Characterization of genetic aberrations in a single case of metastatic thymic adenocarcinoma
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Thymic adenocarcinoma is an extremely rare subtype of thymic epithelial tumors. Due to its rarity, there is currently no sequencing approach for thymic adenocarcinoma. We performed whole exome and transcriptome sequencing on a case of thymic adenocarcinoma and performed subsequent validation using Sanger sequencing. The case of thymic adenocarcinoma showed aggressive behaviors with systemic bone metastases. We identified a high incidence of genetic aberrations, which included somatic mutations in RNASEL, PEG10, TNFSF15, TP53, TGFB2, and FAT1. Copy number analysis revealed a complex chromosomal rearrangement of chromosome 8, which resulted in gene fusion between MCM4 and SNTB1 and dramatic amplification of MYC and NDRG1. Focal deletion was detected at human leukocyte antigen (HLA) class II alleles, which was previously observed in thymic epithelial tumors. We further investigated fusion transcripts using RNA-seq data and found an intergenic splicing event between the CTBS and GNG5 transcript. Finally, enrichment analysis using all the variants represented the immune system dysfunction in thymic adenocarcinoma. Thymic adenocarcinoma shows highly malignant characteristics with alterations in several cancer-related genes.Keywords:
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The landmark of chronic myeloid leukemia (CML) is the reciprocal translocation t(9;22)(q34;q11), generating the BCR-ABL1 hybrid gene. About 15 types of fusion transcripts have been described to date. Among the rarer types, e19a2 was described for the first time in 1990 by Saglio et al. (1). Here, we report on a new case of CML with the e19a2 transcript.A 38 year-old male patient was referred for genetic investigations with a clinical diagnosis of CML. Karyotyping and molecular genetics investigations (reverse-transcription and sequencing) were performed.t(9;22)(q34;q11.2) was found in 100% of metaphases and the patient's BCR-ABL1 fusion gene showed the rare variant transcript e19a3 with no sequence alterations.CML with e19a2 fusion transcript is a rare disease with a large variety of clinical manifestations and unclear biological significance. Adding new cases to the current knowledge will contribute to the understanding of its mechanisms and the clarification of its prognosis.
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Event Abstract Back to Event Identification of fusion genes in pediatric relapsed AML: a preliminary finding Nadiah Abu1, 2, Siti Hawa Osman2, Habsah Aziz2, Hamidah Alias3 and Rahman Jamal2* 1 National University of Malaysia, Malaysia 2 UKM Medical Molecular Biology Institute (UMBI), Malaysia 3 Department of Paediatric, Faculty of Medicine, Universiti Kebangsaan Malaysia, Malaysia Background Pediatric Acute Myeloid Leukemia (AML) is a highly complex and heterogenous disease. To date, the mechanisms of its regulatory network, particularly during relapse, have not been elucidated. One of the causes of its pathogenesis is through chromosomal rearrangements, which may result in fusion genes and transcripts. The pattern of expression of fusion genes in relapsed AML is unclear, especially as predictive biomarkers for response or relapse. The best approach is to profile the patients’ cells at diagnosis, remission and relapse. Methods Total RNA was extracted from the bone-marrow derived mononuclear cells of three pediatric AML patients at different stages; diagnosis, remission and relapse. One patient (PAML1) had a normal karyotype, while the other two patients (PAML2 and PAML3) were positive for the t(8 t(8;21) (q;22 q;22) translocation. We performed deep, paired-end RNA sequencing on these AML trios. Putative fusion transcripts were identified and prioritized using the SOAPFuse algorithm. Further visualization of the fusion genes was conducted using Circosplot. Results PAML1 had several novel fusion transcripts, among which, the fusion transcript NTUM2A-AS1>>MINPP1 was persistent at all three stages of diagnosis, remission and relapse. Commonly reported fusion genes involving the MLL gene (MLL>>MLLT4) were also identified in the diagnosis and the relapsed stages. In PAML2, there were no persistent fusion transcripts identified in all three stages. However, as