, Luisa-Marie Manning, Brian Rubin, Timothy A. Chan, Scott E. Kilpatrick, Rabi Hanna, and Zheng Jin Tu. "Nested set information derived from fusion genes in Ewing sarcoma and other cancers." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e23521-e23521. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e23521.
Анотація:
e23521 Background: Ewing family tumors including Ewing sarcoma (ES) and desmoplastic small round cell tumor (DSRCT) are characterized by EWSR1 and ETS fusion partners including EWS-FLI1, EWS-ERG, EWS-WT1, and others. Since 2019 our Next Generation Sequencing (NGS) sarcoma panel (N = 338) identified both fusion partners and exons containing the EWS breakpoint in ES and DSRCT. Hence, it should be possible to learn more about the exact breakpoints of EWS fusion genes. The molecular diversity and functionality of these fusion transcripts, especially the exact sequence, which could be identical, similar, or unique, may have significant biological implications for diagnostics and treatment options. We have used in-frame analysis of EWS gene fusion breakpoints to identify corresponding polypeptides spanning the breakpoints of the most common EWS gene fusions to provide useful insights about ES and DSRCT. Methods: Pathology reports and EWS gene fusions were analyzed using the Cleveland Clinic NGS panel which is based on anchored multiplex polymerase chain reaction (PCR) enriched for 34 gene targets. The amplicons were subjected to massively parallel sequencing with 151x2 cycle pair-end reads. An informatics pipeline was used for read alignment (GRCh37 as reference genome), fusion identification, and annotation. The DNA sequence across fusion junction and translational amino acid sequences were extracted for comparison in a preliminary teaching set (37/338 EWS fusions). Results: EWS-FLI1 fusions at exon 7-7 (chr22:29683123-chr11:128675261) and exon 7-6 (chr22:29683123-chr11:128651853) were the most common fusion genes in ES (N = 24/32;75%). Other ES gene fusions included exons 10-6, 7-10, 9-8, 7-2 EWS-FEV, 7-8 EWS-ERG, 7-9 EWS-ERG, and 10-9 EWS-ERG. EWS-WT1 gene fusions (chr22:29683123-chr11:32414301) in DSRCT exon 7-7 occurred in 4 of 5 cases (80%). In frame analysis of the common gene fusions in 75% of ES and DSRCT (total n = 37) yielded identical corresponding polypeptides that span the breakpoint (table). Conclusions: Analysis of ES and DSRCT fusion genes provides evidence that cancer-specific fusion genes are associated with common identical breakpoints and corresponding in-frame polypeptides. Our results show that the identification of in-frame polypeptides from the fusion gene sequencing can identify potential nested sets of cancer-specific mRNAs and polypeptides. This information may become relevant for diagnostic and therapeutic targets future vaccines and diagnostics against ES and DSRCT as well as other cancers characterized by fusion genes or frameshift mutations. [Table: see text]
25
Feng, Felix Yi-Chung, Scott Tomlins, Mohammed Alshalalfa, Nicholas Erho, Kasra Yousefi, Shuang Zhao, Robert Benjamin Den, et al. "Molecular and clinical characterization of 1,577 primary prostate cancer tumors to reveal novel clinical and biological insights into its subtypes." Journal of Clinical Oncology 33, no. 7_suppl (March 1, 2015): 9. http://dx.doi.org/10.1200/jco.2015.33.7_suppl.9.
