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KRAS, RAS

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https://www.readbyqxmd.com/read/28523882/phacomatosis-pigmentokeratotica-a-mosaic-rasopathy-with-malignant-potential
#1
Amit Om, Sara S Cathey, Robert M Gathings, Michelle Hudspeth, Jennifer A Lee, Sean Marzolf, Lara Wine Lee
Phacomatosis pigmentokeratotica (PPK) is a rare epidermal nevus syndrome characterized by the co-occurrence of a nevus sebaceous arranged along the lines of Blaschko with a speckled lentiginous nevus (SLN). We report a novel KRAS mutation in a patient with a large nevus sebaceous and an SLN who subsequently developed a vaginal botryoid rhabdomyosarcoma, an association not previously reported in the literature. This case expands our knowledge of the genetic basis for phacomatosis, in which mutations in HRAS have been previously described, although this report provides evidence that activating mutations in KRAS or HRAS may cause PPK...
May 2017: Pediatric Dermatology
https://www.readbyqxmd.com/read/28513830/association-between-mutations-of-critical-pathway-genes-and-survival-outcomes-according-to-the-tumor-location-in-colorectal-cancer
#2
Dae-Won Lee, Sae-Won Han, Yongjun Cha, Jeong Mo Bae, Hwang-Phill Kim, Jaemyun Lyu, Hyojun Han, Hyoki Kim, Hoon Jang, Duhee Bang, Iksoo Huh, Taesung Park, Jae-Kyung Won, Seung-Yong Jeong, Kyu Joo Park, Gyeong Hoon Kang, Tae-You Kim
BACKGROUND: Colorectal cancer (CRC) develops through the alteration of several critical pathways. This study was aimed at evaluating the influence of critical pathways on survival outcomes for patients with CRC. METHODS: Targeted next-generation sequencing of 40 genes included in the 5 critical pathways of CRC (WNT, P53, RTK-RAS, phosphatidylinositol-4,5-bisphosphate 3-kinase [PI3K], and transforming growth factor β [TGF-β]) was performed for 516 patients with stage III or high-risk stage II CRC treated with surgery followed by adjuvant fluoropyrimidine and oxaliplatin chemotherapy...
May 17, 2017: Cancer
https://www.readbyqxmd.com/read/28512242/a-systematic-analysis-of-oncogenic-gene-fusions-in-primary-colon-cancer
#3
Wigard P Kloosterman, Robert R J Coebergh van den Braak, Mark Pieterse, Markus J van Roosmalen, Anieta M Sieuwerts, Christina Stangl, Ronne Brunekreef, Zarina S Lalmahomed, Salo Ooft, Anne van Galen, Marcel Smid, Armel Lefebvre, Fried Zwartkruis, John W M Martens, John A Foekens, Katharina Biermann, Marco J Koudijs, Jan N M IJzermans, Emile E Voest
Genomic rearrangements that give rise to oncogenic gene fusions can offer actionable targets for cancer therapy. Here we present a systematic analysis of oncogenic gene fusions among a clinically well-characterized, prospectively collected set of 278 primary colon cancers spanning diverse tumor stages and clinical outcomes. Gene fusions and somatic genetic variations were identified in fresh frozen clinical specimens by Illumina RNA-sequencing, the STAR fusion gene detection pipeline, and GATK RNA-seq variant calling...
May 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28512021/statin-use-after-diagnosis-of-colon-cancer-and-patient-survival
#4
Philip W Voorneveld, Marlies S Reimers, Esther Bastiaannet, Rutger J Jacobs, Ronald van Eijk, Marjolein M J Zanders, Ron M C Herings, Myrthe P P van Herk-Sukel, Liudmila L Kodach, Tom van Wezel, Peter J K Kuppen, Hans Morreau, Cornelis J H van de Velde, James C H Hardwick, Gerrit Jan Liefers
BACKGROUND & AIMS: Statin use has been associated with a reduced incidence of colorectal cancer, and might also affect survival of patients diagnosed with colon cancer. Statins are believed to inhibit Ras signaling, and also activate the bone morphogenetic protein (BMP) signaling pathway in colorectal cancer cells. We investigated the effects of statins on overall survival of patients with a diagnosis of colon cancer, and whether their effects were associated with changes in KRAS or the BMP signaling pathways...
