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1
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Moreira DC, Mikkelsen M, Robinson GW. Current Landscape of NTRK Inhibition for Pediatric CNS Tumors. CNS Drugs 2024; 38:841-849. [PMID: 39278868 DOI: 10.1007/s40263-024-01121-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/19/2024] [Indexed: 09/18/2024]
Abstract
Over the last decade, as molecular platforms have permitted the characterization of the genomic landscape of pediatric central nervous system (CNS) tumors, pediatric neuro-oncology has dramatically transformed. NTRK fusions are oncogenic driver alterations that have been found in a multitude of tumor types, including pediatric CNS tumors. In recent years, NTRK inhibitors have emerged as a promising class of targeted therapies for pediatric CNS tumors with NTRK gene fusions. The use of larotrectinib and entrectinib in the relapsed setting for pediatric CNS tumors has resulted in rapid and robust responses in an important fraction of patients. These agents are well tolerated, although close to 20% of patients have spontaneous bone fractures. Given the existing data for patients with relapsed disease, clinical trials using NTRK inhibitors in the upfront setting is the next natural progression of efficacy testing and many are currently underway. There are still several challenges that need to be addressed to optimize the use of NTRK inhibitors and identify the patients with NTRK fusion-positive CNS tumors who are most likely to benefit from them. As these agents are more broadly used, resistance will become a more pervasive issue and strategies will need to be determined for this scenario. This article summarizes the current status of NTRK inhibitors for pediatric CNS tumors and discusses the opportunities and challenges of their expanding use in the future.
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Affiliation(s)
- Daniel C Moreira
- Department of Oncology, St. Jude Children's Children Research Hospital, 262 Danny Thomas Pl, Memphis, TN, 38105, USA
- Department of Global Pediatric Medicine, St. Jude Children's Children Research Hospital, Memphis, TN, USA
| | - Margit Mikkelsen
- Department of Oncology, St. Jude Children's Children Research Hospital, 262 Danny Thomas Pl, Memphis, TN, 38105, USA
| | - Giles W Robinson
- Department of Oncology, St. Jude Children's Children Research Hospital, 262 Danny Thomas Pl, Memphis, TN, 38105, USA.
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2
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Mazzoleni A, Awuah WA, Sanker V, Bharadwaj HR, Aderinto N, Tan JK, Huang HYR, Poornaselvan J, Shah MH, Atallah O, Tawfik A, Elmanzalawi MEAE, Ghozlan SH, Abdul-Rahman T, Moyondafoluwa JA, Alexiou A, Papadakis M. Chromosomal instability: a key driver in glioma pathogenesis and progression. Eur J Med Res 2024; 29:451. [PMID: 39227895 PMCID: PMC11373396 DOI: 10.1186/s40001-024-02043-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 08/26/2024] [Indexed: 09/05/2024] Open
Abstract
Chromosomal instability (CIN) is a pivotal factor in gliomas, contributing to their complexity, progression, and therapeutic challenges. CIN, characterized by frequent genomic alterations during mitosis, leads to genetic abnormalities and impacts cellular functions. This instability results from various factors, including replication errors and toxic compounds. While CIN's role is well documented in cancers like ovarian cancer, its implications for gliomas are increasingly recognized. CIN influences glioma progression by affecting key oncological pathways, such as tumor suppressor genes (e.g., TP53), oncogenes (e.g., EGFR), and DNA repair mechanisms. It drives tumor evolution, promotes inflammatory signaling, and affects immune interactions, potentially leading to poor clinical outcomes and treatment resistance. This review examines CIN's impact on gliomas through a narrative approach, analyzing data from PubMed/Medline, EMBASE, the Cochrane Library, and Scopus. It highlights CIN's role across glioma subtypes, from adult glioblastomas and astrocytomas to pediatric oligodendrogliomas and astrocytomas. Key findings include CIN's effect on tumor heterogeneity and its potential as a biomarker for early detection and monitoring. Emerging therapies targeting CIN, such as those modulating tumor mutation burden and DNA damage response pathways, show promise but face challenges. The review underscores the need for integrated therapeutic strategies and improved bioinformatics tools like CINdex to advance understanding and treatment of gliomas. Future research should focus on combining CIN-targeted therapies with immune modulation and personalized medicine to enhance patient outcomes.
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Affiliation(s)
- Adele Mazzoleni
- Barts and the London School of Medicine and Dentistry, London, UK
| | | | - Vivek Sanker
- Department Of Neurosurgery, Trivandrum Medical College, Trivandrum, India
| | | | - Nicholas Aderinto
- Internal Medicine Department, LAUTECH Teaching Hospital, Ogbomoso, Nigeria
| | | | - Helen Ye Rim Huang
- Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland
| | | | | | - Oday Atallah
- Department of Neurosurgery, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany
| | - Aya Tawfik
- Faculty of Biotechnology, October University for Modern Sciences and Arts (MSA), Giza, Egypt
| | | | - Sama Hesham Ghozlan
- Arab Academy for Science, Technology & Maritime Transport, Alexandria, Egypt
| | | | | | - Athanasios Alexiou
- University Centre for Research & Development, Chandigarh University, Chandigarh-Ludhiana Highway, Mohali, Punjab, India
- Funogen, Department of Research & Development, Athens, Greece
- Department of Research & Development, AFNP Med, 1030, Vienna, Austria
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, NSW, 2770, Australia
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten-Herdecke, University of Witten-Herdecke, Heusnerstrasse 40, 42283, Wuppertal, Germany.
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Fan Y, Zhang B, Du X, Wang B, Yan Q, Guo L, Yao W. Regulating Tumorigenicity and Cancer Metastasis through TRKA Signaling. Curr Cancer Drug Targets 2024; 24:271-287. [PMID: 37670705 DOI: 10.2174/1568009623666230904150957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 07/15/2023] [Accepted: 07/25/2023] [Indexed: 09/07/2023]
Abstract
Tropomyosin receptor kinase (TRK) A, TRKA, is a specific binding receptor of nerve growth factor (NGF), which plays an essential role in the occurrence and progression of human cancers. TRKA overexpression has been proven to be a powerful carcinogenic driver and has been verified in many tumors. The TRKA receptor kinase domain is over-activated in an NGF-dependent manner, accompanied by activation of downstream signal pathways, such as RAS-MAPK, PI3K-AKT, JAK2-STAT3 pathway, PLC γ pathway, and Hippo pathway, which participate in tumor cell proliferation, invasion, epithelial-mesenchymal transition (EMT), perineural invasion (PNI), drug resistance, and cancer pain. In addition, chimeric oncogenes produced by the fusion of NTRK1 and other genes are also the direct cause of tumorigenesis and cancer development. The newly developed TRK inhibitors can improve symptoms and tumor regression in cancer patients with overexpression of TRKA or NTRK1 fusion gene. With the emergence of drug resistance, next generation of TRK inhibitors can still maintain strong clinical efficacy in the case of TRK kinase domain mutations, and these inhibitors are in clinical trials. This review summarizes the characteristics and research progress of TRKA, focusing on the regulatory role of the TRKA signal pathway in different tumors. In addition, we have summarized the clinical significance of TRKA and the TRK inhibitors. This review may provide a new reference for the study of the mechanism of TRKA in different tumors, and also provide a new perspective for the in-depth understanding of the role of TRKA as a biomarker and therapeutic target in human cancer.
