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      Oncogenic codon 13 NRAS mutation in a primary mesenchymal brain neoplasm and nevus of a child with neurocutaneous melanosis

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          Abstract

          A 28-month female with a clinical diagnosis of neurocutaneous melanosis and numerous intracranial abnormalities (including a right choroid plexus tumor and left hemimegalencephaly) presented with a rapidly expanding tumor in the left occipital cerebrum. Microscopic examination of the resected specimen revealed a myxoid mesenchymal neoplasm consisting of fusiform cells that were immunoreactive for vimentin, CD34, and P53 but no melanocyte markers. Focused amplicon deep sequencing on DNA extracted from the brain tumor and a cutaneous nevus revealed a heterozygous (c.37G > C; p.G13R) substitution in the NRAS gene. DNA sequencing of “normal” skin and buccal swab showed the identical NRAS change albeit at lower allelic frequency. Her parents did not harbor the NRAS mutation. The skin lesion, but not the brain tumor, had a BRAF mutation (c.1397G > T; p.G466V). A germline single nucleotide polymorphism in MET was found in the child and her father (c.3209C > T; p.T1010I). The findings suggest NRAS mosaicism that occurred sometime after conception and imply an oncogenic role of the activating NRAS mutation in both the brain and skin lesions in this child.

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          Most cited references 47

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          Invasive growth: a MET-driven genetic programme for cancer and stem cells.

          Metastasis follows the inappropriate activation of a genetic programme termed invasive growth, which is a physiological process that occurs during embryonic development and post-natal organ regeneration. Burgeoning evidence indicates that invasive growth is also executed by stem and progenitor cells, and is usurped by cancer stem cells. The MET proto-oncogene, which is expressed in both stem and cancer cells, is a key regulator of invasive growth. Recent findings indicate that the MET tyrosine-kinase receptor is a sensor of adverse microenvironmental conditions (such as hypoxia) and drives cell invasion and metastasis through the transcriptional activation of a set of genes that control blood coagulation.
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            Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1.

            Patients with poorly differentiated thyroid cancers (PDTC), anaplastic thyroid cancers (ATC), and radioactive iodine-refractory (RAIR) differentiated thyroid cancers have a high mortality, particularly if positive on [(18)F]fluorodeoxyglucose (FDG)-positron emission tomography (PET). To obtain comprehensive genetic information on advanced thyroid cancers, we designed an assay panel for mass spectrometry genotyping encompassing the most significant oncogenes in this disease: 111 mutations in RET, BRAF, NRAS, HRAS, KRAS, PIK3CA, AKT1, and other related genes were surveyed in 31 cell lines, 52 primary tumors (34 PDTC and 18 ATC), and 55 RAIR, FDG-PET-positive recurrences and metastases (nodal and distant) from 42 patients. RAS mutations were more prevalent than BRAF (44 versus 12%; P = 0.002) in primary PDTC, whereas BRAF was more common than RAS (39 versus 13%; P = 0.04) in PET-positive metastatic PDTC. BRAF mutations were highly prevalent in ATC (44%) and in metastatic tumors from RAIR PTC patients (95%). Among patients with multiple metastases, 9 of 10 showed between-sample concordance for BRAF or RAS mutations. By contrast, 5 of 6 patients were discordant for mutations of PIK3CA or AKT1. AKT1_G49A was found in 9 specimens, exclusively in metastases. This is the first documentation of AKT1 mutation in thyroid cancer. Thus, RAIR, FDG-PET-positive metastases are enriched for BRAF mutations. If BRAF is mutated in the primary, it is likely that the metastases will harbor the defect. By contrast, absence of PIK3CA/AKT1 mutations in one specimen may not reflect the status at other sites because these mutations arise during progression, an important consideration for therapies directed at phosphoinositide 3-kinase effectors.
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              c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions.

              Small cell lung cancer (SCLC) is an aggressive cancer, and most patients present with cancer already spread beyond the lung. The receptor tyrosine kinase (RTK) c-MET has been implicated in various solid tumors, including SCLC, and is involved in mediating tumorigenesis, cell motility, scattering, invasion and metastasis. Mutations of c-Met have been described in renal papillary carcinoma and gastrointestinal cancers including hepatocellular carcinoma. The sequence of c-MET was examined for possible mutations in the 10 SCLC cell lines and 32 paired-SCLC/normal tissues. Novel c-MET alterations were identified among 3 of 10 separate SCLC cell lines and in 4 of 32 SCLC tumor tissue samples. These include two different c-MET missense mutations in the juxtamembrane (JM) domain (R988C found in NCI-H69 and H249 cell lines; and T1010I in SCLC tumor sample T31). Also, there are one Sema domain missense mutation (E168D in SCLC tumor sample T5), two-base-pair insertional mutations (IVS13- (52-53)insCT in both SCLC tumor samples T26 and T27) within the pre-JM intron 13, as well as an alternative transcript involving exon 10 (H128 cell line). c-MET receptors are expressed at various levels among the 10 SCLC cell lines studied (high expression: H69, H345, H510, and H526; medium-expression: H128 and H146; and low/no-expression: H82, H209, H249, and H446). The level of c-MET expression does not have any apparent correlation with presence or absence of mutations of c-MET in the cell lines. We show that the two identified JM mutations (R988C and T1010I), when introduced into the interleukin-3 (IL-3)-dependent BaF3 cell line, regulated cell proliferation resulting in a small but significant growth factor independence. When introduced into a SCLC cell line (H446, with minimal endogenous wild-type c-MET expression), the JM mutations also regulated cell morphology and adhesion, as well as causing enhanced tumorigenicity by both increases in focus-formation and soft-agar colony-formation assays. Both of the JM mutations also increased cell motility and migration evident in wound healing assay and time-lapse video-microscopy speed analysis. The JM mutations also altered the c-MET RTK signaling, resulting in preferentially increased constitutive tyrosine phosphorylation of various cellular proteins, including the key focal adhesion protein paxillin on tyrosine residue Y31 (first CRKL-binding site), correlating with increased motility. These results suggest a novel and unique role of the JM domain in c-MET signaling in SCLC with significant implications in cytoskeletal functions and metastatic potential. The novel JM gain-of-function somatic mutations described are the first to be reported in SCLC, and may be associated with a more aggressive phenotype. It would now be useful to study the inhibition of c-MET as a therapeutic target against SCLC.
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                Author and article information

                Contributors
                fshih@exchange.hsc.mb.ca
                Stephen.Yip@vch.ca
                PMcDonald@exchange.hsc.mb.ca
                achudley@hsc.mb.ca
                Marc.Delbigio@med.umanitoba.ca
                Journal
                Acta Neuropathol Commun
                Acta Neuropathol Commun
                Acta Neuropathologica Communications
                BioMed Central (London )
                2051-5960
                21 October 2014
                21 October 2014
                2014
                : 2
                : 1
                Affiliations
                [ ]Diagnostic Services Manitoba, Winnipeg, MB Canada
                [ ]Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC Canada
                [ ]Section of Neurosurgery, University of Manitoba, Winnipeg, MB Canada
                [ ]Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, MB Canada
                [ ]Department of Pathology, University of Manitoba and Diagnostic Services Manitoba, Room 401 Brodie Centre, R3E 3P5 Winnipeg, MB Canada
                Article
                140
                10.1186/s40478-014-0140-8
                4209081
                25330907
                © Shih et al.; licensee BioMed Central Ltd. 2014

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Categories
                Case Report
                Custom metadata
                © The Author(s) 2014

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