May 13, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28504689/molecular-signaling-in-multiple-myeloma-association-of-ras-raf-mutations-and-mek-erk-pathway-activation
#5
J Xu, N Pfarr, V Endris, E K Mai, N H Md Hanafiah, N Lehners, R Penzel, W Weichert, A D Ho, P Schirmacher, H Goldschmidt, M Andrulis, M S Raab
Multiple myeloma (MM) is a plasma cell malignancy that is still considered to be incurable in most cases. A dominant mutation cluster has been identified in RAS/RAF genes, emphasizing the potential significance of RAS/RAF/MEK/ERK signaling as a therapeutic target. As yet, however, the clinical relevance of this finding is unclear as clinical responses to MEK inhibition in RAS-mutant MM have been mixed. We therefore assessed RAS/RAF mutation status and MEK/ERK pathway activation by both targeted sequencing and phospho-ERK immunohistochemistry in 180 tissue biopsies from 103 patients with newly diagnosed MM (NDMM) and 77 patients with relapsed/refractory MM (rrMM)...
May 15, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28500641/t-and-b-cell-clonal-expansion-in-ras-associated-lymphoproliferative-disease-rald-as-revealed-by-next-generation-sequencing
#6
Sarina Levy-Mendelovich, Atar Lev, Erez Rechavi, Ortal Barel, Hana Golan, Bela Bielorai, Yoram Neumann, Amos J Simon, Raz Somech
Ras associated lymphoproliferative disease (RALD) is an autoimmune lymphoproliferative syndrome (ALPS)-like disease caused by mutations in KRAS or NRAS. The immunological phenotype and pathogenesis of RALD have yet to be extensively studied. Here we report a thorough immunological investigation of a RALD patient with a somatic KRAS mutation. Patient lymphocytes were analyzed for phenotype, immunoglobulin levels and T cell proliferation capacity. T and B cell receptor excision circles (TREC and KREC, respectively), markers of naïve T and B cell production, were serially measured over three years...
May 12, 2017: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/28493027/clinicopathological-characteristics-of-thyroid-cancer-in-the-federal-state-of-salzburg
#7
Gundula Rendl, Margarida Rodrigues, Gregor Schweighofer-Zwink, Josef Hutter, Anton Hittmair, Barbara Zellinger, Cornelia Hauser-Kronberger, Christian Pirich
OBJECTIVE: The aim of our investigation was to evaluate the clinicopathological characteristics and mutation patterns in newly diagnosed cases of thyroid cancer in the federal state of Salzburg, Austria, in the year 2013. METHODS: The medical records of all patients newly diagnosed with thyroid cancer in 2013 in the federal state of Salzburg were retrospectively reviewed. The clinicopathological characteristics and mutations of thyroid cancers were analyzed. RESULTS: 63 patients (mean age: 51...
May 10, 2017: Wiener Klinische Wochenschrift
https://www.readbyqxmd.com/read/28476195/tobacco-smoke-and-ras-mutations-among-latino-and-non-latino-children-with-acute-lymphoblastic-leukemia
#8
Maneet Kaur, Adam J de Smith, Steve Selvin, Luoping Zhang, Marc Cunningham, Michelle W Kang, Helen M Hansen, Robert M Cooper, Roberta McKean-Cowdin, Joseph L Wiemels, Catherine Metayer
BACKGROUND AND AIMS: Childhood acute lymphoblastic leukemia (ALL) is a biologically heterogeneous disease, and mutations in the KRAS and NRAS oncogenes are present at diagnosis in about one-fifth of cases. Ras mutations were previously associated with environmental exposures in leukemias as well as in many other cancer types. This study examined whether Ras mutation could define a unique etiologic group of childhood ALL associated with tobacco smoke, a well-established mutagen and carcinogen...