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Affiliation(s)
- Yichao Fan
- Henan Cancer Hospital, Department of Bone and Soft Tissue Cancer, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Boya Zhang
- Henan Cancer Hospital, Department of Bone and Soft Tissue Cancer, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Xinhui Du
- Henan Cancer Hospital, Department of Bone and Soft Tissue Cancer, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Bangmin Wang
- Henan Cancer Hospital, Department of Bone and Soft Tissue Cancer, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Qiang Yan
- Henan Cancer Hospital, Department of Bone and Soft Tissue Cancer, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Liangyu Guo
- Henan Cancer Hospital, Department of Bone and Soft Tissue Cancer, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Weitao Yao
- Henan Cancer Hospital, Department of Bone and Soft Tissue Cancer, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
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Cipri S, Fabozzi F, Del Baldo G, Milano GM, Boccuto L, Carai A, Mastronuzzi A. Targeted therapy for pediatric central nervous system tumors harboring mutagenic tropomyosin receptor kinases. Front Oncol 2023; 13:1235794. [PMID: 38144536 PMCID: PMC10748602 DOI: 10.3389/fonc.2023.1235794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 11/17/2023] [Indexed: 12/26/2023] Open
Abstract
The family of the neurotrophic tyrosine kinase receptor (NTRK) gene encodes for members of the tropomyosin receptor kinase (TRK) family. Rearrangements involving NTRK1/2/3 are rare oncogenic factors reported with variable frequencies in an extensive range of cancers in pediatrics and adult populations, although they are more common in the former than in the latter. The alterations in these genes are causative of the constitutive activation of TRKs that drive carcinogenesis. In 2017, first-generation TRK inhibitor (TRKi) larotrectinib was granted accelerated approval from the FDA, having demonstrated histologic-agnostic activity against NTRKs fusions tumors. Since this new era has begun, resistance to first-generation TRKi has been described and has opened the development of second-generation molecules, such as selitrectinib and repotrectinib. In this review, we provide a brief overview of the studies on NTRK alterations found in pediatric central nervous system tumors and first and second-generation TRKi useful in clinical practice.
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Affiliation(s)
- Selene Cipri
- Department of Hematology/Oncology, Cell Therapy, Gene Therapies and Hemopoietic Transplant, Bambino Gesù Children’s Hospital, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Francesco Fabozzi
- Department of Hematology/Oncology, Cell Therapy, Gene Therapies and Hemopoietic Transplant, Bambino Gesù Children’s Hospital, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Giada Del Baldo
- Department of Hematology/Oncology, Cell Therapy, Gene Therapies and Hemopoietic Transplant, Bambino Gesù Children’s Hospital, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Giuseppe Maria Milano
- Department of Hematology/Oncology, Cell Therapy, Gene Therapies and Hemopoietic Transplant, Bambino Gesù Children’s Hospital, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Luigi Boccuto
- Healthcare Genetics Program, School of Nursing, College of Behavioral, Social and Health Sciences, Clemson University, Clemson, SC, United States
| | - Andrea Carai
- Department of Neurosciences, Neurosurgery Unit, Bambino Gesù Children’s Hospital, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Angela Mastronuzzi
- Department of Hematology/Oncology, Cell Therapy, Gene Therapies and Hemopoietic Transplant, Bambino Gesù Children’s Hospital, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
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Zhang Q, Wang Y, Zhou J, Zhou R, Liu A, Meng L, Ji X, Hu P, Xu Z. 11q13.3q13.4 deletion plus 9q21.13q21.33 duplication in an affected girl arising from a familial four-way balanced chromosomal translocation. Mol Genet Genomic Med 2023; 11:e2248. [PMID: 37475652 PMCID: PMC10568374 DOI: 10.1002/mgg3.2248] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 05/23/2023] [Accepted: 07/12/2023] [Indexed: 07/22/2023] Open
Abstract
BACKGROUND We describe a 13-year-old girl with a 11q13.3q13.4 deletion encompassing the SHANK2 gene and a 9q21.13q21.33 duplication. She presented with pre- and postnatal growth retardation, global developmental delay, severe language delay, cardiac abnormalities, and dysmorphisms. Her maternal family members all had histories of reproductive problems. METHODS Maternal family members with histories of reproductive problems were studied using G-banded karyotyping and optical genome mapping (OGM). Long-range PCR (LR-PCR) and Sanger sequencing were used to confirm the precise break point sequences obtained by OGM. RESULTS G-banded karyotyping characterized the cytogenetic results as 46,XX,der(9)?del(9)(q21q22)t(9;14)(q22;q24),der(11)ins(11;?9)(q13;?q21q22),der(14)t(9;14). Using OGM, we determined that asymptomatic female family members with reproductive problems were carriers of a four-way balanced chromosome translocation. Their karyotype results were further refined as 46,XX,der(9)del(9)(q21.13q21.33)t(9;14)(q21.33;q22.31),der(11)del(11)(q13.3q13.4)ins(11;9)(q13.3;q21.33q21.13),der(14)t(9:14)ins(14;11)(q23.1;q13.4q13.3). Thus, we confirmed that the affected girl inherited the maternally derived chromosome 11. Furthermore, using LR-PCR, we showed that three disease-related genes (TMC1, NTRK2, and KIAA0586) were disrupted by the breakpoints. CONCLUSIONS Our case highlights the importance of timely parental origin testing for patients with rare copy number variations, as well as the accurate characterization of balanced chromosomal rearrangements in families with reproductive problems. In addition, our case demonstrates that OGM is a useful clinical application for analyzing complex structural variations within the human genome.