predicted, the RUNX1>>RUNXT1 fusion transcripts were detected in the diagnosis stage and later, reappeared in the relapsed stage. This was also observed for the RRN3P3>>DARS fusion gene. In PAML3, the fusion gene PARP6-JHD1MD persisted in all three stages. Similarly, the RUNX1>>RUNXT1 fusion genes were also detected in PAML3. Interestingly, the fusion gene C15orf57>>CBX3 was found to be expressed in the relapsed stage of all three samples. However, no common fusion genes were detected in the diagnosis and remission stage of all three samples. Conclusion Based on our preliminary findings, fusion genes are selectively expressed at different stages of the disease and in different patients. However, further validation as well as understanding the true biological function of the fusion genes should be investigated. This should be further correlated with the respective gene expression profile, as well as its mutational status. Acknowledgements FRGS/1/2015/SKK08/UKM/03/2 Keywords: Pediatric AML, fusion gene, RNA-Seq, relapse, biomarker, Transcriptome Conference: International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18) “Seizing Opportunities and Addressing Challenges of Precision Medicine”, Putrajaya, Malaysia, 3 Dec - 5 Feb, 2019. Presentation Type: Oral Presentation Topic: Metabolic diseases Citation: Abu N, Osman S, Aziz H, Alias H and Jamal R (2019). Identification of fusion genes in pediatric relapsed AML: a preliminary finding. Front. Pharmacol. Conference Abstract: International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18) “Seizing Opportunities and Addressing Challenges of Precision Medicine”. doi: 10.3389/conf.fphar.2018.63.00144 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 30 Nov 2018; Published Online: 17 Jan 2019. * Correspondence: Prof. Rahman Jamal, UKM Medical Molecular Biology Institute (UMBI), Kuala Lumpur, Malaysia, rahmanj@ppukm.ukm.edu.my Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Nadiah Abu Siti Hawa Osman Habsah Aziz Hamidah Alias Rahman Jamal Google Nadiah Abu Siti Hawa Osman Habsah Aziz Hamidah Alias Rahman Jamal Google Scholar Nadiah Abu Siti Hawa Osman Habsah Aziz Hamidah Alias Rahman Jamal PubMed Nadiah Abu Siti Hawa Osman Habsah Aziz Hamidah Alias Rahman Jamal Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.
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Abstract The role of fusion gene transcripts such as BRC-ABL1 has been long appreciated in hematopoietic malignancies. Recent evidence from next generation sequencing projects has suggested that gene fusion events and the resultant chimaeric transcripts may be expressed in solid tumors. We have developed a novel bioinformatics analytical pipeline to detect fusion gene transcripts from paired-end mRNA-seq data. The bioinformatics tool used for fusion transcript discovery employs multiple steps of false positive filtering and nominates the fusion transcript candidates with high confidence (approaching 100%). The screening and validation of the fusion candidates were quickly carried out using the recommended primer design regions as one of the outputs of the SnowShoes-FD pipeline. This pipeline was used to analyze the transcriptome of 22 breast cancer cell lines and 9 non-transformed breast cell populations. Fifty-four fusion candidates were nominated, all of which were validated using reverse transcription PCR and Sanger sequencing. Five fusion products were predicted to have a second fusion junction point between two fusion partners. These 54 fusion transcripts consist of 103 partner genes that are involved in cell cycle and/or nuclear receptor signaling. No fusion transcripts were identified from the non-transformed breast cell lines. We subsequently analyzed a panel of primary breast tumors, 8 each HER2+, triple negative, and ER+. Fifteen novel fusion transcript candidates have been nominated. Validation and functional analysis of these candidates is in progress. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-276. doi:10.1158/1538-7445.AM2011-LB-276
