scholarly journals EPEN-25. EXCEPTIONAL CLINICAL AND IMAGING RESPONSE TO TRK-INHIBITION IN A PATIENT WITH SUPRATENTORIAL EPENDYMOMA HARBORING NTRK2 GENE FUSION

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii312-iii313
Author(s):  
Ross Mangum ◽  
Jacquelyn Reuther ◽  
Adekunle Adesina ◽  
Marcia Kukreja ◽  
Daniel Curry ◽  
...  
Keyword(s):  
Tumor Recurrence ◽  
Gene Fusion ◽  
Genomic Analysis ◽  
Leptomeningeal Carcinomatosis ◽  
Kinase Domain ◽  
Dna And Rna ◽  
Pediatric Ependymoma ◽  
Ffpe Tumor ◽  
Poor Outcomes ◽  
Supratentorial Ependymoma

Abstract BACKGROUND Patients with metastatic pediatric ependymoma have limited therapeutic options and poor outcomes. Approximately ¾ of supratentorial ependymomas are driven by C11ORF95-RELA fusions, and the remaining by a heterogeneous group of fusion events. We present a six year-old male diagnosed with supratentorial ependymoma with leptomeningeal carcinomatosis harboring an NTRK2-fusion. Local and distant multifocal, intracranial and intraspinal tumor recurrence occurred seven months following gross total resection of the primary lesion and proton beam craniospinal irradiation. METHODS DNA and RNA from FFPE tumor were used for targeted sequencing using an 81-gene fusion panel and 124-gene mutation panel. Separately, capture transcriptome sequencing, exome sequencing, and copy number array were performed as part of the Texas KidsCanSeq study, an NHGRI/NCI-funded Clinical Sequencing Evidence-Generating Research (CSER) consortium project. All sequencing was carried out in CLIA-certified laboratories. RESULTS An in-frame fusion between 5’ exons 1–3 of KANK1 and 3’ exons 16–21 of NTRK2, predicted to retain the kinase domain, was identified. At tumor recurrence, therapy was initiated with Larotrectinib, an FDA-approved pan-TRK inhibitor. Clinical improvement in cognitive speed, motor strength, and coordination was observed at two weeks with significant tumor response on MRI at two and four months. CONCLUSION TRK gene fusions have not previously been reported in ependymoma. Further tumor characterization by methylation profiling is underway and will be of diagnostic interest given the apparent discordance between tumor histology and molecular findings. This case highlights the potential impact of clinical genomic analysis for children with CNS tumors.

scholarly journals Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high-risk disease

Blood ◽  
2018 ◽  
Vol 132 (9) ◽  
pp. 948-961 ◽  
Author(s):  
Susan Branford ◽  
Paul Wang ◽  
David T. Yeung ◽  
Daniel Thomson ◽  
Adrian Purins ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
High Risk ◽  
Genomic Analysis ◽  
Kinase Domain ◽  
Cancer Genes ◽  
High Risk Disease ◽  
Key Points ◽  
Kinase Domain Mutations ◽  
Poor Outcomes ◽  
Generation Sequencing

Key Points Next-generation sequencing revealed variants in cancer-associated genes at diagnosis of CML more frequently in patients with poor outcomes. All patients at BC had mutated cancer genes, including fusions, that predated BCR-ABL1 kinase domain mutations in a majority.

scholarly journals Temporal and Clonal Progression in a Pediatric Ependymoma Patient Through Multiple Treatments

2017 ◽  
Author(s):  
Christopher A. Miller ◽  
Sonika Dahiya ◽  
Tiandao Li ◽  
Robert S. Fulton ◽  
Matthew D. Smyth ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Molecular Mechanisms ◽  
Treatment Resistance ◽  
Response To Therapy ◽  
Prognostic Indicators ◽  
Patient Death ◽  
Dna And Rna ◽  
Pediatric Ependymoma ◽  
The Impact ◽  
Supratentorial Ependymoma