November 2016: Archives of Medical Research
https://www.readbyqxmd.com/read/28475299/consistency-and-reproducibility-of-next-generation-sequencing-and-other-multigene-mutational-assays-a-worldwide-ring-trial-study-on-quantitative-cytological-molecular-reference-specimens
#9
Umberto Malapelle, Clara Mayo-de-Las-Casas, Miguel A Molina-Vila, Rafael Rosell, Spasenija Savic, Michel Bihl, Lukas Bubendorf, Manuel Salto-Tellez, Dario de Biase, Giovanni Tallini, David H Hwang, Lynette M Sholl, Rajyalakshmi Luthra, Birgit Weynand, Sara Vander Borght, Edoardo Missiaglia, Massimo Bongiovanni, Daniel Stieber, Philippe Vielh, Fernando Schmitt, Alessandra Rappa, Massimo Barberis, Francesco Pepe, Pasquale Pisapia, Nicola Serra, Elena Vigliar, Claudio Bellevicine, Matteo Fassan, Massimo Rugge, Carlos E de Andrea, Maria D Lozano, Fulvio Basolo, Gabriella Fontanini, Yuri E Nikiforov, Suzanne Kamel-Reid, Gilda da Cunha Santos, Marina N Nikiforova, Sinchita Roy-Chowdhuri, Giancarlo Troncone
BACKGROUND: Molecular testing of cytological lung cancer specimens includes, beyond epidermal growth factor receptor (EGFR), emerging predictive/prognostic genomic biomarkers such as Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral [v-ras] oncogene homolog (NRAS), B-Raf proto-oncogene, serine/threonine kinase (BRAF), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA). Next-generation sequencing (NGS) and other multigene mutational assays are suitable for cytological specimens, including smears...
May 5, 2017: Cancer
https://www.readbyqxmd.com/read/28463756/impact-of-braf-and-ras-mutations-on-first-line-efficacy-of-folfiri-plus-cetuximab-versus-folfiri-plus-bevacizumab-analysis-of-the-fire-3-aio-krk-0306-study
#10
S Stintzing, L Miller-Phillips, D P Modest, L Fischer von Weikersthal, T Decker, A Kiani, U Vehling-Kaiser, S-E Al-Batran, T Heintges, C Kahl, G Seipelt, F Kullmann, M Stauch, W Scheithauer, S Held, M Moehler, A Jagenburg, T Kirchner, A Jung, V Heinemann
BACKGROUND: RAS and BRAF mutations have been identified as negative prognostic factors in metastatic colorectal cancer. Efficacy of 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) plus bevacizumab in patients with RAS-mutant tumours needs to be further evaluated. Whether to treat patients with BRAF-mutant tumours with either bevacizumab or anti-epidermal growth factor receptor (EGFR) antibodies remains unclear. METHODS: Patients treated within the FIRE-3 trial were retrospectively tested for BRAF and RAS mutations using formalin fixated paraffin embedded (FFPE) tumour material applying pyrosequencing for KRAS and NRAS exon 2, 3 and 4 mutations as far as for BRAF mutations...
April 29, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28462395/calmodulin-and-pi3k-signaling-in-kras-cancers
#11
Ruth Nussinov, Guanqiao Wang, Chung-Jung Tsai, Hyunbum Jang, Shaoyong Lu, Avik Banerjee, Jian Zhang, Vadim Gaponenko
Calmodulin (CaM) uniquely promotes signaling of oncogenic K-Ras; but not N-Ras or H-Ras. How CaM interacts with K-Ras and how this stimulates cell proliferation are among the most challenging questions in KRAS-driven cancers. Earlier data pointed to formation of a ternary complex consisting of K-Ras, PI3Kα and CaM. Recent data point to phosphorylated CaM binding to the SH2 domains of the p85 subunit of PI3Kα and activating it. Modeling suggests that the high affinity interaction between the phosphorylated CaM tyrosine motif and PI3Kα, can promote full PI3Kα activation by oncogenic K-Ras...
March 2017: Trends in Cancer
https://www.readbyqxmd.com/read/28455994/molecular-profiling-of-colorectal-pulmonary-metastases-and-primary-tumours-implications-for-targeted-treatment
#12
Sing Yu Moorcraft, Thomas Jones, Brian A Walker, George Ladas, E Kalaitzaki, Lina Yuan, Ruwaida Begum, Zakaria Eltahir, Andrew Wotherspoon, Angeles Montero Fernandez, Larissa S Teixeira Mendes, David Gonzalez de Castro, Sanna Hulkki Wilson, Paula Proszek, Ye Mong To, Eliza Hawkes, Amitesh Roy, David Cunningham, Sheela Rao, David Watkins, Naureen Starling, Anne M Bowcock, Ian Chau
This study aimed to molecularly characterise colorectal pulmonary metastases (PM) and investigate whether their molecular profiles were concordant with those of the primary tumour. Clinical data and archival formalin fixed paraffin embedded tissue samples were retrospectively collected from patients who underwent ≥ 1 pulmonary metastasectomies for colorectal cancer between 1997-2012. Primary tumour and metastatic samples were analysed using a targeted capture sequencing panel of 46 cancer-associated genes...