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Objective To investigate the expression of the chimeric genes resulting from the specific chromosomal translocations in soft tissue sarcomas (STS) and its diagnostic significance for STS. Methods The variety of fusion transcripts were detected in 103 cases of STS, including 30 cases of synovial sarcoma (SS), 15 cases of rhabdomyosarcoma (RMS), 25 cases of Ewing's sarcoma/peripheral primitive neuroectodermal tumors (ES/pPNET), 12 cases of dermatofibrosarcoma protuberans (DFSP), 14 cases of aveolar soft part sarcoma (ASPS), 3 cases of leiomyosarcoma (LMS), 2 cases of malignant fibrous histocytoma (MFH), and 2 cases of fibrosarcoma (FS); and 20 cases of control tumors by reverse transcription-polymerase chain reaction (RT-PCR) using formalin fixed, paraffin embedded specimens. Results Of the 34 cases of SS 28 (93.3%) expressed SSX-SYT chimeric transcripts (14 were positive for SYT-SSX1, 9 for SYT-SSX2). Four of the six cases of alveolar RMS had a PAX3/PAX7-FKHR fusion transcript. None of the 9 cases of embryonic and polymorphic RMS expressed PAX3/PAX7-FKHR. Of the 25 cases of ES/pPNET, 19 were positive for EWS-FLI1 fusion transcript and 1 for EWS-ERG fusion transcript. COL1A1-PDGFB fusion transcript was expressed in 8 of the 12 cases (66.7%) of DFSP. Of the fourteen cases of ASPS, ten expressed ASPL-TFE3 fusion transcript. None of the 3 cases of LMS, 2 cases of MFH, 2 cases of FS, and 20 control cases contained any of the fusion transcript. Conclusion Chimeric gene transcript resulting from specific chromosomal translocations is a reliable index for the molecular diagnosis of STS and RT-PCR assay for detection of specific fusion gene provides a useful tool for confirmation of the diagnosis of STS in diagnostically difficult cases and in retrospective studies.
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In myxoid and round cell liposarcomas, a specific chromosomal translocation [(12;16)(q13;p11)] results in the expression of chimeric fusion transcripts encompassing parts of the FUS gene (16p11) at their 5' ends and the CHOP gene (12q13) at their 3' ends. Using a reverse transcription-PCR protocol, we determined the prevalence of FUS-CHOP fusion transcripts in a series of liposarcoma samples. Fusion transcripts were detected in 13 of 30 biopsy samples from soft tissue liposarcomas. Expression of fusion transcripts was not restricted to myxoid and round cell liposarcomas, as suggested previously; it was also detected in 1 of 3 well-differentiated and 4 of 14 pleomorphic liposarcomas. Sequence analysis revealed four different FUS-CHOP fusion transcript variants, two of which have not been described before. Furthermore, using FUS-CHOP fusion transcripts as targets in reverse transcription-PCR assays, we detected disseminated tumor cells in peripheral blood or bone marrow in 3 of 5 patients undergoing surgery for soft tissue liposarcoma.
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Studies of gene rearrangements and the consequent oncogenic fusion proteins have laid the foundation for targeted cancer therapy. To identify oncogenic fusions associated with glioma progression, we catalogued fusion transcripts by RNA-seq of 272 gliomas. Fusion transcripts were more frequently found in high-grade gliomas, in the classical subtype of gliomas, and in gliomas treated with radiation/temozolomide. Sixty-seven in-frame fusion transcripts were identified, including three recurrent fusion transcripts: FGFR3-TACC3 , RNF213-SLC26A11 , and PTPRZ1-MET ( ZM ). Interestingly, the ZM fusion was found only in grade III astrocytomas (1/13; 7.7%) or secondary GBMs (sGBMs, 3/20; 15.0%). In an independent cohort of sGBMs, the ZM fusion was found in three of 20 (15%) specimens. Genomic analysis revealed that the fusion arose from translocation events involving introns 3 or 8 of PTPRZ and intron 1 of MET . ZM fusion transcripts were found in GBMs irrespective of isocitrate dehydrogenase 1 ( IDH1 ) mutation status. sGBMs harboring ZM fusion showed higher expression of genes required for PIK3CA signaling and lowered expression of genes that suppressed RB1 or TP53 function. Expression of the ZM fusion was mutually exclusive with EGFR overexpression in sGBMs. Exogenous expression of the ZM fusion in the U87MG glioblastoma line enhanced cell migration and invasion. Clinically, patients afflicted with ZM fusion harboring glioblastomas survived poorly relative to those afflicted with non- ZM -harboring sGBMs ( P < 0.001). Our study profiles the shifting RNA landscape of gliomas during progression and reveled ZM as a novel, recurrent fusion transcript in sGBMs.