Анотація:
9 Background: Prostate cancer molecular subtypes based on ETS gene fusions and SPINK1 were originally identified through outlier gene expression profiling analysis. Such molecular subtypes may have utility in disease stratification and clonality assessment, complementing available purely prognostic tests. Hence, we determined the analytical validity of molecular subtyping in a large sample of PCa treated with radical prostatectomy. Methods: We analyzed Affymetrix Human Exon 1.0ST GeneChip expression profiles for 1,577 patients from 8 radical prostatectomy (RP) cohorts. Multi-feature random forest classifiers and outlier analysis were used to define microarray-based molecular subtypes. Results: A random forest (RF) classifier was trained and validated to predict ERG fusion status using a subset with known ERG rearrangement status defined by FISH, achieving >95% sensitivity and specificity in the validation subset. Less frequent rearrangements involving other ETS genes or SPINK1 over-expression were predicted based on gene expression outlier analysis. Across cohorts, 45%, 9% 8% and 38% of PCa were classified as ERG+, ETS+, SPINK+, and Triple Negative, respectively. Global gene expression analysis shows that the four subtypes could be collapsed into three entities (ERG+, ETS+ and SPINK+/Triple Negative) based on expression patterns and clinical characteristics similarity. A series of multivariable analyses further revealed, ERG+ to be associated with lower pre PSA and Gleason scores but more likely to have EPE and occur in patients with European American ancestry compared to the ETS+, SPINK+/Triple Negative tumors (p<0.001). In contrast, patients with ETS+ were more likely to have SVI compared to both ERG+ and SPINK/Triple Negative (p=0.01), while SPINK+/Triple Negative had higher Gleason scores and were more likely to occur in African Americans (p<0.001). Conclusions: The Decipher platform can accurately determine ERG rearrangement status and PCa molecular subtypes. Inclusion of molecular subtyping, such as m-ERG status, may enable additional precision medicine opportunities in prognostic tests
26
Smit, F. P., M. Salagierski, D. Hessels, S. A. Jannink, and J. A. Schalken. "786 IDENTIFICATION OF ETS GENE FUSIONS USING AFFYMETRIX EXON 1.0 ARRAYS." European Urology Supplements 8, no. 4 (March 2009): 317. http://dx.doi.org/10.1016/s1569-9056(09)60774-0.
27
Hammer, Liat, Ryan Rebernick, Matthew McFarlane, Thomas Westbrook, Munna Hazime, Tanya Hammoud, Pin-en Chiu, et al. "Clinical impact of mutations in driver oncogenes and TP53/RB1 in advanced prostate cancer." Journal of Clinical Oncology 41, no. 6_suppl (February 20, 2023): 263. http://dx.doi.org/10.1200/jco.2023.41.6_suppl.263.
Анотація:
263 Background: Prostate cancer (PCa) is characterized by considerable genetic heterogeneity, and complex genomic features may influence prognosis and treatment response. We created a database of aggressive PCa that integrates comprehensive genomic sequencing with detailed clinical outcomes to better understand the optimal use of genomic sequencing. Methods: From 4/2005-7/2021, PCa cancer patients older than 18 years of age underwent tissue collection for tumoral RNA-sequencing and tumor/normal whole exome sequencing at our institution (HUM00046018, HUM00048105, HUM00067928, SU2C). Genomic and transcriptomic sequencing data was processed using Turnkey Precision Oncology. Genetic alterations, including ETS fusions, SPOP, FOXA1 class 1, and CDK12 mutations, as well as TP53 and RB1 mutations were analyzed. Clinical data was collected from 05/2021-01/2022, and clinical associations (metastasis free survival (MFS), time to castrate resistant prostate cancer (CRPC), and overall survival (OS)) were determined. Results: Data was available for 325 men. Median follow up from diagnosis was 106 months (IQR, 90-121), median age at diagnosis was 61 (IQR, 54-67), and most (91%) presented with PCa adenocarcinoma (n=292/325). At diagnosis, 51% (n=165) had localized, 5% (n=18) had clinical node positive, and 40% (n=128) had de-novo M1 disease. At time of tissue sampling, 87% (n=283) had metastatic disease, and 59% (n=192) were castrate resistant. Established PCa driver mutations included 140 ETS fusions (49%), 26 SPOP mutations (9%), 22 FOXA1 class 1 mutations (8%), and 15 (5%) CDK12 mutations. For men with localized disease at diagnosis (n=197/325), ETS fusion was associated with improved MFS (HR: 0.55; 95% CI: 0.37-0.81), time to CRPC (HR: 0.53; 0.35-0.80), and OS (HR: 0.56; 0.35-0.89). SPOP mutations were also associated with improved prognosis in this population (n=197/325): MFS (HR: 0.45; 0.24-0.84), time to CRPC (HR: 0.36; 0.18-0.73), and OS (HR: 0.46; 0.21-0.99). TP53 mutations were identified in 38% (n=122) of all patients and were associated with worse OS from the time of biopsy after adjusting for PCa castration state and disease spread at biopsy (HR: 2.2; 1.7-2.9, p<0.001). RB1 mutations were identified in 12% (n=40; 24/40 also TP53 mutants). OS from the time of biopsy was worse in the presence of dual TP53/RB1 mutants when compared to TP53 or RB1 mutants alone, independent of the disease state at time of biopsy (HR, 4.3; 95%CI: 2.7-7.0). Conclusions: In a cohort of aggressive PCa, oncogenic driver mutations were associated with significant differences in prognosis. ETS fusions and SPOP mutations correlated with improved outcomes for men with localized disease at presentation. TP53 loss was associated with worse prognosis, as was the combination with RB1 loss, across the disease spectrum. Future efforts will focus on correlating sensitivity to PCa treatments with genetic alterations throughout the disease course.
