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https://www.readbyqxmd.com/read/27936234/cell-density-dependent-increase-in-tyrosine-monophosphorylated-erk2-in-mdck-cells-expressing-active-ras-or-raf
#1
Noriyuki Kawabata, Michiyuki Matsuda
The extracellular signal-regulated kinase (ERK) is one of the principal hub proteins that transmit growth signals from upstream oncogene products including Ras and BRaf to downstream effector proteins. However, there are both reports supporting and refuting the increase in ERK activity in cancer tissues expressing the active Ras and BRaf proteins. We considered that the cell density might account for this discrepancy. To examine this possibility, we prepared Madin-Darby canine kidney (MDCK) cells that expressed an active HRas, NRas, KRas, or BRaf and an ERK biosensor based on the principle of Förster resonance energy transfer (FRET)...
2016: PloS One
https://www.readbyqxmd.com/read/27936046/the-ras-effector-interface-isoform-specific-differences-in-the-effector-binding-regions
#2
Hossein Nakhaeizadeh, Ehsan Amin, Saeideh Nakhaei-Rad, Radovan Dvorsky, Mohammad Reza Ahmadian
RAS effectors specifically interact with the GTP-bound form of RAS in response to extracellular signals and link them to downstream signaling pathways. The molecular nature of effector interaction by RAS is well-studied but yet still incompletely understood in a comprehensive and systematic way. Here, structure-function relationships in the interaction between different RAS proteins and various effectors were investigated in detail by combining our in vitro data with in silico data. Equilibrium dissociation constants were determined for the binding of HRAS, KRAS, NRAS, RRAS1 and RRAS2 to both the RAS binding (RB) domain of CRAF and PI3Kα, and the RAS association (RA) domain of RASSF5, RALGDS and PLCε, respectively, using fluorescence polarization...
2016: PloS One
https://www.readbyqxmd.com/read/27934878/activating-cysteinyl-leukotriene-receptor-2-cysltr2-mutations-in-blue-nevi
#3
Inga Möller, Rajmohan Murali, Hansgeorg Müller, Thomas Wiesner, Louise A Jackett, Simone L Scholz, Ioana Cosgarea, Johannes Ap van de Nes, Antje Sucker, Uwe Hillen, Bastian Schilling, Annette Paschen, Heinz Kutzner, Arno Rütten, Martin Böckers, Richard A Scolyer, Dirk Schadendorf, Klaus G Griewank
Blue nevi are common melanocytic tumors arising in the dermal layer of the skin. Similar to uveal melanomas, blue nevi frequently harbor GNAQ and GNA11 mutations. Recently, recurrent CYSLTR2 and PLCB4 mutations were identified in uveal melanomas not harboring GNAQ or GNA11 mutations. All four genes (GNAQ, GNA11, CYSLTR2, and PLCB4) code for proteins involved in the same signaling pathway, which is activated by mutations in these genes. Given the related functional consequences of these mutations and the known genetic similarities between uveal melanoma and blue nevi, we analyzed a cohort of blue nevi to investigate whether CYSLTR2 and PLCB4 mutations occur in tumors lacking GNAQ or GNA11 mutations (as in uveal melanoma)...
December 9, 2016: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/27926791/high-prevalence-of-mitf-staining-in-undifferentiated-pleomorphic-sarcoma-caution-in-use-of-melanocytic-markers-in-sarcoma
#4
Bonnie Choy, Elizabeth Hyjek, Anthony G Montag, Peter Pytel, Rex Haydon, Hue H Luu, Chao Jie Zhen, Bradley C Long, Sabah Kadri, Jeremy P Segal, Larissa V Furtado, Nicole A Cipriani
AIMS: Diagnosis of undifferentiated pleomorphic sarcoma (UPS) may be challenging, as other lesions with undifferentiated spindle cell morphology must be excluded, including melanoma. Microphthalmia-associated transcription factor (MiTF) stains nevi and epithelioid melanomas, as well as some mesenchymal neoplasms. We evaluated the prevalence of MiTF and melanocytic markers in UPS and a subset of atypical fibroxanthoma (AFX). METHODS AND RESULTS: MiTF, SOX10, Melan-A, HMB45, and S100 immunostains were performed on resection specimens from 19 UPS and 5 AFX...