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Affiliation(s)
- Qinxin Zhang
- Department of Prenatal DiagnosisWomen's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care HospitalNanjingChina
| | - Yan Wang
- Department of Prenatal DiagnosisWomen's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care HospitalNanjingChina
| | - Jing Zhou
- Department of Prenatal DiagnosisWomen's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care HospitalNanjingChina
| | - Ran Zhou
- Department of Prenatal DiagnosisWomen's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care HospitalNanjingChina
| | - An Liu
- Department of Prenatal DiagnosisWomen's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care HospitalNanjingChina
| | - Lulu Meng
- Department of Prenatal DiagnosisWomen's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care HospitalNanjingChina
| | - Xiuqing Ji
- Department of Prenatal DiagnosisWomen's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care HospitalNanjingChina
| | - Ping Hu
- Department of Prenatal DiagnosisWomen's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care HospitalNanjingChina
| | - Zhengfeng Xu
- Department of Prenatal DiagnosisWomen's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care HospitalNanjingChina
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Damayanti NP, Saadatzadeh MR, Dobrota E, Ordaz JD, Bailey BJ, Pandya PH, Bijangi-Vishehsaraei K, Shannon HE, Alfonso A, Coy K, Trowbridge M, Sinn AL, Zhang ZY, Gallagher RI, Wulfkuhle J, Petricoin E, Richardson AM, Marshall MS, Lion A, Ferguson MJ, Balsara KE, Pollok KE. Establishment and characterization of patient-derived xenograft of a rare pediatric anaplastic pleomorphic xanthoastrocytoma (PXA) bearing a CDC42SE2-BRAF fusion. Sci Rep 2023; 13:9163. [PMID: 37280243 PMCID: PMC10244396 DOI: 10.1038/s41598-023-36107-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 05/30/2023] [Indexed: 06/08/2023] Open
Abstract
Pleomorphic xanthoastrocytoma (PXA) is a rare subset of primary pediatric glioma with 70% 5-year disease free survival. However, up to 20% of cases present with local recurrence and malignant transformation into more aggressive type anaplastic PXA (AXPA) or glioblastoma. The understanding of disease etiology and mechanisms driving PXA and APXA are limited, and there is no standard of care. Therefore, development of relevant preclinical models to investigate molecular underpinnings of disease and to guide novel therapeutic approaches are of interest. Here, for the first time we established, and characterized a patient-derived xenograft (PDX) from a leptomeningeal spread of a patient with recurrent APXA bearing a novel CDC42SE2-BRAF fusion. An integrated -omics analysis was conducted to assess model fidelity of the genomic, transcriptomic, and proteomic/phosphoproteomic landscapes. A stable xenoline was derived directly from the patient recurrent tumor and maintained in 2D and 3D culture systems. Conserved histology features between the PDX and matched APXA specimen were maintained through serial passages. Whole exome sequencing (WES) demonstrated a high degree of conservation in the genomic landscape between PDX and matched human tumor, including small variants (Pearson's r = 0.794-0.839) and tumor mutational burden (~ 3 mutations/MB). Large chromosomal variations including chromosomal gains and losses were preserved in PDX. Notably, chromosomal gain in chromosomes 4-9, 17 and 18 and loss in the short arm of chromosome 9 associated with homozygous 9p21.3 deletion involving CDKN2A/B locus were identified in both patient tumor and PDX sample. Moreover, chromosomal rearrangement involving 7q34 fusion; CDC42SE-BRAF t (5;7) (q31.1, q34) (5:130,721,239, 7:140,482,820) was identified in the PDX tumor, xenoline and matched human tumor. Transcriptomic profile of the patient's tumor was retained in PDX (Pearson r = 0.88) and in xenoline (Pearson r = 0.63) as well as preservation of enriched signaling pathways (FDR Adjusted P < 0.05) including MAPK, EGFR and PI3K/AKT pathways. The multi-omics data of (WES, transcriptome, and reverse phase protein array (RPPA) was integrated to deduce potential actionable pathways for treatment (FDR < 0.05) including KEGG01521, KEGG05202, and KEGG05200. Both xenoline and PDX were resistant to the MEK inhibitors trametinib or mirdametinib at clinically relevant doses, recapitulating the patient's resistance to such treatment in the clinic. This set of APXA models will serve as a preclinical resource for developing novel therapeutic regimens for rare anaplastic PXAs and pediatric high-grade gliomas bearing BRAF fusions.
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Affiliation(s)
- Nur P Damayanti
- Neuro-Oncology Program, Pediatric Neurosurgery, Department of Neurosurgery, Indiana University, Indianapolis, IN, 46202, USA
- Department of Neurosurgery, Indiana University, Indianapolis, IN, 46202, USA
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA
| | - M Reza Saadatzadeh
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Erika Dobrota
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Josue D Ordaz
- Department of Neurosurgery, Indiana University, Indianapolis, IN, 46202, USA
| | - Barbara J Bailey
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Indiana University Simon Comprehensive Cancer Center Preclinical Modeling and Therapeutics Core, Indianapolis, USA
| | - Pankita H Pandya
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Khadijeh Bijangi-Vishehsaraei
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Translational Research Integrated Biology Laboratory/Indiana Pediatric Biobank, Riley Children Hospital, Indianapolis, IN, 46202, USA
| | - Harlan E Shannon
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | | | - Kathy Coy
- Indiana University Simon Comprehensive Cancer Center Preclinical Modeling and Therapeutics Core, Indianapolis, USA
| | - Melissa Trowbridge
- Indiana University Simon Comprehensive Cancer Center Preclinical Modeling and Therapeutics Core, Indianapolis, USA
| | - Anthony L Sinn
- Indiana University Simon Comprehensive Cancer Center Preclinical Modeling and Therapeutics Core, Indianapolis, USA
| | - Zhong-Yin Zhang
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana, IN, 47907, USA
| | - Rosa I Gallagher
- Center for Applied Proteomics and Molecular Medicine, Institute for Biomedical Innovation, George Mason University, Manassas, VA, 20110, USA
| | - Julia Wulfkuhle
- Center for Applied Proteomics and Molecular Medicine, Institute for Biomedical Innovation, George Mason University, Manassas, VA, 20110, USA
| | - Emanuel Petricoin
- Center for Applied Proteomics and Molecular Medicine, Institute for Biomedical Innovation, George Mason University, Manassas, VA, 20110, USA
| | - Angela M Richardson
- Department of Neurosurgery, Indiana University, Indianapolis, IN, 46202, USA
- Indiana University Simon Comprehensive Cancer Center Preclinical Modeling and Therapeutics Core, Indianapolis, USA
| | - Mark S Marshall
- Pediatric Cancer Precision Genomics Program, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Alex Lion
- Division of Pediatric Hematology-Oncology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Michael J Ferguson
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA
- Pediatric Cancer Precision Genomics Program, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Division of Pediatric Hematology-Oncology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Karl E Balsara
- Neuro-Oncology Program, Pediatric Neurosurgery, Department of Neurosurgery, Indiana University, Indianapolis, IN, 46202, USA.
- Department of Neurosurgery, University of Oklahoma School of Medicine, Oklahoma City, OH, 73104, USA.
| | - Karen E Pollok
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA.
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
- Indiana University Simon Comprehensive Cancer Center Preclinical Modeling and Therapeutics Core, Indianapolis, USA.
