High-Grade Glial Tumors Associated with ETV6-NTRK3 Gene Fusion: Imaging Appearance with Pathologic Correlate
Joshua P. NickersonMatthew D. WoodM. Mossa-BashaC.G. FilippiD. ZarnowJ. JiJaclyn A. BiegelYassmine AkkariG. IshakRamon Barajas
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Genetic analysis of high-grade glial tumors in children has revealed the presence of the ETV6-NTRK3 gene fusion in a small number of highly aggressive‐appearing neoplasms. Identification of this gene fusion is important in that these patients may benefit from new, targeted therapies. Clinical presentation, imaging, and pathologic confirmation were obtained from 5 patients with confirmed ETV6-NTRK3 gene fusion. This case series may raise awareness of this entity and prompt genetic evaluation.Keywords:
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Abstract Translocations of Meningioma-1 (MN1) occur in a subset of acute myeloid leukemias (AML) and result in high expression of MN1, either as a full-length protein, or as a fusion protein that includes most of the N-terminus of MN1. High levels of MN1 correlate with poor prognosis. When overexpressed in murine hematopoietic progenitors, MN1 causes an aggressive AML characterized by an aberrant myeloid precursor-like gene expression program that shares features of KMT2A -rearranged ( KMT2A -r) leukemia, including high levels of Hoxa and Meis1 gene expression. Compounds that target a critical KMT2A–Menin interaction have proven effective in KMT2A -r leukemia. Here, we demonstrate that Menin ( Men1 ) is also critical for the self-renewal of MN1-driven AML through the maintenance of a distinct gene expression program. Genetic inactivation of Men1 led to a decrease in the number of functional leukemia-initiating cells. Pharmacologic inhibition of the KMT2A–Menin interaction decreased colony-forming activity, induced differentiation programs in MN1-driven murine leukemia and decreased leukemic burden in a human AML xenograft carrying an MN1-ETV6 translocation. Collectively, these results nominate Menin inhibition as a promising therapeutic strategy in MN1-driven leukemia.
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Abstract Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and comprises a heterogeneous group of diseases. A number of recurrent leukemogenic gene mutations or chromosomal rearrangements have been identified and clinically validated in AML. However, nearly 50% of AML patient samples lack any known canonical AML driver mutations. Advances in molecular diagnostics have resulted in the identification of novel and actionable gene mutations or chromosomal rearrangements in a subset of these AML samples. The ETV6-NTRK3 fusion gene is one such rearrangement identified in samples from patients with AML. Fusion of ETV6 to the tyrosine kinase domain of TRKC (encoded by NTRK3) results in constitutive activation of the TRKC kinase, and ETV6-TRKC fusion protein expression has been shown to be sufficient for leukemogenesis. Constitutive activation of TRK family tyrosine kinases has also been detected in a wide range solid tumor and hematologic malignancies including lung, colorectal, salivary gland, sarcoma, thyroid, glioblastoma, melanoma, anaplastic large cell lymphoma, and Philadelphia-like acute lymphoblastic leukemia. Entrectinib (RXDX-101) is an investigational, orally available, CNS-active, highly potent, and selective kinase inhibitor with low nanomolar potency against TRKA/B/C, ROS1 and ALK kinase activities (encoded by NTRK1/2/3, ROS1, and ALK genes, respectively). In these studies, we have demonstrated sensitivity to entrectinib in AML cell lines with endogenous expression of the ETV6-NTRK3 fusion gene. Entrectinib treatment blocked cell proliferation and induced apoptotic cell death in vitro with sub-nanomolar IC50 values. Phosphorylation of the ETV6-TRKC fusion protein, as well as phosphorylation of known TRKC downstream signaling effectors, was inhibited by entrectinib treatment in a dose-dependent manner. Sensitivity to entrectinib was dependent on expression of the TRKC fusion protein. In xenograft models, entrectinib treatment at clinically relevant doses resulted in tumor regression, which was accompanied by elimination of residual cancer cells from the bone marrow. The clinical relevance of activated oncogenic tyrosine kinases resulting from chromosomal rearrangements has been validated by the efficacy of selective tyrosine kinase inhibitors. Entrectinib is currently the subject of STARTRK-2, an ongoing global phase 2 basket study enrolling patients across multiple tumor histologies containing TRK, ROS1, or ALK fusions. Our preclinical data demonstrate the potential of entrectinib as an effective treatment for patients with NTRK rearranged acute myeloid leukemia and provide a rationale for the clinical development of entrectinib in molecularly defined hematologic malignancies. Citation Format: Patrick Fagan, Maria Barrera, Colin Walsh, Danielle Murphy, Ian Silverman, Robert Shoemaker, Ge Wei, Zachary Hornby, Gary Li, Kristen M. Smith. Antitumor activity of entrectinib, a highly potent pan-TRK, ROS1, and ALK inhibitor, in NTRK-fusion positive acute myeloid leukemia [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 52.
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Targeted therapy for metastatic colorectal carcinoma consists of anti-EGFR therapy for patients with RAS/RAF wild-type tumors. However, the response rate remains low, suggesting the presence of alternative drivers possibly also representing potential therapeutic targets. We investigated receptor tyrosine kinase (RTK) alterations and MAP2K1 (MEK1) mutations in a large cohort of colorectal carcinoma patients studied by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and The Cancer Genome Atlas, focusing on amplifications, fusions, and hotspot mutations in RTK genes and MAP2K1. RTK gene amplifications were confirmed with FISH and immunohistochemical (IHC) staining. Among 751 colorectal carcinoma cases with next-generation sequencing data, 7% and 1% of colorectal carcinoma harbored RTK alterations and MAP2K1 hotspot mutations (n = 7), respectively. RTK-altered cases had fewer concurrent RAS/RAF mutations (P = 0.003) than RTK/MAP2K1 wild-type colorectal carcinoma. MAP2K1-mutated colorectal carcinoma showed no RAS/RAF mutations. ERBB2 (n = 32) and EGFR (n = 13) were the most frequently altered RTKs, both activated by amplification and/or hotspot mutations. Three RTK fusions were identified: NCOA4-RET, ERBB2-GRB7, and ETV6-NTRK3. Only 1 of 6 patients with an RTK or MAP2K1 alteration who received anti-EGFR and/or anti-ERBB2 therapy demonstrated stable disease; the rest progressed immediately. Overall, RTK alterations and MAP2K1 mutations occur in approximately 8% of colorectal carcinoma. In spite of the usual absence of RAS/RAF mutations, response to anti-EGFR and/or anti-ERBB2 therapy was poor in this limited group. Larger studies are warranted to further define these kinase alterations as novel therapeutic targets in colorectal carcinoma and as negative predictors of response to anti-EGFR therapy.Targetable kinase alterations were identified in a subset of advanced colorectal carcinoma patients, preferentially associated with wild-type RAS/RAF, and may predict poor response to standard anti-EGFR therapy.
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Background: Mammary analogue secretory carcinoma (MASC) is characterized by similar histologic, immunohistochemical, and molecular features with breast secretory carcinoma. MASC usually occurs in adults. Case report: A 4-year-old boy presented with a right infra-auricular mass. Features of the tumor include solid, tubular, and papillary growth patterns, with homogenous eosinophilic secretions inside microcystic structures. Immunohistochemical stains showed strong, diffuse staining for CK7, S100, pan-TRK protein. P63 was positive in a peripheral pattern. Fluorescence in situ hybridization (FISH) analysis showed the characteristic ETV6-NTRK3 gene fusion. Conclusion: Typical histological, immunohistochemical, and molecular features are present in MASC occurring early in childhood.
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