28
Ho, Jen M. Y., Bryan K. Beattie, Jeremy A. Squire, David A. Frank, and Dwayne L. Barber. "Fusion of the ets Transcription Factor TEL to Jak2 Results in Constitutive Jak-Stat Signaling." Blood 93, no. 12 (June 15, 1999): 4354–64. http://dx.doi.org/10.1182/blood.v93.12.4354.
Анотація:
Abstract To study constitutive Janus kinase signaling, chimeric proteins were generated between the pointed domain of the etstranscription factor TEL and the cytosolic tyrosine kinase Jak2. The effects of these proteins on interleukin-3 (IL-3)–dependent proliferation of the hematopoietic cell line, Ba/F3, were studied. Fusion of TEL to the functional kinase (JH1) domain of Jak2 resulted in conversion of Ba/F3 cells to factor-independence. Importantly, fusion of TEL to the Jak2 pseudokinase (JH2) domain or a kinase-inactive Jak2 JH1 domain had no effect on IL-3–dependent proliferation of Ba/F3 cells. Active TEL-Jak2 constructs (consisting of either Jak2 JH1 or Jak2 JH2+JH1 domain fusions) were constitutively tyrosine-phosphorylated but did not affect phosphorylation of endogeneous Jak1, Jak2, or Jak3. TEL-Jak2 activation resulted in the constitutive tyrosine phosphorylation of Stat1, Stat3, and Stat5 as determined by detection of phosphorylation using activation-specific antibodies and by binding of each protein to a preferential GAS sequence in electrophoretic mobility shift assays. Elucidation of signaling events downstream of TEL-Jak2 activation may provide insight into the mechanism of leukemogenesis mediated by this oncogenic fusion protein.
29
Ho, Jen M. Y., Bryan K. Beattie, Jeremy A. Squire, David A. Frank, and Dwayne L. Barber. "Fusion of the ets Transcription Factor TEL to Jak2 Results in Constitutive Jak-Stat Signaling." Blood 93, no. 12 (June 15, 1999): 4354–64. http://dx.doi.org/10.1182/blood.v93.12.4354.412k30_4354_4364.
Анотація:
To study constitutive Janus kinase signaling, chimeric proteins were generated between the pointed domain of the etstranscription factor TEL and the cytosolic tyrosine kinase Jak2. The effects of these proteins on interleukin-3 (IL-3)–dependent proliferation of the hematopoietic cell line, Ba/F3, were studied. Fusion of TEL to the functional kinase (JH1) domain of Jak2 resulted in conversion of Ba/F3 cells to factor-independence. Importantly, fusion of TEL to the Jak2 pseudokinase (JH2) domain or a kinase-inactive Jak2 JH1 domain had no effect on IL-3–dependent proliferation of Ba/F3 cells. Active TEL-Jak2 constructs (consisting of either Jak2 JH1 or Jak2 JH2+JH1 domain fusions) were constitutively tyrosine-phosphorylated but did not affect phosphorylation of endogeneous Jak1, Jak2, or Jak3. TEL-Jak2 activation resulted in the constitutive tyrosine phosphorylation of Stat1, Stat3, and Stat5 as determined by detection of phosphorylation using activation-specific antibodies and by binding of each protein to a preferential GAS sequence in electrophoretic mobility shift assays. Elucidation of signaling events downstream of TEL-Jak2 activation may provide insight into the mechanism of leukemogenesis mediated by this oncogenic fusion protein.