- Pediatric Cancer Precision Genomics Program, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
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Allen MJ, Zhang A, Bavi P, Kim JC, Jang GH, Kelly D, Perera S, Denroche RE, Notta F, Wilson JM, Dodd A, Ramotar S, Hutchinson S, Fischer SE, Grant RC, Gallinger S, Knox JJ, O'Kane GM. Molecular characterisation of pancreatic ductal adenocarcinoma with NTRK fusions and review of the literature. J Clin Pathol 2023; 76:158-165. [PMID: 34583947 DOI: 10.1136/jclinpath-2021-207781] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 09/01/2021] [Indexed: 12/09/2022]
Abstract
AIMS The majority of pancreatic ductal adenocarcinomas (PDACs) harbour oncogenic mutations in KRAS with variants in TP53, CDKN2A and SMAD4 also prevalent. The presence of oncogenic fusions including NTRK fusions are rare but important to identify. Here we ascertain the prevalence of NTRK fusions and document their genomic characteristics in a large series of PDAC. METHODS Whole genome sequencing and RNAseq were performed on a series of patients with resected or locally advanced/metastatic PDAC collected between 2008 and 2020 at a single institution. A subset of specimens underwent immunohistochemistry (IHC) analysis. Clinical and molecular characterisation and IHC sensitivity and specificity were evaluated. RESULTS 400 patients were included (resected n=167; locally advanced/metastatic n=233). Three patients were identified as harbouring an NTRK fusion, two EML4-NTRK3 (KRAS-WT) and a single novel KANK1-NTRK3 fusion. The latter occurring in the presence of a subclonal KRAS mutation. Typical PDAC drivers were present including mutations in TP53 and CDKN2A. Substitution base signatures and tumour mutational burden were similar to typical PDAC. The prevalence of NTRK fusions was 0.8% (3/400), while in KRAS wild-type tumours, it was 6.25% (2/32). DNA prediction alone documented six false-positive cases. RNA analysis correctly identified the in-frame fusion transcripts. IHC analysis was negative in the KANK1-NTRK3 fusion but positive in a EML4-NTRK3 case, highlighting lower sensitivity of IHC. CONCLUSION NTRK fusions are rare; however, with emerging therapeutic options targeting these fusions, detection is vital. Reflex testing for KRAS mutations and subsequent RNA-based screening could help identify these cases in PDAC.
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Affiliation(s)
- Michael J Allen
- Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Hospital, Toronto, Ontario, Canada
| | - Amy Zhang
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Prashant Bavi
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Jaeseung C Kim
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Gun Ho Jang
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Deirdre Kelly
- Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Hospital, Toronto, Ontario, Canada
| | - Sheron Perera
- Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Hospital, Toronto, Ontario, Canada
| | - Rob E Denroche
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Faiyaz Notta
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Julie M Wilson
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Anna Dodd
- Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Hospital, Toronto, Ontario, Canada
| | - Stephanie Ramotar
- Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Hospital, Toronto, Ontario, Canada
| | - Shawn Hutchinson
- Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Hospital, Toronto, Ontario, Canada
| | - Sandra E Fischer
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Robert C Grant
- Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Hospital, Toronto, Ontario, Canada
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Steven Gallinger
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
- Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
- Department of Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Jennifer J Knox
- Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Hospital, Toronto, Ontario, Canada
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Grainne M O'Kane
- Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Hospital, Toronto, Ontario, Canada Grainne.O'
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
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8
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Kurdi M, Moshref RH, Katib Y, Faizo E, Najjar AA, Bahakeem B, Bamaga AK. Simple approach for the histomolecular diagnosis of central nervous system gliomas based on 2021 World Health Organization Classification. World J Clin Oncol 2022; 13:567-576. [PMID: 36157161 PMCID: PMC9346424 DOI: 10.5306/wjco.v13.i7.567] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 04/24/2022] [Accepted: 06/27/2022] [Indexed: 02/06/2023] Open
Abstract
The classification of central nervous system (CNS) glioma went through a sequence of developments, between 2006 and 2021, started with only histological approach then has been aided with a major emphasis on molecular signatures in the 4th and 5th editions of the World Health Organization (WHO). The recent reformation in the 5th edition of the WHO classification has focused more on the molecularly defined entities with better characterized natural histories as well as new tumor types and subtypes in the adult and pediatric populations. These new subclassified entities have been incorporated in the 5th edition after the continuous exploration of new genomic, epigenomic and transcriptomic discovery. Indeed, the current guidelines of 2021 WHO classification of CNS tumors and European Association of Neuro-Oncology (EANO) exploited the molecular signatures in the diagnostic approach of CNS gliomas. Our current review presents a practical diagnostic approach for diffuse CNS gliomas and circumscribed astrocytomas using histomolecular criteria adopted by the recent WHO classification. We also describe the treatment strategies for these tumors based on EANO guidelines.
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Affiliation(s)
- Maher Kurdi
- Department of Pathology, Faculty of Medicine, King Abdulaziz University, Jeddah 213733, Saudi Arabia
| | - Rana H Moshref
- Department of Neurosciences, King Faisal Specialist Hospital and Research Center, Jeddah 213733, Saudi Arabia
| | - Yousef Katib
- Department of Radiology, Faculty of Medicine, Taibah University, Almadinah Almunawwarah 213733, Saudi Arabia
| | - Eyad Faizo
- Division of Neurosurgery, Department of Surgery, Faculty of Medicine, Tabuk University, Tabuk 213733, Saudi Arabia
| | - Ahmed A Najjar
- College of Medicine, Taibah University, Almadinah Almunawwarah 213733, Saudi Arabia
| | - Basem Bahakeem
- Faculty of Medicine, Umm-Alqura University, Makkah 213733, Saudi Arabia
| | - Ahmed K Bamaga
- Department of Pediatric, Neuromuscular Medicine Unit, Faculty of Medicine and King Abdulaziz University Hospital, King Abdulaziz University, Jeddah 213733, Saudi Arabia
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9
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NTRK2 gene fusions are uncommon in pilocytic astrocytoma. Mol Biol Rep 2022; 49:7567-7573. [PMID: 35713800 DOI: 10.1007/s11033-022-07567-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 04/23/2022] [Accepted: 05/04/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND Pilocytic astrocytoma is the most frequent pediatric glioma. Despite its overall good prognosis, complete surgical resection is sometimes unfeasible, especially for patients with deep-seated tumors. For these patients, the identification of targetable genetic alterations such as NTRK fusions, raised as a new hope for therapy. The presence of gene fusions involving NTRK2 has been rarely reported in pilocytic astrocytoma. The aim of the present study was to investigate the frequency of NTRK2 alterations in a series of Brazilian pilocytic astrocytomas. METHODS Sixty-nine pilocytic astrocytomas, previously characterized for BRAF and FGFR1 alterations were evaluated. The analysis of NTRK2 alterations was performed using a dual color break apart fluorescence in situ hybridization (FISH) assay. RESULTS NTRK2 fusions were successfully evaluated by FISH in 62 of the 69 cases. Neither evidence of NTRK2 gene rearrangements nor NTRK2 copy number alterations were found. CONCLUSIONS NTRK2 alterations are uncommon genetic events in pilocytic astrocytomas, regardless of patients' clinicopathological and molecular features.