December 7, 2016: Histopathology
https://www.readbyqxmd.com/read/27916952/high-intra-and-inter-tumoral-heterogeneity-of-ras-mutations-in-colorectal-cancer
#5
Marion Jeantet, David Tougeron, Gaelle Tachon, Ulrich Cortes, Céline Archambaut, Gaelle Fromont, Lucie Karayan-Tapon
Approximately 30% of patients with wild type RAS metastatic colorectal cancer are non-responders to anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR mAbs), possibly due to undetected tumoral subclones harboring RAS mutations. The aim of this study was to analyze the distribution of RAS mutations in different areas of the primary tumor, metastatic lymph nodes and distant metastasis. A retrospective cohort of 18 patients with a colorectal cancer (CRC) was included in the study. Multiregion analysis was performed in 60 spatially separated tumor areas according to the pathological tumor node metastasis (pTNM) staging and KRAS, NRAS and BRAF mutations were tested using pyrosequencing...
December 1, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27914687/braf-nras-kit-tert-gnaq-gna11-mutation-profile-analysis-of-head-and-neck-mucosal-melanomas-a-study-of-42-cases
#6
Şule Öztürk Sari, İsmaİl Yilmaz, Orhun Çiğ Taşkin, Gİzem Narli, Fatma Şen, Şenol Çomoğlu, Pinar Firat, Bİlge Bİlgİç, Dİlek Yilmazbayhan, Yasemİn Özlük, Nesİmİ Büyükbabanİ
Head and neck mucosal melanoma (HNMuM), which occurs mostly in the sinonasal and oral cavity, constitutes less than 1% of all malignant melanomas. Treatment options fail to improve the prognosis of this aggressive tumour that has low overall survival rates. Thus, development of new targeted therapies is essential. Unfortunately, limited data exist regarding their molecular profile. BRAF, NRAS, KIT, TERT and GNAQ/GNA11 oncogene mutations were investigated in 42 HNMuMs (28 sinonasal, 13 oral, 1 nasopharyngeal)...
November 30, 2016: Pathology
https://www.readbyqxmd.com/read/27913534/myelodysplastic-and-myeloproliferative-disorders-of-childhood
#7
Henrik Hasle
Myelodysplastic syndrome (MDS) and myeloproliferative disorders are rare in children; they are divided into low-grade MDS (refractory cytopenia of childhood [RCC]), advanced MDS (refractory anemia with excess blasts in transformation), and juvenile myelomonocytic leukemia (JMML), each with different characteristics and management strategies. Underlying genetic predisposition is recognized in an increasing number of patients. Germ line GATA2 mutation is found in 70% of adolescents with MDS and monosomy 7. It is challenging to distinguish RCC from aplastic anemia, inherited bone marrow failure, and reactive conditions...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27911979/clinicopathological-features-and-clinical-outcomes-associated-with-tp53-and-braf-n-on-v-600-mutations-in-cutaneous-melanoma-patients
#8
Dae Won Kim, Lauren E Haydu, Aron Y Joon, Roland L Bassett, Alan E Siroy, Michael T Tetzlaff, Mark J Routbort, Rodabe N Amaria, Jennifer A Wargo, Jennifer L McQuade, Jan Kemnade, Patrick Hwu, Scott E Woodman, Jason Roszik, Kevin B Kim, Jeffrey E Gershenwald, Alexander J Lazar, Michael A Davies
BACKGROUND: BRAF(V600) , NRAS, TP53, and BRAF(Non-V600) are among the most common mutations detected in non-acral cutaneous melanoma patients. Although several studies have identified clinical and pathological features associated with BRAF(V600) and NRAS mutations, limited data are available regarding the correlates and significance of TP53 and BRAF(Non-V600) mutations. METHODS: This study analyzed the patient demographics, primary tumor features, and clinical outcomes of a large cohort of non-acral cutaneous melanoma patients who had undergone clinically indicated molecular testing (n = 926)...