30
Yaseen, Nabeel R., Akiko Takeda, Reza Nazari, Helen Shio, Gunter Blobel, and Hualin Zhong. "Carrier-Independent Nuclear Import of the Transcription Factor PU.1." Blood 104, no. 11 (November 16, 2004): 3561. http://dx.doi.org/10.1182/blood.v104.11.3561.3561.
Анотація:
Abstract PU.1 is a transcription factor of the Ets family with important functions in hematopoietic cell differentiation. Using GFP-PU.1 fusions, we show that the Ets DNA-binding domain of PU.1 is necessary and sufficient for its nuclear localization. Fluorescence and ultrastructural nuclear import assays showed that PU.1 nuclear import requires energy but not soluble carriers. PU.1 interacted with the FG repeats of nucleoporins Nup62 and Nup153. The binding of PU.1 to Nup153, but not to Nup62, dramatically increased in the presence of RanGMPPNP, indicating the formation of a PU.1/RanGTP/Nup153 complex. The Ets domain accounted for the bulk of the interaction of PU.1 with Nup153 and RanGMPPNP. Since Nup62 is located close to the midplane of the nuclear pore complex (NPC) while Nup153 is at its nuclear side, these findings suggest a model whereby RanGTP propels PU.1 towards the nuclear side of the NPC by increasing its affinity for Nup153. This notion was confirmed by ultrastructural studies using gold-labeled PU.1 in permeabilized cells.
31
Feng, F. Y., S. Han, C. Brenner, A. Sabolch, D. A. Hamstra, T. S. Lawrence, and A. Chinnaiyan. "PARP inhibition reverses radiation resistance conferred by ETS fusions in prostate cancer." Journal of Clinical Oncology 29, no. 15_suppl (May 20, 2011): 4545. http://dx.doi.org/10.1200/jco.2011.29.15_suppl.4545.
32
Tomlins, Scott A., Anders Bjartell, Arul M. Chinnaiyan, Guido Jenster, Robert K. Nam, Mark A. Rubin, and Jack A. Schalken. "ETS Gene Fusions in Prostate Cancer: From Discovery to Daily Clinical Practice." European Urology 56, no. 2 (August 2009): 275–86. http://dx.doi.org/10.1016/j.eururo.2009.04.036.
33
Dong, Rongfang, Lan Li, Lihua Gong, Mengmeng Tian, Tingting Zhang, Wen Zhang, and Yi Ding. "Abstract 2152: Targetable oncogenic fusions and other alterations in bone and soft-tissue tumors assessed by RNA and DNA-based next-generation sequencing in real-world experience." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2152. http://dx.doi.org/10.1158/1538-7445.am2023-2152.
Анотація:
Abstract Background: Bone and soft-tissue tumors, especially soft-tissue sarcoma may have an underlying genetic mechanism, where fusion oncoproteins serve as drivers of the disease. This genetic simplicity provides an exceptional opportunity to develop effective and specific therapies. Here, we used RNA and DNA- based next-generation sequencing (NGS) to identify potentially druggable oncogene fusions in our patients that can be used for clinical trial involvement. Methods: Pediatric and adult patients with bone and soft tissue tumors treated in our hospital undergoing biopsy or surgery were enrolled. Fusion transcript detection and mutation analysis in formalin-fixed, paraffin-embedded (FFPE) tumor samples were studied by both DNA-based next-generation sequencing (NGS) assay (520-gene panel) (Burning Rock OncoScreen Plus, Burning Rock Biotech, China) and targeted RNA platform (115 fusion-related-gene panel) (OncoRNA, Burning Rock Biotech, China) to identify additional molecular alterations and to potentially aid in patient management. Results: Among 99 enrolled patients (108 tissue samples), 62.6% of patients were diagnosed as soft-tissue sarcoma. DNA-based NGS detected 108 tissue samples from 99 patients. RNA-based NGS successfully detected 99 samples from 91 patients, excluding 9 RNA-degraded samples. Oncogenic fusions were identified in 50.5% (46/91) of patients by RNA-based NGS. At least 2 kinds of fusion transcripts were detected in 18 patients. The fusion transcripts in only 5 cases detected by DNA-based NGS matched with the results by RNA-based NGS. The most frequent fusion partners were EWSR1 (n=12), DDIT3 (n=7), and PLAG1 (n=6). Six patients (6.6%) with druggable or potential druggable fusion for genetically matched therapies, including a case of NTRK-rearranged neoplasm patient with ETV6::NTRK3 fusion (TRK inhibitors), two cases of spindle cell tumors with RAF1 fusions (MEK inhibitors), a case of Ewing sarcoma with EWSR1::FLI1 fusion (ETS inhibitors), a case of FGFR1 fusion (FGFR inhibitors) and a case of ALK fusion (ALK inhibitors). A total of 50 patients were identified with actionable