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10
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Saliba J, Church AJ, Rao S, Danos A, Furtado LV, Laetsch T, Zhang L, Nardi V, Lin WH, Ritter DI, Madhavan S, Li MM, Griffith OL, Griffith M, Raca G, Roy A. Standardized evidence-based approach for assessment of oncogenic and clinical significance of NTRK fusions. Cancer Genet 2022; 264-265:50-59. [PMID: 35366592 PMCID: PMC9252326 DOI: 10.1016/j.cancergen.2022.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 02/13/2022] [Accepted: 03/07/2022] [Indexed: 11/17/2022]
Abstract
Gene fusions involving the neurotrophic receptor tyrosine kinase genes NTRK1, NTRK2, and NTRK3, are well established oncogenic drivers in a broad range of pediatric and adult tumors. These fusions are also important actionable markers, predicting often dramatic response to FDA approved kinase inhibitors. Accurate interpretation of the clinical significance of NTRK fusions is a high priority for diagnostic laboratories, but remains challenging and time consuming given the rapid pace of new data accumulation, the diversity of fusion partners and tumor types, and heterogeneous and incomplete information in variant databases and knowledgebases. The ClinGen NTRK Fusions Somatic Cancer Variant Curation Expert Panel (SC-VCEP) was formed to systematically address these challenges and create an expert-curated resource to support clinicians, researchers, patients and their families in making accurate interpretations and informed treatment decisions for NTRK fusion-driven tumors. We describe a system for NTRK fusion interpretation (including compilation of key elements and annotations) developed by the NTRK fusions SC-VCEP. We illustrate this stepwise process on examples of LMNA::NTRK1 and KANK1::NTRK2 fusions. Finally, we provide detailed analysis of current representation of NTRK fusions in public fusion databases and the CIViC knowledgebase, performed by the NTRK fusions SC-VCEP to determine existing gaps and prioritize future curation activities.
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Affiliation(s)
- Jason Saliba
- Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO United States
| | - Alanna J Church
- Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States
| | - Shruti Rao
- Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington D.C., United States
| | - Arpad Danos
- Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO United States
| | - Larissa V Furtado
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, United States
| | - Theodore Laetsch
- Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Liying Zhang
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, United States
| | - Valentina Nardi
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Wan-Hsin Lin
- Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, FL, United States
| | - Deborah I Ritter
- Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, United States
| | - Subha Madhavan
- Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington D.C., United States; AstraZeneca, Cambridge, United Kingdom
| | - Marilyn M Li
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
| | - Obi L Griffith
- Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO United States
| | - Malachi Griffith
- Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO United States
| | - Gordana Raca
- Department of Pathology and Laboratory Medicine, Children's Hospital of Los Angeles, Los Angeles, CA, United States
| | - Angshumoy Roy
- Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, United States; Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, United States; Department of Pathology, Texas Children's Hospital, Houston, TX, United States.
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11
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Roosen M, Odé Z, Bunt J, Kool M. The oncogenic fusion landscape in pediatric CNS neoplasms. Acta Neuropathol 2022; 143:427-451. [PMID: 35169893 PMCID: PMC8960661 DOI: 10.1007/s00401-022-02405-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/31/2022] [Accepted: 01/31/2022] [Indexed: 01/09/2023]
Abstract
Pediatric neoplasms in the central nervous system (CNS) are the leading cause of cancer-related deaths in children. Recent developments in molecular analyses have greatly contributed to a more accurate diagnosis and risk stratification of CNS tumors. Additionally, sequencing studies have identified various, often entity specific, tumor-driving events. In contrast to adult tumors, which often harbor multiple mutated oncogenic drivers, the number of mutated genes in pediatric cancers is much lower and many tumors can have a single oncogenic driver. Moreover, in children, much more than in adults, fusion proteins play an important role in driving tumorigenesis, and many different fusions have been identified as potential driver events in pediatric CNS neoplasms. However, a comprehensive overview of all the different reported oncogenic fusion proteins in pediatric CNS neoplasms is still lacking. A better understanding of the fusion proteins detected in these tumors and of the molecular mechanisms how these proteins drive tumorigenesis, could improve diagnosis and further benefit translational research into targeted therapies necessary to treat these distinct entities. In this review, we discuss the different oncogenic fusions reported in pediatric CNS neoplasms and their structure to create an overview of the variety of oncogenic fusion proteins to date, the tumor entities they occur in and their proposed mode of action.
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Affiliation(s)
- Mieke Roosen
- Princess Máxima Center for Pediatric Oncology, 3584CS, Utrecht, The Netherlands
| | - Zelda Odé
- Princess Máxima Center for Pediatric Oncology, 3584CS, Utrecht, The Netherlands
| | - Jens Bunt
- Princess Máxima Center for Pediatric Oncology, 3584CS, Utrecht, The Netherlands
| | - Marcel Kool
- Princess Máxima Center for Pediatric Oncology, 3584CS, Utrecht, The Netherlands.
- Hopp Children's Cancer Center (KiTZ), 69120, Heidelberg, Germany.
- Division of Pediatric Neurooncology, German Cancer Research Center DKFZ and German Cancer Consortium DKTK, 69120, Heidelberg, Germany.