AbstractBackgroundMultiple recurrences after complete resection and irradiation of supratentorial ependymoma are common and frequently result in patient death. However, the molecular basis for treatment resistance, the impact that radiation and other adjuvant therapies have in promoting recurrence, and the use of this information to rationally design effective approaches to treat recurrent ependymoma are unknown. Due to the rarity of these tumors and the even less likely banking of multiple recurrent samples from the same patient, we initiated a study to characterize the evolution of a single patient’s ependymoma in response to therapy.Methods and FindingsA combination of high depth, whole genome and exome-based DNA sequencing of germline and tumor specimens, RNA sequencing of tumor specimens, and advanced computational analyses were employed to reconstruct the natural history of a supratentorial ependymoma case in which there were four local recurrences. The findings reveal the extent to which treatment with radiation and chemotherapies resulted in the diversification of the tumor subclonal architecture and shaped the neo-antigen landscape, and provide new insights into possible molecular mechanisms of oncogenesis, treatment response and recurrence.ConclusionsAlthough the recurrent tumors we studied were clearly shaped by therapy, the founding clone was never eradicated by any treatment. We conclude that DNA and RNA sequencing may provide critical prognostic indicators to identify ependymoma patients that should be observed, rather than irradiated, post gross total resection.

BRAF-MAD1L1 and BRAF-ZC3H7A: novel gene fusion in Rhabdomyosarcoma and Lung adenocarcinoma

2021 ◽  
Author(s):  
Jiang Da ◽  
Hui Jin ◽  
Xinliang Zhou ◽  
Shaoshuang Fan ◽  
Mian Xu ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Gene Fusion ◽  
Tumor Resection ◽  
Kinase Domain ◽  
Rapid Progression ◽  
First Line ◽  
Case Presentation ◽  
First Case ◽  
Exon 11 ◽  
Domain Exon

Abstract Background: Rhabdomyosarcoma (RMS) and lung adenocarcinoma (LADC) epitomizes the success of cancer prevention by the development of conventional therapy, but huge challenges remain in the therapy of advanced diseases.Case presentation: We reported two cases of novel BRAF gene fusion. The first case was a 34-year-old female with RMS harboring a BRAF-MAD1L1 fusion. She suffered tumor resection, recurrence and rapid progression. The second case was a 72-year-old female with LADC harboring a BRAF-ZC3H7A fusion, and she gained rapid progression after receiving a first-line course of chemotherapy.Conclusions: These two BRAF fusions retain the intact BRAF kinase domain (exon 11-18) and showed poor prognosis in RMS and LADC.

scholarly journals Integrative Genomics with Mediation Analysis in a Survival Context

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Szilárd Nemes ◽  
Toshima Z. Parris ◽  
Anna Danielsson ◽  
Zakaria Einbeigi ◽  
Gunnar Steineck ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Genomic Analysis ◽  
Mrna Levels ◽  
Integrative Genomics ◽  
Asymptotic Results ◽  
Data Set ◽  
Cancer Data ◽  
Dna And Rna ◽  
Altered Gene

DNA copy number aberrations (DCNA) and subsequent altered gene expression profiles may have a major impact on tumor initiation, on development, and eventually on recurrence and cancer-specific mortality. However, most methods employed in integrative genomic analysis of the two biological levels, DNA and RNA, do not consider survival time. In the present note, we propose the adoption of a survival analysis-based framework for the integrative analysis of DCNA and mRNA levels to reveal their implication on patient clinical outcome with the prerequisite that the effect of DCNA on survival is mediated by mRNA levels. The specific aim of the paper is to offer a feasible framework to test the DCNA-mRNA-survival pathway. We provide statistical inference algorithms for mediation based on asymptotic results. Furthermore, we illustrate the applicability of the method in an integrative genomic analysis setting by using a breast cancer data set consisting of 141 invasive breast tumors. In addition, we provide implementation in R.

scholarly journals Epigenomic, genomic, and transcriptomic landscape of schwannomatosis