alterations by DNA-based NGS. Actionable alterations were most often located in MDM2 amplification (n=13), CDK4 amplification (n=12), and CDKN2A deletion (n=8). Conclusion: The combination of RNA and DNA-based NGS techniques brings relevant information about tumor molecular alterations into the precision management of patients with bone and soft-tissue tumors. Those with tumors harboring targetable gene fusions and other alterations may benefit from target therapy, especially in the case of limited or exhausted standard therapy. Citation Format: Rongfang Dong, Lan Li, Lihua Gong, Mengmeng Tian, Tingting Zhang, Wen Zhang, Yi Ding. Targetable oncogenic fusions and other alterations in bone and soft-tissue tumors assessed by RNA and DNA-based next-generation sequencing in real-world experience [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2152.
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Bilke, Sven, Raphaela Schwentner, Fan Yang, Maximilian Kauer, Gunhild Jug, Robert L. Walker, Sean Davis, et al. "Oncogenic ETS fusions deregulate E2F3 target genes in Ewing sarcoma and prostate cancer." Genome Research 23, no. 11 (August 12, 2013): 1797–809. http://dx.doi.org/10.1101/gr.151340.112.
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Tomlins, Scott A., Bharathi Laxman, Saravana M. Dhanasekaran, Beth E. Helgeson, Xuhong Cao, David S. Morris, Anjana Menon, et al. "Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer." Nature 448, no. 7153 (August 2007): 595–99. http://dx.doi.org/10.1038/nature06024.
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Dehm, Scott M. "Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer." Urologic Oncology: Seminars and Original Investigations 26, no. 6 (November 2008): 687–88. http://dx.doi.org/10.1016/j.urolonc.2008.09.003.
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Dong, Jun, Li Xiao, Lu Sheng, Jun Xu, and Zhong-Quan Sun. "TMPRSS2:ETS Fusions and Clinicopathologic Characteristics of Prostate Cancer Patients from Eastern China." Asian Pacific Journal of Cancer Prevention 15, no. 7 (April 1, 2014): 3099–103. http://dx.doi.org/10.7314/apjcp.2014.15.7.3099.
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Dan, Yuqing, Ruibao Ren, Donghe Li, and Ping Liu. "Novel Fusion Gene Aven-NUTM1 Induces Mice Myeloid Leukemia Vulnerable to HDAC Inhibitors." Blood 142, Supplement 1 (November 28, 2023): 4123. http://dx.doi.org/10.1182/blood-2023-188034.
Анотація:
Chromosomal rearrangements involving the NUTM1 gene produce fusion genes commonly found in NUT carcinoma. While recurring NUTM1 fusions have been reported in other neoplasms, including AML, their roles in leukemogenesis remain unclear. We identified the AVEN-NUTM1 (AN) fusion gene in an AML patient resistant to standard chemotherapy, and went to assess AN's leukemogenicity via bone marrow transduction and transplantation. Mice transplanted with AN-transduced hematopoietic stem/progenitor cells (HSPCs) developed transplantable myeloid leukemia with a median survival of 342 days. RNA sequencing revealed downregulation of genes related to hematopoietic cell lineage commitment and upregulation of genes related to early hematopoietic progenitors and MYC-targeted genes in AN-transformed leukemic cells. Co-immunoprecipitation confirmed that AVEN-NUTM1 can interact with and activate EP300 as previously reported. To determine whether AN's interaction with EP300 is related to its ability to induce malignant transformation, we mutated the interaction site and constructed mutants of other structural domains. Colony-forming and replating assays showed that HSPCs expressing AN with mutations in the EP300 binding site lost their ability to self-renew and form colonies. A CUT&RUN assay followed by sequencing showed that the most enriched motif in overlapping peaks between AN and EP300 were ETS motifs, suggesting the involvement of an ETS transcription factor family member in AN-activated EP300-induced leukemia. We further found that both the patient's primary cells and bone marrow cells from leukemic mice were especially vulnerable to HDAC inhibitors. These results demonstrate that the AVEN-NUTM1 fusion gene can drive the development of myeloid leukemia in mice, AN's ability to bind and activate P300 is closely linked to its leukemogenicity, and that HDAC inhibitors are effective in targeting AN leukemia cells. The study provids valuable insights for the targeted treatment of NUTM1-related leukemia patients.