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12
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Lang SS, Kumar NK, Madsen P, Gajjar AA, Gajjar E, Resnick AC, Storm PB. Neurotrophic Tyrosine Receptor Kinase Fusion in Pediatric Central Nervous System Tumors. Cancer Genet 2022; 262-263:64-70. [DOI: 10.1016/j.cancergen.2022.01.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 11/29/2021] [Accepted: 01/18/2022] [Indexed: 12/16/2022]
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13
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Mangum R, Reuther J, Bertrand KC, Chandramohan R, Kukreja MK, Paulino AC, Muzny D, Hu J, Gibbs RA, Curry DJ, Malbari F, Chintagumpala MM, Adesina AM, Fisher KE, Mack SC, Plon SE, Roy A, Parsons DW, Lin FY. Durable Response to Larotrectinib in a Child With Histologic Diagnosis of Recurrent Disseminated Ependymoma Discovered to Harbor an NTRK2 Fusion: The Impact of Integrated Genomic Profiling. JCO Precis Oncol 2021; 5:PO.20.00375. [PMID: 34651095 DOI: 10.1200/po.20.00375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 01/11/2021] [Accepted: 05/26/2021] [Indexed: 11/20/2022] Open
Affiliation(s)
- Ross Mangum
- Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX
| | - Jacquelyn Reuther
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX
| | - Kelsey C Bertrand
- Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX
| | - Raghu Chandramohan
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
| | | | - Arnold C Paulino
- Department of Radiation Oncology, MD Anderson Cancer Center, Houston, TX
| | - Donna Muzny
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.,The Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX
| | - Jianhong Hu
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.,The Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX
| | - Richard A Gibbs
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.,The Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX
| | - Daniel J Curry
- Division of Pediatric Neurosurgery, Department of Neurosurgery, Baylor College of Medicine, Houston, TX
| | - Fatema Malbari
- Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.,Division of Pediatric Neurology and Developmental Neurosciences, Department of Pediatrics, Texas Children's Hospital, Houston, TX
| | - Murali M Chintagumpala
- Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.,The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX
| | - Adekunle M Adesina
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX.,The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX.,Department of Pathology, Texas Children's Hospital, Houston, TX
| | - Kevin E Fisher
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX.,The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX.,Department of Pathology, Texas Children's Hospital, Houston, TX
| | - Stephen C Mack
- Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.,The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX
| | - Sharon E Plon
- Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.,Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.,The Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX.,The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX
| | - Angshumoy Roy
- Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.,Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX.,The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX.,Department of Pathology, Texas Children's Hospital, Houston, TX
| | - D Williams Parsons
- Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.,Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.,The Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX.,The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX
| | - Frank Y Lin
- Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.,The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX
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14
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Deland L, Keane S, Olsson Bontell T, Sjögren H, Fagman H, Øra I, De La Cuesta E, Tisell M, Nilsson JA, Ejeskär K, Sabel M, Abel F. Discovery of a rare GKAP1-NTRK2 fusion in a pediatric low-grade glioma, leading to targeted treatment with TRK-inhibitor larotrectinib. Cancer Biol Ther 2021; 22:184-195. [PMID: 33820494 PMCID: PMC8043191 DOI: 10.1080/15384047.2021.1899573] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Here we report a case of an 11-year-old girl with an inoperable tumor in the optic chiasm/hypothalamus, who experienced several tumor progressions despite three lines of chemotherapy treatment. Routine clinical examination classified the tumor as a BRAF-negative pilocytic astrocytoma. Copy-number variation profiling of fresh frozen tumor material identified two duplications in 9q21.32–33 leading to breakpoints within the GKAP1 and NTRK2 genes. RT-PCR Sanger sequencing revealed a GKAP1-NTRK2 exon 10–16 in-frame fusion, generating a putative fusion protein of 658 amino acids with a retained tyrosine kinase (TK) domain. Functional analysis by transient transfection of HEK293 cells showed the GKAP1-NTRK2 fusion protein to be activated through phosphorylation of the TK domain (Tyr705). Subsequently, downstream mediators of the MAPK- and PI3K-signaling pathways were upregulated in GKAP1-NTRK2 cells compared to NTRK2 wild-type; phosphorylated (p)ERK (3.6-fold), pAKT (1.8- fold), and pS6 ribosomal protein (1.4-fold). Following these findings, the patient was enrolled in a clinical trial and treated with the specific TRK-inhibitor larotrectinib, resulting in the arrest of tumor growth. The patient’s condition is currently stable and the quality of life has improved significantly. Our findings highlight the value of comprehensive clinical molecular screening of BRAF-negative pediatric low-grade gliomas, to reveal rare fusions serving as targets for precision therapy.
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Affiliation(s)
- Lily Deland
- Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden.,Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Simon Keane
- Translational Medicine, School of Health Sciences, University of Skövde, Skövde, Sweden
| | - Thomas Olsson Bontell
- Department of Clinical Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden.,Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Helene Sjögren
- Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Henrik Fagman
- Department of Clinical Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Ingrid Øra
- Department of Clinical Sciences, Lund University Hospital, Lund, Sweden.,HOPE/ITCC Phase I/II Trial Unit, Pediatric Oncology, Karolinska Hospital, Stockholm, Sweden
| | - Esther De La Cuesta
- Pharmaceuticals, Global Medical Affairs - Oncology, Bayer U.S., Whippany, USA
| | - Magnus Tisell
- Department of Clinical Neuroscience and Rehabilitation, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Jonas A Nilsson
- Sahlgrenska Cancer Center, Department of Laboratory Medicine Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Katarina Ejeskär
- Translational Medicine, School of Health Sciences, University of Skövde, Skövde, Sweden
| | - Magnus Sabel
- Childhood Cancer Centre, Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden.,Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Frida Abel
- Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden.,Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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15
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Zhao X, Kotch C, Fox E, Surrey LF, Wertheim GB, Baloch ZW, Lin F, Pillai V, Luo M, Kreiger PA, Pogoriler JE, Linn RL, Russo PA, Santi M, Resnick AC, Storm PB, Hunger SP, Bauer AJ, Li MM. NTRK Fusions Identified in Pediatric Tumors: The Frequency, Fusion Partners, and Clinical Outcome. JCO Precis Oncol 2021; 1:PO.20.00250. [PMID: 34036219 PMCID: PMC8140782 DOI: 10.1200/po.20.00250] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 08/26/2020] [Accepted: 12/04/2020] [Indexed: 12/18/2022] Open
Abstract
Neurotrophic tyrosine receptor kinase (NTRK) fusions have been described as
oncogenic drivers in a variety of tumors. However, little is known about the
overall frequency of NTRK fusion in unselected pediatric tumors. Here, we
assessed the frequency, fusion partners, and clinical course in pediatric
patients with NTRK fusion–positive tumors.
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Affiliation(s)
- Xiaonan Zhao
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Chelsea Kotch
- Department of Pediatrics, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.,Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Elizabeth Fox
- Department of Pediatrics, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.,Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Lea F Surrey
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Gerald B Wertheim
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Zubair W Baloch
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Fumin Lin
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Vinodh Pillai
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Minjie Luo
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Portia A Kreiger
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Jennifer E Pogoriler
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Rebecca L Linn
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Pierre A Russo
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Mariarita Santi
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Adam C Resnick
- Department of Pediatrics, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.,Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Phillip B Storm
- Department of Pediatrics, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.,Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Stephen P Hunger
- Department of Pediatrics, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.,Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Andrew J Bauer
- Department of Pediatrics, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.,Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Marilyn M Li
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.,Department of Pediatrics, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.,Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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16
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Zou W, Hu X, Jiang L. Advances in Regulating Tumorigenicity and Metastasis of Cancer Through TrkB Signaling. Curr Cancer Drug Targets 2020; 20:779-788. [PMID: 32748747 DOI: 10.2174/1568009620999200730183631] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 06/27/2020] [Accepted: 06/29/2020] [Indexed: 01/12/2023]
Abstract
The clinical pathology of various human malignancies is supported by tropomyosin receptor kinase (Trk) B TrkB which is a specific binding receptor of the brain-derived neurotrophic factor (BDNF). TrkB and TrkB fusion proteins have been observed to be over-expressed in many cancer patients. Moreover, these proteins have been observed in multiple types of cells. A few signaling pathways can be modulated by the abnormal activation of the BDNF/TrkB pathway. These signaling pathways include PI3K/Akt pathway, transactivation of EGFR, phospholipase C-gamma (PLCγ) pathway, Ras-Raf-MEK-ERK pathway, Jak/STAT pathway, and nuclear factor kappalight- chain-enhancer of activated B cells (NF-kB) pathway. The BDNF/TrkB pathway, when overexpressed in tumors, is correlated with reduced clinical prognosis and short survival time of patients. Targeting the BDNF/TrkB pathway and the use of Trk inhibitors, such as entrectinib, larotrectinib, etc. are promising methods for targeted therapy of tumors. The present review provides an overview of the role of the TrkB pathway in the pathogenesis of cancer and its value as a potential therapeutic target.