December 2, 2016: Cancer
https://www.readbyqxmd.com/read/27911940/isoform-specific-effects-of-wild-type-ras-genes-on-carcinogen-induced-lung-tumorigenesis-in-mice
#9
Jamie D Weyandt, John M Carney, Elizabeth N Pavlisko, MengMeng Xu, Christopher M Counter
The gene KRAS is commonly mutated in lung cancer to encode a constitutively active and oncogenic protein that is well established to initiate and maintain lung tumorigenesis. However, the remaining wild-type KRAS protein, or the other family members HRAS and NRAS, can still be activated in the presence of oncogenic KRAS. Moreover, loss of any one of these three genes has been shown to increase the sensitivity of mice to the carcinogen urethane, which induces Kras mutation-positive early lung lesions. To determine the contribution of progressively disrupting Hras and Nras genes on urethane lung tumorigenesis, mice with different combinations of wild-type and null alleles of Hras and Nras were exposed with urethane and tumor burden was assessed...
2016: PloS One
https://www.readbyqxmd.com/read/27911794/activation-of-mutant-tert-promoter-by-ras-erk-signaling-is-a-key-step-in-malignant-progression-of-braf-mutant-human-melanomas
#10
Yinghui Li, Hui Shan Cheng, Wee Joo Chng, Vinay Tergaonkar
Although activating BRAF/NRAS mutations are frequently seen in melanomas, they are not sufficient to drive malignant transformation and require additional events. Frequent co-occurrence of mutations in the promoter for telomerase reverse transcriptase (TERT), along with BRAF alterations, has recently been noted and correlated with poorer prognosis, implicating a functional link between BRAF signaling and telomerase reactivation in melanomas. Here, we report that RAS-ERK signaling in BRAF mutant melanomas is critical for regulating active chromatin state and recruitment of RNA polymerase II at mutant TERT promoters...
November 23, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27903987/mapping-heterogeneity-in-patient-derived-melanoma-cultures-by-single-cell-rna-seq
#11
Tobias Gerber, Edith Willscher, Henry Loeffler-Wirth, Lydia Hopp, Dirk Schadendorf, Manfred Schartl, Ulf Anderegg, Gray Camp, Barbara Treutlein, Hans Binder, Manfred Kunz
Recent technological advances in single-cell genomics make it possible to analyze cellular heterogeneity of tumor samples. Here, we applied single-cell RNA-seq to measure the transcriptomes of 307 single cells cultured from three biopsies of three different patients with a BRAF/NRAS wild type, BRAF mutant/NRAS wild type and BRAF wild type/NRAS mutant melanoma metastasis, respectively. Analysis based on self-organizing maps identified sub-populations defined by multiple gene expression modules involved in proliferation, oxidative phosphorylation, pigmentation and cellular stroma...
November 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27900779/mosaic-nras-q61r-mutation-in-a-child-with-giant-congenital-melanocytic-naevus-epidermal-naevus-syndrome-and-hypophosphataemic-rickets
#12
R Ramesh, N Shaw, E K Miles, B Richard, I Colmenero, C Moss
The association of hypophosphataemic rickets with verrucous epidermal naevus (EN) and elevated fibroblast growth factor 23 levels is known as cutaneous-skeletal hypophosphataemia syndrome (CSHS), and can be caused by somatic activating mutations in RAS genes. We report a unique patient with CSHS associated with giant congenital melanocytic naevus (CMN), neurocutaneous melanosis and EN syndrome, manifesting as facial linear sebaceous naevus, developmental delay and ocular dermoids. An activating mutation Q61R in the NRAS gene was found in affected skin and ocular tissue but not blood, implying that the disparate manifestations are due to a multilineage activating mutation (mosaic RASopathy)...