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Cools, Jan, Chrystèle Bilhou-Nabera, Iwona Wlodarska, Christine Cabrol, Pascaline Talmant, Philippe Bernard, Anne Hagemeijer, and Peter Marynen. "Fusion of a Novel Gene, BTL, to ETV6 in Acute Myeloid Leukemias With a t(4;12)(q11-q12;p13)." Blood 94, no. 5 (September 1, 1999): 1820–24. http://dx.doi.org/10.1182/blood.v94.5.1820.
Анотація:
Abstract The ETV6 gene (also known as TEL) is the main target of chromosomal translocations affecting chromosome band 12p13. The rearrangements fuse ETV6 to a wide variety of partner genes in both myeloid and lymphoid malignancies. We report here 4 new cases of acute myeloid leukemia (AML) with very immature myeloblasts (French-American-British [FAB]-M0) and with a t(4;12)(q11-q12;p13). In all cases, ETV6 was found recombined to a new gene, homologous to the mouse Brx gene. The gene was named BTL (Brx-likeTranslocated in Leukemia). Reverse transcriptase-polymerase chain reaction (RT-PCR) experiments indicate that the expression of the BTL-ETV6 transcript, but not of the reciprocal ETV6-BTL transcript, is a common finding in these leukemias. In contrast to the majority of other ETV6 fusions, both the complete helix-loop-helix (HLH) and ETS DNA binding domains of ETV6 are present in the predicted BTL-ETV6 fusion protein, and the chimeric gene is transcribed from theBTL promoter.
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Cools, Jan, Chrystèle Bilhou-Nabera, Iwona Wlodarska, Christine Cabrol, Pascaline Talmant, Philippe Bernard, Anne Hagemeijer, and Peter Marynen. "Fusion of a Novel Gene, BTL, to ETV6 in Acute Myeloid Leukemias With a t(4;12)(q11-q12;p13)." Blood 94, no. 5 (September 1, 1999): 1820–24. http://dx.doi.org/10.1182/blood.v94.5.1820.417k09_1820_1824.
Анотація:
The ETV6 gene (also known as TEL) is the main target of chromosomal translocations affecting chromosome band 12p13. The rearrangements fuse ETV6 to a wide variety of partner genes in both myeloid and lymphoid malignancies. We report here 4 new cases of acute myeloid leukemia (AML) with very immature myeloblasts (French-American-British [FAB]-M0) and with a t(4;12)(q11-q12;p13). In all cases, ETV6 was found recombined to a new gene, homologous to the mouse Brx gene. The gene was named BTL (Brx-likeTranslocated in Leukemia). Reverse transcriptase-polymerase chain reaction (RT-PCR) experiments indicate that the expression of the BTL-ETV6 transcript, but not of the reciprocal ETV6-BTL transcript, is a common finding in these leukemias. In contrast to the majority of other ETV6 fusions, both the complete helix-loop-helix (HLH) and ETS DNA binding domains of ETV6 are present in the predicted BTL-ETV6 fusion protein, and the chimeric gene is transcribed from theBTL promoter.
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Thompson, Andrew D., Michael A. Teitell, Afsane Arvand, and Christopher T. Denny. "Divergent Ewing's sarcoma EWS/ETS fusions confer a common tumorigenic phenotype on NIH3T3 cells." Oncogene 18, no. 40 (September 1999): 5506–13. http://dx.doi.org/10.1038/sj.onc.1202928.