2020 ◽  
Vol 141 (1) ◽  
pp. 101-116
Author(s):  
Sheila Mansouri ◽  
Suganth Suppiah ◽  
Yasin Mamatjan ◽  
Irene Paganini ◽  
Jeffrey C. Liu ◽  
...  
Keyword(s):  
Gene Fusion ◽  
Somatic Mutations ◽  
Genomic Analysis ◽  
Germline Mutations ◽  
Tumor Location ◽  
Molecular Signature ◽  
Structural Rearrangements ◽  
Genomic Features ◽  
Cancer Predisposition Syndrome ◽  
Neuronal Tumors

AbstractSchwannomatosis (SWNTS) is a genetic cancer predisposition syndrome that manifests as multiple and often painful neuronal tumors called schwannomas (SWNs). While germline mutations in SMARCB1 or LZTR1, plus somatic mutations in NF2 and loss of heterozygosity in chromosome 22q have been identified in a subset of patients, little is known about the epigenomic and genomic alterations that drive SWNTS-related SWNs (SWNTS-SWNs) in a majority of the cases. We performed multiplatform genomic analysis and established the molecular signature of SWNTS-SWNs. We show that SWNTS-SWNs harbor distinct genomic features relative to the histologically identical non-syndromic sporadic SWNs (NS-SWNS). We demonstrate the existence of four distinct DNA methylation subgroups of SWNTS-SWNs that are associated with specific transcriptional programs and tumor location. We show several novel recurrent non-22q deletions and structural rearrangements. We detected the SH3PXD2A-HTRA1 gene fusion in SWNTS-SWNs, with predominance in LZTR1-mutant tumors. In addition, we identified specific genetic, epigenetic, and actionable transcriptional programs associated with painful SWNTS-SWNs including PIGF, VEGF, MEK, and MTOR pathways, which may be harnessed for management of this syndrome.

Comprehensive genomic landscape in Chinese patients with urothelial carcinoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17009-e17009
Author(s):  
Haige Chen ◽  
Ruiyun Zhang ◽  
Shiqing Chen ◽  
Yuezong Bai
Keyword(s):  
Urothelial Carcinoma ◽  
Large Scale ◽  
Clinical Laboratory ◽  
Genomic Analysis ◽  
Chinese Patients ◽  
Variants Of Unknown Significance ◽  
Molecular Features ◽  
Genomic Landscape ◽  
Ffpe Tumor ◽  
Somatic Alterations

e17009 Background: Recent therapeutic advances, such as immunotherapy and FGFR-targeted therapy, have greatly improved the prognosis of patients with urothelial carcinoma (UC). Revealing comprehensive genomic features could evolve our understanding of UC, however the genomic landscape in Chinese UC has not been fully elucidated. In the present study, we investigated the molecular features of Chinese UC patients. Methods: Genomic profiling was performed through next generation sequencing (NGS) from Chinese patients with UC between January, 2017 and November, 2019 in a College of American Pathologists-certified and Clinical Laboratory Improvement Amendments-accredited lab. DNA was extracted from formalin fixed paraffin-embedded (FFPE) tumor specimens or fresh tumor tissue. 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 298 Chinese UC patients who have undergone NGS were included in this study, including 210 (70.5%) male and 88 (29.5%) female patients. The median age was 66 (range, 19-91) years old. The most common somatic alterations were detected in TP53 (57.0%), KMT2D (42.6%), TERT (28.2%), KDM6A (26.5%) and PIK3CA (18.8%). Of the 243 patients who were evaluated for PD-L1 expression, 78 (32.1%) had a PD-L1 Tumor Proportion Score (TPS) of 1% or greater, and 18 (7.4%) had a PD-L1 TPS of 50% or greater. The median TMB value was 9.7 muts/Mb (range: 0-175.0). 138 (46.3%) patients harbored alterations in DNA damage repair (DDR) genes, including pathogenic or likely pathogenic mutations (MUT) and variants of unknown significance (VOUS). The most common somatic alterations in DDR genes were detected in ATM (9.4%), BRCA2 (9.4%), BRIP1 (5.0%), ATR (4.7%) and BRCA1 (4.7%). Significant differences of TMB were observed among DDR-MUT group, DDR-VOUS group and DDR-WT group (mTMB = 16.1, 14.0 and 7.3 muts/Mb, respectively, P < 0.001). Seven (2.4%) patients were identified as MSI-H, including five patients in DDR-MUT group (12.8%) and two patients in DDR-VOUS group (2.0%). Conclusions: This is the first large-scale comprehensive genomic analysis for Chinese patients with UC. These results provide a better understanding of molecular features in Chinese UC patients which may lead to an improvement in the personalized treatment for these patients.