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Affiliation(s)
- Wujun Zou
- Department of Otorhinolaryngology, Head and Neck Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, China
| | - Xiaoyan Hu
- Department of Pathogenic Biology, School of Basic Medicine, Southwest Medical University, Luzhou, Sichuan, China
| | - Liang Jiang
- Department of Otorhinolaryngology, Head and Neck Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, China
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17
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Torre M, Vasudevaraja V, Serrano J, DeLorenzo M, Malinowski S, Blandin AF, Pages M, Ligon AH, Dong F, Meredith DM, Nasrallah MP, Horbinski C, Dahiya S, Ligon KL, Santi M, Ramkissoon SH, Filbin MG, Snuderl M, Alexandrescu S. Molecular and clinicopathologic features of gliomas harboring NTRK fusions. Acta Neuropathol Commun 2020; 8:107. [PMID: 32665022 PMCID: PMC7362646 DOI: 10.1186/s40478-020-00980-z] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 06/24/2020] [Indexed: 01/07/2023] Open
Abstract
Fusions involving neurotrophic tyrosine receptor kinase (NTRK) genes are detected in ≤2% of gliomas and can promote gliomagenesis. The remarkable therapeutic efficacy of TRK inhibitors, which are among the first Food and Drug Administration-approved targeted therapies for NTRK-fused gliomas, has generated significant clinical interest in characterizing these tumors. In this multi-institutional retrospective study of 42 gliomas with NTRK fusions, next generation DNA sequencing (n = 41), next generation RNA sequencing (n = 1), RNA-sequencing fusion panel (n = 16), methylation profile analysis (n = 18), and histologic evaluation (n = 42) were performed. All infantile NTRK-fused gliomas (n = 7) had high-grade histology and, with one exception, no other significant genetic alterations. Pediatric NTRK-fused gliomas (n = 13) typically involved NTRK2, ranged from low- to high-histologic grade, and demonstrated histologic overlap with desmoplastic infantile ganglioglioma, pilocytic astrocytoma, ganglioglioma, and glioblastoma, among other entities, but they rarely matched with high confidence to known methylation class families or with each other; alterations involving ATRX, PTEN, and CDKN2A/2B were present in a subset of cases. Adult NTRK-fused gliomas (n = 22) typically involved NTRK1 and had predominantly high-grade histology; genetic alterations involving IDH1, ATRX, TP53, PTEN, TERT promoter, RB1, CDKN2A/2B, NF1, and polysomy 7 were common. Unsupervised principal component analysis of methylation profiles demonstrated no obvious grouping by histologic grade, NTRK gene involved, or age group. KEGG pathway analysis detected methylation differences in genes involved in PI3K/AKT, MAPK, and other pathways. In summary, the study highlights the clinical, histologic, and molecular heterogeneity of NTRK-fused gliomas, particularly when stratified by age group.
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Affiliation(s)
- Matthew Torre
- Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115 USA
- Department of Pathology, Boston Children’s Hospital and Harvard Medical School, 300 Longwood Ave, Bader Building, Boston, MA 02115 USA
| | - Varshini Vasudevaraja
- Department of Pathology, NYU Langone Health, 550 First Avenue, New York, NY 10016 USA
| | - Jonathan Serrano
- Department of Pathology, NYU Langone Health, 550 First Avenue, New York, NY 10016 USA
| | - Michael DeLorenzo
- Department of Pathology, NYU Langone Health, 550 First Avenue, New York, NY 10016 USA
| | - Seth Malinowski
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115 USA
| | - Anne-Florence Blandin
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115 USA
| | - Melanie Pages
- Department of Neuropathology, GHU Paris Sainte-Anne Hospital, 1 Rue Cabanis, 75014 Paris, France
| | - Azra H. Ligon
- Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115 USA
- Center for Advanced Molecular Diagnostics, Brigham and Women’s Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115 USA
| | - Fei Dong
- Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115 USA
| | - David M. Meredith
- Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115 USA
| | - MacLean P. Nasrallah
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street 34th St, Philadelphia, PA 19104 USA
| | - Craig Horbinski
- Department of Neurological Surgery, Northwestern University, Chicago, IL USA
- Department of Pathology, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611 USA
| | - Sonika Dahiya
- Division of Neuropathology, Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8118, St. Louis, MO 63110 USA
| | - Keith L. Ligon
- Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115 USA
- Department of Pathology, Boston Children’s Hospital and Harvard Medical School, 300 Longwood Ave, Bader Building, Boston, MA 02115 USA
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115 USA
| | - Mariarita Santi
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street 34th St, Philadelphia, PA 19104 USA
- Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA USA
| | - Shakti H. Ramkissoon
- Foundation Medicine, 7010 Kit Creek Road, Morrisville, NC 27560 USA
- Wake Forest Comprehensive Cancer Center and Department of Pathology, Wake Forest School of Medicine, Winston-Salem, 27157 NC USA
| | - Mariella G. Filbin
- Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215 USA
| | - Matija Snuderl
- Department of Pathology, NYU Langone Health, 550 First Avenue, New York, NY 10016 USA
| | - Sanda Alexandrescu
- Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115 USA
- Department of Pathology, Boston Children’s Hospital and Harvard Medical School, 300 Longwood Ave, Bader Building, Boston, MA 02115 USA
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18
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Pattwell SS, Arora S, Cimino PJ, Ozawa T, Szulzewsky F, Hoellerbauer P, Bonifert T, Hoffstrom BG, Boiani NE, Bolouri H, Correnti CE, Oldrini B, Silber JR, Squatrito M, Paddison PJ, Holland EC. A kinase-deficient NTRK2 splice variant predominates in glioma and amplifies several oncogenic signaling pathways. Nat Commun 2020; 11:2977. [PMID: 32532995 PMCID: PMC7293284 DOI: 10.1038/s41467-020-16786-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 05/26/2020] [Indexed: 12/17/2022] Open
Abstract
Independent scientific achievements have led to the discovery of aberrant splicing patterns in oncogenesis, while more recent advances have uncovered novel gene fusions involving neurotrophic tyrosine receptor kinases (NTRKs) in gliomas. The exploration of NTRK splice variants in normal and neoplastic brain provides an intersection of these two rapidly evolving fields. Tropomyosin receptor kinase B (TrkB), encoded NTRK2, is known for critical roles in neuronal survival, differentiation, molecular properties associated with memory, and exhibits intricate splicing patterns and post-translational modifications. Here, we show a role for a truncated NTRK2 splice variant, TrkB.T1, in human glioma. TrkB.T1 enhances PDGF-driven gliomas in vivo, augments PDGF-induced Akt and STAT3 signaling in vitro, while next generation sequencing broadly implicates TrkB.T1 in the PI3K signaling cascades in a ligand-independent fashion. These TrkB.T1 findings highlight the importance of expanding upon whole gene and gene fusion analyses to include splice variants in basic and translational neuro-oncology research.