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Braunreiter, Chi L., Jeffery D. Hancock, Cheryl Coffin, Kenneth M. Boucher, and Stephen L. Lessnick. "Expression of EWS-ETS Fusions in NIH3T3 Cells Reveals Significant Differences to Ewing’s Sarcoma." Cell Cycle 5, no. 23 (November 17, 2006): 2753–59. http://dx.doi.org/10.4161/cc.5.23.3505.
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Paulo, Paula, João D. Barros-Silva, Franclim R. Ribeiro, João Ramalho-Carvalho, Carmen Jerónimo, Rui Henrique, Guro E. Lind, Rolf I. Skotheim, Ragnhild A. Lothe, and Manuel R. Teixeira. "FLI1 is a novel ETS transcription factor involved in gene fusions in prostate cancer." Genes, Chromosomes and Cancer 51, no. 3 (November 12, 2011): 240–49. http://dx.doi.org/10.1002/gcc.20948.
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Seligson, Nathan David, Richard D. Maradiaga, Colin W. Stets, Howard Katzenstein, Sherri Z. Millis, John L. Hays, and James Lin Chen. "Multiscale omic assessment of EWSR1-NFATc2 fusion positive sarcomas to identify conserved fusion breakpoint and activation of the mTOR pathway." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e23536-e23536. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e23536.
Анотація:
e23536 Background: EWSR1-NFATc2 ( E-N) fusion positive sarcomas are rare cancers historically categorized as Ewing sarcomas. Emerging evidence suggests unique molecular characteristics and chemotherapy sensitivities in these cancers. Here we present the largest cohort of genomically profiled E-N fusion positive sarcomas and evaluate their breakpoints and putative pathway alterations. Methods: Comprehensive genomic profiling of 1,024 EWSR1 fusion positive sarcomas, including 14 E-N fusions, was obtained through the Foundation Medicine research database (FMI). Additional data from the Gene Expression Omnibus, the Genomics of Drug Sensitivity in Cancer (GDSC), and The Cancer Genome Atlas (TCGA) datasets were used. Descriptive statistics, principle component analysis, differential expression, and pathway analysis were used as appropriate. Results: E-N fusions identified in the FMI database demonstrated consistent breakpoints located between exon 2 and 3 on NFATc2; consistent with previous reports suggesting that the primary transactivation domain and regulatory domains of NFATc2 are conserved in the EWRS1-NFATc2 fusion. Cluster analysis demonstrated separate E-N fusion positive sarcoma grouping than other EWRS1 sarcomas, while identifying an enrichment of mTOR pathway variants in E-N fusion positive samples (p = 0.05). Gene expression data from E-N identified a significant activation of the mTOR pathway in E-N positive sarcomas compared to either EWSR1-ETS (p = 0.002) or CIC-DUX4 positive sarcomas (p < 0.001). In the GDSC database, NFATc2-High lines exhibited activation of the mTOR pathway (p < 0.0001) and were more sensitive to the mTOR inhibitor rapamycin (p = 0.0006). Pan-cancer analysis of 33 non-overlapping TCGA datasets, elevated NFATc2 mRNA expression was significantly associated with activated RICTOR and mTOR signaling (p < 0.0001). Elevated NFATc2 correlated with higher tumor grade and poorer progression-free survival and overall survival. Conclusions: Taken together, the data presented here suggests that E-N fusion positive sarcomas represent a distinct molecularly entity in comparison to traditional Ewing sarcomas. Conserved action of NFATc2 may correlate to mTOR over activation.
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GUO, Xiao-Qiang, Yao-Ting GUI, and Zhi-Ming CAI. "The progress of TMPRSS2-ETS gene fusions and their mechanism in prostate cancer." Hereditas (Beijing) 33, no. 2 (May 5, 2011): 117–22. http://dx.doi.org/10.3724/sp.j.1005.2011.00117.
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Pflueger, D., S. Terry, A. Sboner, L. Habegger, R. Esgueva, P. C. Lin, M. A. Svensson, et al. "Discovery of non-ETS gene fusions in human prostate cancer using next-generation RNA sequencing." Genome Research 21, no. 1 (October 29, 2010): 56–67. http://dx.doi.org/10.1101/gr.110684.110.