November 30, 2016: Clinical and Experimental Dermatology
https://www.readbyqxmd.com/read/27899992/beside-p53-and-pten-identification-of-molecular-alterations-of-the-ras-mapk-and-pi3k-akt-signaling-pathways-in-high-grade-serous-ovarian-carcinomas-to-determine-potential-novel-therapeutic-targets
#13
Shuhui Chen, Elisa Cavazza, Catherine Barlier, Julia Salleron, Pierre Filhine-Tresarrieu, Céline Gavoilles, Jean-Louis Merlin, Alexandre Harlé
Despite great histological and molecular heterogeneity, the clinical management of high-grade ovarian carcinomas remains unspecialized. As a major subgroup, high-grade serous ovarian carcinomas (HGSOCs) require novel therapies. In addition to utilizing conventional histological prognostic markers and performing oncogenetic investigations, the molecular diagnostic method of next generation sequencing (NGS) was performed to identify 'druggable' targets that could provide access to innovative therapy. The present study was performed in 45 HGSOC patients (mean age, 59...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27899805/circulating-tumour-dna-analysis-demonstrates-spatial-mutational-heterogeneity-that-coincides-with-disease-relapse-in-myeloma
#14
S Mithraprabhu, T Khong, M Ramachandran, A Chow, D Klarica, L Mai, S Walsh, D Broemeling, A Marziali, M Wiggin, J Hocking, A Kalff, B Durie, A Spencer
Mutational characterisation in multiple myeloma (MM) currently relies on bone marrow (BM) biopsy, which fails to capture the putative spatial and genetic heterogeneity of this multi-focal disease. Analysis of plasma (PL)-derived circulating free tumour DNA (ctDNA) as an adjunct to BM biopsy, for mutational characterisation and tracking disease progression, was evaluated. Paired BM MM cell DNA and ctDNA from 33 relapsed [RR] and 15 newly diagnosed [ND] patients were analysed for KRAS, NRAS, BRAF and TP53 mutations using the OnTarget™ Mutation Detection (OMD) platform...
November 30, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27898753/-oncogen-dependent-regulation-of-the-migration-and-proliferation-of-human-tumor-cells
#15
Tamás M Garay
The high mortality of solid tumors can be attributed to their invasive and metastatic potential that is based on their migration and proliferation. Importantly, growth factor receptor (GF) signaling pathways regulating proliferation and migration are often affected by oncogenic mutations and are important targets for antitumor therapy. We found positive correlation between migration and proliferation in melanoma and lung cancer cells using videomicroscopy, not supporting the "go or grow" hypothesis. Furthermore, the invasion into collagen I matrices from brain tumor spheroids was not impaired upon the inhibition of proliferation...
November 29, 2016: Magyar Onkologia
https://www.readbyqxmd.com/read/27893191/young-investigator-challenge-molecular-testing-in-noninvasive-follicular-thyroid-neoplasm-with-papillary-like-nuclear-features
#16
Xiaoyin Sara Jiang, Grant P Harrison, Michael B Datto
BACKGROUND: Molecular testing provides an important ancillary study for thyroid nodules with indeterminate cytology. The nomenclature shift to "noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) will impact the performance of molecular tests. For the current study, the authors reviewed the performance of the Afirma gene-expression classifier (GEC) and the University of Pittsburgh Medical Center (UPMC) targeted mutation panel tests in thyroid nodules that were subsequently diagnosed as NIFTP on surgical resection...