scholarly journals Novel RNA Markers in Prostate Cancer: Functional Considerations and Clinical Translation

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Julia M. A. Pickl ◽  
Doreen Heckmann ◽  
Leonie Ratz ◽  
Sabine M. Klauck ◽  
Holger Sültmann
Keyword(s):  
Prostate Cancer ◽  
Noncoding Rna ◽  
Tumor Development ◽  
Genomic Analysis ◽  
Diagnosis And Therapy ◽  
Sequencing Technologies ◽  
Dna And Rna ◽  
Functional Genomic Analysis ◽  
Novel Transcripts

The availability of ultra-high throughput DNA and RNA sequencing technologies in recent years has led to the identification of numerous novel transcripts, whose functions are unknown as yet. Evidence is accumulating that many of these molecules are deregulated in diseases, including prostate cancer, and potentially represent novel targets for diagnosis and therapy. In particular, functional genomic analysis of microRNA (miRNA) and long noncoding RNA (lncRNA) in cancer is likely to contribute insights into tumor development. Here, we compile recent efforts to catalog differential expression of miRNA and lncRNA in prostate cancer and to understand RNA function in tumor progression. We further highlight technologies for molecular characterization of noncoding RNAs and provide an overview of current activities to exploit them for the diagnosis and therapy of this complex tumor.

The Nationwide Cancer Genome Screening Project in Japan, SCRUM-Japan GI-screen: Efficient identification of cancer genome alterations in advanced esophageal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4062-4062
Author(s):  
Yuichiro Nakashima ◽  
Takashi Kojima ◽  
Hiroki Hara ◽  
Ken Kato ◽  
Takeshi Kajiwara ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Esophageal Cancer ◽  
Copy Number Variant ◽  
Cancer Genome ◽  
Loss Of Function ◽  
Advanced Esophageal Cancer ◽  
Surgical Specimen ◽  
Dna And Rna ◽  
Ffpe Tumor ◽  
Genome Screening

4062 Background: We have conducted the Nationwide Cancer Genome Screening Project in Japan since April 2015 using Next Generation Sequencing in advanced non-colorectal gastrointestinal (GI) cancer (aNon-CRC), called as the SCRUM-Japan GI-SCREEN. The objective is to evaluate the frequency of cancer genome alterations in aNon-CRC and to identify patients who are candidate for clinical trial for corresponding targeting agents. Methods: This study is ongoing with the participation of 20 major cancer centers. Patients with aNon-CRC, including advanced esophageal cancer (aEC), who plan to or receive chemotherapy were eligible. DNA and RNA were extracted from FFPE tumor samples and were analyzed by the Oncomine Cancer Research Panel (OCP) which allows to detect gene mutation, copy number variant (CNV) and fusions across 143 genes in a CLIA certified CAP accredited laboratory. The detected genomic variant data were classified according to genetic drivers of cancer including gain- and loss-of-function or single nucleotide variant based on the Oncomine Knowledgebase. In this presentation, we show the results of aEC cohort. Results: As of October 31st in 2016, a total of 180 aEC samples were analyzed. The sequence with the OCP was successfully performed in 121 (67.2%). Out of 157 patients except for the 23 patients in which precise data is not collected, the proportion of sample and histology type is followed; surgical specimen 58.0%, squamous cell carcinoma 92.4%. The frequently detected mutations in 114 samples of which results were available were TP53 (77.2%), NFE2L2 (23.7%), CDKN2A (9.6%), PIK3CA (7.0%), RB1 (6.1%), and CNVs were CCND1 (37.7%), EGFR (7.9%), MYC (7.9%), SOX2 (6.1%), ATP11B (5.3%), NKX2-1 (5.3%). ERBB2 amplification was identified in 3 cases (2.6%) and FGFR3-TACC3fusion was identified in one case (0.9%). Conclusions: This nationwide screening system is efficient to detect rare gene alterations in aEC. This novel knowledge provides an intriguing background to investigate new target approaches and represents a progress toward more precision medicine. Clinical trial information: UMIN000016344.