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Miyagi, Yohei, Takeshi Sasaki, Kiyoshi Fujinami, Jinyu Sano, Yutaka Senga, Takeshi Miura, Yoichi Kameda, et al. "ETS family-associated gene fusions in Japanese prostate cancer: analysis of 194 radical prostatectomy samples." Modern Pathology 23, no. 11 (August 6, 2010): 1492–98. http://dx.doi.org/10.1038/modpathol.2010.149.
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Xu, Kemin, Alexandra Budhai, Rugved Pattarkine, and Minghao Zhong. "Detecting FLI1 Fusion by Immunohistochemistry (IHC) Stain in Prostatic Adenocarcinoma." American Journal of Clinical Pathology 152, Supplement_1 (September 11, 2019): S72—S73. http://dx.doi.org/10.1093/ajcp/aqz113.087.
Анотація:
Abstract Objectives The most common genetic alterations in prostate cancer are fusions of ERG and other members of the E26 transformation-specific (ETS) family of transcription factors, including ETV1, ETV4, and FLI1. Analyzing TCGA data, we found that similar to ERG fusion, FLI1 fusion-associated FLI1 mRNA level increases. ERG IHC stain has been a surrogate test for ERG fusion. Therefore, we hypothesize that FLI IHC stain could also be used to detect FLI1 fusion in prostate cancer. Methods In total, 111 primary prostate adenocarcinoma (>10% by volume) cases from our institute were selected for tissue microarray (TMA) construction. The regular full section slides and TMA slides were subject to IHC stain of ERG and FLI1 (Santa Cruz, SC-113). The criteria for positive FLI1 are (1) nuclear staining; (2) only in tumor cells, not in nontumor cells; and (3) FLI1-positive cells should be negative for ERG IHC staining. Results For prostate TMA slides, ~50% of cases were positive for ERG; ~30% of cases were weakly positive for FLI1. However, all of the FLI1 weakly positive cases were positive for ERG as well possibly due to cross-reactivity between ERG and FLI1, which was demonstrated in other studies. Conclusion Overall, we conclude that the cross-reactivity between FL1 and ERG precluded the detection of FLI1 fusion in prostatic adenocarcinoma under current conditions. We are in the process of selecting some cases to detect FLI1 fusion by next-generation sequencing (NGS) and FISH.
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Nakagawa, Hidewaki. "Prostate cancer genomics by high-throughput technologies: genome-wide association study and sequencing analysis." Endocrine-Related Cancer 20, no. 4 (April 26, 2013): R171—R181. http://dx.doi.org/10.1530/erc-13-0113.
Анотація:
Prostate cancer (PC) is the most common malignancy in males. It is evident that genetic factors at both germline and somatic levels play critical roles in prostate carcinogenesis. Recently, genome-wide association studies (GWAS) by high-throughput genotyping technology have identified more than 70 germline variants of various genes or chromosome loci that are significantly associated with PC susceptibility. They include multiple 8q24 loci, prostate-specific genes, and metabolism-related genes. Somatic alterations in PC genomes have been explored by high-throughput sequencing technologies such as whole-genome sequencing and RNA sequencing, which have identified a variety of androgen-responsive events and fusion transcripts represented by E26 transformation-specific (ETS) gene fusions. Recent innovations in high-throughput genomic technologies have enabled us to analyze PC genomics more comprehensively, more precisely, and on a larger scale in multiple ethnic groups to increase our understanding of PC genomics and biology in germline and somatic studies, which can ultimately lead to personalized medicine for PC diagnosis, prevention, and therapy. However, these data indicate that the PC genome is more complex and heterogeneous than we expected from GWAS and sequencing analyses.
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Morris, David S., Scott A. Tomlins, Daniel R. Rhodes, Jianjun Yu, Mark A. Rubin, Anders S. Bjartell, and Arul M. Chinnaiyan. "OUTLIER EXPRESSION OF SPINK1 IDENTIFIES AN AGGRESSIVE MOLECULAR SUBTYPE IN PROSTATE CANCERS WITHOUT ETS GENE FUSIONS." Journal of Urology 179, no. 4S (April 2008): 707. http://dx.doi.org/10.1016/s0022-5347(08)62060-1.