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28451421/role-of-ras-mutation-status-as-a-prognostic-factor-for-patients-with-advanced-colorectal-cancer-treated-with-first-line-chemotherapy-based-on-fluoropyrimidines-and-oxaliplatin-with-or-without-bevavizumab-a-retrospective-analysis
#13
Javier Garde Noguera, Eloisa Jantus-Lewintre, Mireia Gil-Raga, Elena Evgenyeva, Sonia Maciá Escalante, Antonio Llombart-Cussac, Carlos Camps Herrero
The role of Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral oncogene homolog (NRAS) mutations as negative predictors for anti-epidermal growth factor receptor (EGFR) therapies in metastatic colorectal cancer (CRC) has been firmly established. However, whether the RAS mutation status plays a role as a biomarker for anti-vascular endothelial growth factor (VEGF) treatment remains controversial. Data from 93 CRC patients who received first-line cytotoxic chemotherapy with fluoropyrimidines and oxaliplatin, with or without bevacizumab, were analyzed...
March 2017: Molecular and Clinical Oncology
https://www.readbyqxmd.com/read/28449008/extended-ras-analysis-and-correlation-with-overall-survival-in-advanced-pancreatic-cancer
#14
Michael Haas, Steffen Ormanns, Sibylle Baechmann, Anna Remold, Stephan Kruger, Christoph B Westphalen, Jens T Siveke, Patrick Wenzel, Anna Melissa Schlitter, Irene Esposito, Detlef Quietzsch, Michael R Clemens, Erika Kettner, Ruediger P Laubender, Andreas Jung, Thomas Kirchner, Stefan Boeck, Volker Heinemann
BACKGROUND: Mutations in the KRAS gene can be detected in about 70-90% of pancreatic cancer (PC) cases. Whether these mutations have a prognostic or predictive value remains elusive. Furthermore, the clinical relevance of the extended RAS (KRAS+NRAS) mutational status is unclear in PC. METHODS: We prospectively defined a PC patient population who received erlotinib-free chemotherapy regimens. A statistically significant difference between KRAS wild-type and KRAS mutated tumours in at least 160 patients in this population would support the assumption of a rather prognostic role of KRAS...
May 23, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28448128/total-chemical-synthesis-and-folding-of-all-l-and-all-d-variants-of-oncogenic-kras-g12v
#15
Adam M Levinson, John H McGee, Andrew G Roberts, Gardner S Creech, Ting Wang, Michael T Peterson, Ronald C Hendrickson, Gregory L Verdine, Samuel J Danishefsky
The Ras proteins are essential GTPases involved in the regulation of cell proliferation and survival. Mutated oncogenic forms of Ras alter effector binding and innate GTPase activity, leading to deregulation of downstream signal transduction. Mutated forms of Ras are involved in approximately 30% of human cancers. Despite decades of effort to develop direct Ras inhibitors, Ras has long been considered "undruggable" due to its high affinity for GTP and its lack of hydrophobic binding pockets. Herein, we report a total chemical synthesis of all-l- and all-d-amino acid biotinylated variants of oncogenic mutant KRas(G12V)...
May 22, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28447565/risk-factors-for-brain-metastases-in-patients-with-metastatic-colorectal-cancer
#16
Troels Dreier Christensen, Jesper Andreas Palshof, Finn Ole Larsen, Estrid Høgdall, Tim Svenstrup Poulsen, Per Pfeiffer, Benny Vittrup Jensen, Mette Karen Yilmaz, Ib Jarle Christensen, Dorte Nielsen
BACKGROUND: Brain metastases (BM) from colorectal cancer (CRC) are rare, but the incidence is suspected to rise as treatment of metastatic (m) CRC improves. The aim of this study was to identify possible biological and clinical characteristics at initial presentation of mCRC that could predict later risk of developing BM. Furthermore, we wished to estimate the incidence of BM in long-term surviving patients. MATERIAL AND METHODS: We conducted a retrospective study on a Danish multicenter cohort of patients with mCRC who received cetuximab and irinotecan (CetIri) as third-line treatment...