scholarly journals Introduction: Metals in Biology: α-Ketoglutarate/Iron-Dependent Dioxygenases

2015 ◽  
Vol 290 (34) ◽  
pp. 20700-20701 ◽  
Author(s):  
F. Peter Guengerich
Keyword(s):  
Protein Modification ◽  
Genomic Analysis ◽  
Current Understanding ◽  
Epigenetic Mechanisms ◽  
Oxidation Reactions ◽  
General Introduction ◽  
Dna And Rna ◽  
Damaged Dna

Four minireviews deal with aspects of the α-ketoglutarate/iron-dependent dioxygenases in this eighth Thematic Series on Metals in Biology. The minireviews cover a general introduction and synopsis of the current understanding of mechanisms of catalysis, the roles of these dioxygenases in post-translational protein modification and de-modification, the roles of the ten-eleven translocation (Tet) dioxygenases in the modification of methylated bases (5mC, T) in DNA relevant to epigenetic mechanisms, and the roles of the AlkB-related dioxygenases in the repair of damaged DNA and RNA. The use of α-ketoglutarate (alternatively termed 2-oxoglutarate) as a co-substrate in so many oxidation reactions throughout much of nature is notable and has surprisingly emerged from biochemical and genomic analysis. About 60 of these enzymes are now recognized in humans, and a number have been identified as having critical functions.

scholarly journals DNAJB1-PRKACA fusion kinase interacts with β-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma

2017 ◽  
Author(s):  
Edward R. Kastenhuber ◽  
Gadi Lalazar ◽  
Shauna L. Houlihan ◽  
Darjus F. Tschaharganeh ◽  
Timour Baslan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Gene Fusion ◽  
Kinase Inhibitors ◽  
Liver Tumors ◽  
Tissue Injury ◽  
Kinase Domain ◽  
Wild Type ◽  
Fibrolamellar Hepatocellular Carcinoma ◽  
Genetic Event ◽  
Genetic And Environmental Factors

AbstractA segmental deletion resulting in DNAJB1-PRKACA gene fusion is now recognized as the signature genetic event of fibrolamellar hepatocellular carcinoma (FL-HCC), a rare but lethal liver cancer that primarily affects adolescents and young adults. Here, we implement CRISPR/Cas9 genome editing and transposon-mediated somatic gene transfer to demonstrate that expression of both the endogenous fusion protein or a chimeric cDNA leads to the formation of indolent liver tumors in mice that closely resemble human FL-HCC. Notably, overexpression of the wild type PRKACA was unable to fully recapitulate the oncogenic activity of DNAJB1-PRKACA, implying that FL-HCC does not simply result from enhanced PRKACA expression. Tumorigenesis was significantly enhanced by genetic activation of β-catenin, an observation supported by evidence of recurrent Wnt pathway mutations in human FL-HCC, as well as treatment with hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), which causes tissue injury, inflammation and fibrosis. Our study validates the DNAJB1-PRKACA fusion kinase as an oncogenic driver and candidate drug target for FL-HCC and establishes a practical model for preclinical studies to identify strategies to treat this disease.SignificanceEfforts to understand and treat FL-HCC have been confounded by a lack of models that accurately reflect the genetics and biology of the disease. Here, we demonstrate that the Dnajb1-Prkaca gene fusion drives tumorigenesis in mice, and that fusion to DNAJB1 drives FL-HCC initiation more effectively than wild type PRKACA overexpression. The requirement of the PRKACA kinase domain in tumor initiation establishes the potential utility of kinase inhibitors targeting the fusion. By identifying genetic and environmental factors that can enhance the consistency and aggressiveness of disease progression, we reveal biological characteristics of the disease and advance a robust platform for future pre-clinical studies.

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