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Affiliation(s)
- Siobhan S Pattwell
- Human Biology Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Mailstop C3-168, Seattle, WA, 98109, USA
| | - Sonali Arora
- Human Biology Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Mailstop C3-168, Seattle, WA, 98109, USA
| | - Patrick J Cimino
- Human Biology Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Mailstop C3-168, Seattle, WA, 98109, USA
- Department of Pathology, University of Washington School of Medicine, 325 9th Avenue, Box 359791, Seattle, WA, 98104, USA
| | - Tatsuya Ozawa
- Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Frank Szulzewsky
- Human Biology Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Mailstop C3-168, Seattle, WA, 98109, USA
| | - Pia Hoellerbauer
- Human Biology Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Mailstop C3-168, Seattle, WA, 98109, USA
- Molecular and Cellular Biology Program, University of Washington, Seattle, WA, 98195, USA
| | - Tobias Bonifert
- Human Biology Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Mailstop C3-168, Seattle, WA, 98109, USA
| | - Benjamin G Hoffstrom
- Antibody Technology Resource, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA, 98109, USA
| | - Norman E Boiani
- Antibody Technology Resource, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA, 98109, USA
| | - Hamid Bolouri
- Human Biology Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Mailstop C3-168, Seattle, WA, 98109, USA
- Systems Immunology, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA, 98101, USA
| | - Colin E Correnti
- Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA, 98109, USA
| | - Barbara Oldrini
- Seve Ballesteros Foundation Brain Tumor Group, Spanish National Cancer Research Centre, 28209, Madrid, Spain
| | - John R Silber
- Department of Neurological Surgery, Alvord Brain Tumor Center, University of Washington School of Medicine, Seattle, WA, 98104, USA
| | - Massimo Squatrito
- Seve Ballesteros Foundation Brain Tumor Group, Spanish National Cancer Research Centre, 28209, Madrid, Spain
| | - Patrick J Paddison
- Human Biology Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Mailstop C3-168, Seattle, WA, 98109, USA
- Molecular and Cellular Biology Program, University of Washington, Seattle, WA, 98195, USA
| | - Eric C Holland
- Human Biology Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Mailstop C3-168, Seattle, WA, 98109, USA.
- Department of Neurological Surgery, Alvord Brain Tumor Center, University of Washington School of Medicine, Seattle, WA, 98104, USA.
- Seattle Tumor Translational Research Center, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA, 98109, USA.
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19
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The histomolecular criteria established for adult anaplastic pilocytic astrocytoma are not applicable to the pediatric population. Acta Neuropathol 2020; 139:287-303. [PMID: 31677015 PMCID: PMC6989446 DOI: 10.1007/s00401-019-02088-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 10/21/2019] [Accepted: 10/22/2019] [Indexed: 12/18/2022]
Abstract
Pilocytic astrocytoma (PA) is the most common pediatric glioma, arising from a single driver MAPK pathway alteration. Classified as a grade I tumor according to the 2016 WHO classification, prognosis is excellent with a 10-year survival rate > 95% after surgery. However, rare cases present with anaplastic features, including an unexpected high mitotic/proliferative index, thus posing a diagnostic and therapeutic challenge. Based on small histomolecular series and case reports, such tumors arising at the time of diagnosis or recurrence have been designated by many names including pilocytic astrocytoma with anaplastic features (PAAF). Recent DNA methylation-profiling studies performed mainly on adult cases have revealed that PAAF exhibit a specific methylation signature, thus constituting a distinct methylation class from typical PA [methylation class anaplastic astrocytoma with piloid features-(MC-AAP)]. However, the diagnostic and prognostic significance of MC-AAP remains to be determined in children. We performed an integrative work on the largest pediatric cohort of PAAF, defined according to strict criteria: morphology compatible with the diagnosis of PA, with or without necrosis, ≥ 4 mitoses for 2.3 mm2, and MAPK pathway alteration. We subjected 31 tumors to clinical, imaging, morphological and molecular analyses, including DNA methylation profiling. We identified only one tumor belonging to the MC-AAP (3%), the others exhibiting a methylation profile typical for PA (77%), IDH-wild-type glioblastoma (7%), and diffuse leptomeningeal glioneuronal tumor (3%), while three cases (10%) did not match to a known DNA methylation class. No significant outcome differences were observed between PAAF with necrosis versus no necrosis (p = 0.07), or with 4-6 mitoses versus 7 or more mitoses (p = 0.857). Our findings argue that the diagnostic histomolecular criteria established for anaplasia in adult PA are not of diagnostic or prognostic value in a pediatric setting. Further extensive and comprehensive integrative studies are necessary to accurately define this exceptional entity in children.
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20
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Neurotrophic Receptor Tyrosine Kinase 2 ( NTRK2) Alterations in Low-Grade Gliomas: Report of a Novel Gene Fusion Partner in a Pilocytic Astrocytoma and Review of the Literature. Case Rep Pathol 2020; 2020:5903863. [PMID: 32082673 PMCID: PMC7013287 DOI: 10.1155/2020/5903863] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 12/14/2019] [Indexed: 12/16/2022] Open
Abstract
Pilocytic astrocytoma is a low-grade glial neoplasm of the central nervous system (CNS) that tends to occur in the pediatric population and less commonly presents in adults. Hereditary pilocytic astrocytoma is often associated with germline genetic alterations in the tumor suppressor NF1, the gene responsible for the syndrome neurofibromatosis type 1. Sporadic pilocytic astrocytoma frequently harbors somatic alterations in BRAF, with rare pilocytic astrocytomas containing alterations in FGFR1 and NTRK2. NTRK2 encodes for the protein tropomyosin receptor kinase B (TrkB), which is a neurotrophin receptor with high affinity for Brain-Derived Neurotrophic Factor (BDNF), and plays a role in several physiological functions of neurons, including cell survival and differentiation. In this report, we describe a novel PML-NTRK2 gene fusion occurring in an adult sporadic pilocytic astrocytoma and review the biology and implications of specific NTRK2 mutations occurring in CNS neoplasms.
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