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Abstract Acute Myeloid Leukemia (AML) is a highly heterogeneous disease and somatic mutations and fusion genes have a crucial diagnostic, prognostic and therapeutic role in AML. However, the leukemogenic potential of the fusions, their cooperation with somatic mutations and their prognostic role are still unknown. The aim of the study was to identify novel rare gene fusions having a causative role in leukemogenesis and to identify cooperative somatic mutations as potential targets for personalized therapies in AML cases with rare and poorly described chromosomal translocations. We performed RNAseq on bone marrow samples from 5 AML patients (#59810, #20, #84, #21 and #32). The presence of gene fusions was assessed with deFuse and Chimerascan. Putative fusion genes were prioritized using Pegasus and Oncofuse to select biologically relevant fusions. WES was performed on samples #59810, #20 and #21 and variants were detected using the software Mutect and GATK. The CBFβ-MYH11 chimera was identified in sample #84, with inv(16), thus confirming the reliability of our analysis. Sample #59810 carried the fusion transcript ZEB2-BCL11B (Driver Score, DS = 0.7), an in-frame fusion and a rare event in AML associated with t(2;14). The fusion transcript showed 3 splicing isoforms and ZEB2 and BCL11B transcripts were upregulated in patient's blasts, compared with 53 AML samples with no chromosomal aberrations in the 14q32 region. The WT1-CNOT2 chimera was also detected, which is a novel out-of-frame fusion (DS = 0.008) related to t(11;12) translocation. WES analysis showed SNVs in TET2 and BCOR genes. In sample #20 we identified two different fusion transcripts: CPD-PXT1 (DS = 0.07), which was the reciprocal fusion product of t(6;17) translocation, and SAV1-GYPB, which was cryptic at cytogenetic analysis (DS = 0.8). Interestingly, the latter fusion involved a tumour suppressor gene. Moreover, mutations in BCOR and NRAS were detected by WES. RNAseq on sample #21 identified a novel fusion event between chromosomes 19 and 7, involving the genes OAZ and MAFK (DS = 0.9). The 3’ partner gene is a transcription factor, a functional class recurrently altered in AML. This patient showed SNVs in CBL and SMC1A genes. Finally, no chimeras were confirmed in sample #32 having a t(12;18) translocation. Our data suggest that fusion events are frequent in AML and a number of them cannot be detected by current cytogenetic analyses. Gene fusions cooperate with somatic mutations in the genomic landscape driving AML pathogenesis and its heterogeneity. Moreover, the results indicate that different approaches, including WES, RNAseq bioinformatic and statistic tools need to be integrated in order to identify potential targets for personalized therapies. Acknowledgements: ELN, AIL, AIRC, progetto Regione-Università 2010-12 (L. Bolondi), Fondazione del Monte di Bologna e Ravenna, FP7 NGS-PTL project. Citation Format: Antonella Padella, Giorgia Simonetti, Anna Ferrari, Giulia Paciello, Elisa Zago, Carmen Baldazzi, Viviana Guadagnuolo, Cristina Papayannidis, Valentina Robustelli, Enrica Imbrogno, Nicoletta Testoni, Massimo Delledonne, Ilaria Iacobucci, Tiziana Clelia Storlazzi, Elisa Ficarra, Pier-Luigi Lollini, Giovanni Martinelli. Novel fusion transcripts identified by RNAseq cooperate with somatic mutations in the pathogenesis of acute myeloid leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 113.
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