May 2017: Acta Oncologica
https://www.readbyqxmd.com/read/28446505/clinical-features-and-outcomes-of-patients-with-colorectal-cancers-harboring-nras-mutations
#17
Andrea Cercek, Maria Ignez Braghiroli, Joanne F Chou, Jaclyn F Hechtman, Nancy E Kemeny, Leonard Saltz, Marinela Capanu, Rona Yaeger
Purpose: NRAS mutations are now routinely included in RAS testing prior to EGFR (epidermal growth factor receptor) inhibitor therapy for metastatic colorectal cancer (mCRC).  The clinical implications of NRAS mutation beyond lack of response to anti-EGFR therapy, however, are not known.  We undertook this study to determine the clinical features and treatment outcomes of patients with NRAS mutant mCRC.<br />Experimental Design: We reviewed clinical characteristics, concurrent mutations, and outcomes for all mCRC cases with NRAS mutations undergoing standard genotyping at our institution from 2008-2015...
April 26, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28445136/selective-eradication-of-cancer-cells-by-delivery-of-adenovirus-based-toxins
#18
Shiran Shapira, Assaf Shapira, Diana Kazanov, Gil Hevroni, Sarah Kraus, Nadir Arber
BACKGROUND AND OBJECTIVE: KRAS mutation is an early event in colorectal cancer carcinogenesis. We previously reported that a recombinant adenovirus, carrying a pro-apoptotic gene (PUMA) under the regulation of Ets/AP1 (RAS-responsive elements) suppressed the growth of cancer cells harboring hyperactive KRAS. We propose to exploit the hyperactive RAS pathway, rather than to inhibit it as was previously tried and failed repeatedly. We aim to improve efficacy by substituting PUMA with a more potent toxin, the bacterial MazF-MazE toxin-antitoxin system, under a very tight regulation...
April 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28439013/biliary-epithelial-injury-induced-regenerative-response-by-il-33-promotes-cholangiocarcinogenesis-from-peribiliary-glands
#19
Hayato Nakagawa, Nobumi Suzuki, Yoshihiro Hirata, Yohko Hikiba, Yoku Hayakawa, Hiroto Kinoshita, Sozaburo Ihara, Koji Uchino, Yuji Nishikawa, Hideaki Ijichi, Motoyuki Otsuka, Junichi Arita, Yoshihiro Sakamoto, Kiyoshi Hasegawa, Norihiro Kokudo, Keisuke Tateishi, Kazuhiko Koike
The carcinogenic mechanism of extrahepatic cholangiocarcinoma (ECC) is unclear, due at least in part to the lack of an appropriate mouse model. Because human studies have reported frequent genetic alterations in the Ras- and TGFβ/SMAD-signaling pathways in ECC, mice with tamoxifen-inducible, duct-cell-specific Kras activation and a TGFβ receptor type 2 (TGFβR2) deletion were first generated by crossing LSL-Kras(G12D) , Tgfbr2(flox/flox) , and K19(CreERT) mice (KT-K19(CreERT) ). However, KT-K19(CreERT) mice showed only mild hyperplasia of biliary epithelial cells (BECs) in the extrahepatic bile duct (EHBD) and died within 7 wk, probably a result of lung adenocarcinomas...
April 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28433077/development-and-clinical-utility-of-a-blood-based-test-service-for-the-rapid-identification-of-actionable-mutations-in-non-small-cell-lung-carcinoma
#20
Hestia Mellert, Trudi Foreman, Leisa Jackson, Dianna Maar, Scott Thurston, Kristina Koch, Amanda Weaver, Samantha Cooper, Nicholas Dupuis, Ubaradka G Sathyanarayana, Jakkie Greer, Westen Hahn, Dawne Shelton, Paula Stonemetz, Gary A Pestano
Nearly 80% of cancer patients do not have genetic mutation results available at initial oncology consultation; up to 25% of patients begin treatment before receiving their results. These factors hinder the ability to pursue optimal treatment strategies. This study validates a blood-based genome-testing service that provides accurate results within 72 hours. We focused on targetable variants in advanced non-small cell lung carcinoma-epidermal growth factor receptor gene (EGFR) variant L858R, exon 19 deletion (ΔE746-A750), and T790M; GTPase Kirsten ras gene (KRAS) variants G12C/D/V; and echinoderm microtubule associated protein like and 4 anaplastic lymphoma receptor tyrosine kinase fusion (EML4-ALK) transcripts 1/2/3...
May 2017: Journal of Molecular Diagnostics: JMD
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