November 28, 2016: Cancer
https://www.readbyqxmd.com/read/27886225/no-evidence-of-nras-mutation-in-squamous-cell-anal-carcinoma-scac
#17
Laura Capelli, Andrea Casadei Gardini, Emanuela Scarpi, Giovanni Luca Frassineti, Luca Saragoni, Maurizio Puccetti, Mario Scartozzi, Massimo Giannini, Stefano Tamberi, Jody Corbelli, Paola Ulivi
Epidermal growth factor receptor (EGFR) is usually expressed in squamous cell anal carcinoma (SCAC) and anti-EGFR agents could represent a valid treatment strategy, also considering that KRAS and BRAF mutations are rare events in this type of cancer. However, no data are available on NRAS status in SCAC. In this study we analyzed NRAS status (exons 2-4) by Pyrosequencing in a case series of 50 SCAC patients previously characterized in our laboratory for KRAS, BRAF, PIK3CA mutations and HPV and HIV infections...
November 25, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27883322/molecular-biology-and-genetic-mechanisms-in-the-progression-of-the-malignant-skin-melanoma
#18
Sofija Pejkova, Gjorgje Dzokic, Smilja Tudzarova-Gjorgova, Sasho Panov
Malignant skin melanoma is a tumor deriving from transformed skin melanocytes as a result of complex interactions between genetic and environmental factors. This melanoma has a potential to metastasize early and very often it is resistant to the existing modalities of the systemic therapy. As in any other neoplasms, certain types of melanoma may skip certain stages of progression. The progression from one stage to another is accompanied by specific biological changes. Several key changes in the melanoma tumorogenesis influence the regulation of the cell proliferation and vitality, including the RAS-RAF-ERK, PI3K-AKT, and p16INK4/CDK4/RB pathways...
November 1, 2016: Prilozi (Makedonska Akademija Na Naukite i Umetnostite. Oddelenie za Medicinski Nauki)
https://www.readbyqxmd.com/read/27880995/frequency-of-k-ras-and-n-ras-gene-mutations-in-colorectal-cancers-in-southeastern-iran
#19
Naseri Mohsen, Sebzari Ahmadreza, Haghighi Fatemeh, Hajipoor Fatemeh, Emadian Razavi Fariba
Background: K-RAS and N-RAS gene mutations cause resistance to treatment in patients with colorectal cancer. Based on this, awareness of mutation of these genes is considered a clinically important step towards better diagnosis and appropriate treatment. Materials and Methods: Fifty paraffin-embedded blocks of colorectal cancer were obtained from Imam Reza Hospital of Birjand, Iran. Following DNA extraction, the samples were analyzed for common mutations of exons 2, 3 and 4 of KRAS and NRAS genes using real time PCR and pyrosequencing...
January 9, 2016: Asian Pacific Journal of Cancer Prevention: APJCP
https://www.readbyqxmd.com/read/27879995/egfr-gene-copy-number-predicts-response-to-anti-egfr-treatment-in-ras-wild-type-and-ras-braf-pik3ca-wild-type-metastatic-colorectal-cancer
#20
Annika Ålgars, Jari Sundström, Minnamaija Lintunen, Terhi Jokilehto, Soili Kytölä, Milja Kaare, Reetta Vainionpää, Arto Orpana, Pia Österlund, Ari Ristimäki, Olli Carpen, Raija Ristamäki
Anti-EGFR antibodies are used for the treatment of RAS wild type metastatic colorectal cancer. We previously showed that EGFR gene copy number (GCN) predicts response to anti-EGFR therapy in KRAS exon 2 wild type metastatic colorectal cancer. The aim of our study was to analyse the predictive role of EGFR GCN in RAS/BRAF/PIK3CA wild type metastatic colorectal cancer. The material included 102 patients with KRAS exon 2 wild type metastatic colorectal cancer treated with anti-EGFR ± cytotoxic therapy. Next generation sequencing was used for KRAS, NRAS, BRAF and PIK3CA gene mutation analyses...
November 5, 2016: International Journal of Cancer. Journal International du Cancer
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