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https://www.readbyqxmd.com/read/29769200/long-chain-n-3-fatty-acids-attenuate-oncogenic-kras-driven-proliferation-by-altering-plasma-membrane-nanoscale-proteolipid-composition
#1
Natividad R Fuentes, Mohamed Mlih, Rola Barhoumi, Yang-Yi Fan, Paul Hardin, Trevor J Steele, Spencer Behmer, Ian A Prior, Jason Karpac, Robert S Chapkin
Ras signaling originates from transient nanoscale compartmentalized regions of the plasma membrane composed of specific proteins and lipids. The highly specific lipid composition of these nanodomains, termed nanoclusters, facilitates effector recruitment and therefore influences signal transduction. This suggests that Ras nanocluster proteolipid composition could represent a novel target for future chemoprevention interventions. There is evidence that consumption of fish oil containing long-chain n-3 polyunsaturated fatty acids (n-3 PUFA) such as eicosapentaenoic acid (EPA, 20:5Δ5,8,11,14,17) and docosahexaenoic acid (DHA, 22:6Δ4,7,10,13,16,19) may reduce colon cancer risk in humans, yet the mechanism underlying this effect is unknown...
May 16, 2018: Cancer Research
https://www.readbyqxmd.com/read/29765524/cross-platform-comparison-for-the-detection-of-ras-mutations-in-cfdna-ddpcr-biorad-detection-assay-beaming-assay-and-ngs-strategy
#2
Jessica Garcia, Julien Forestier, Eric Dusserre, Anne-Sophie Wozny, Florence Geiguer, Patrick Merle, Claire Tissot, Carole Ferraro-Peyret, Frederick S Jones, Daniel L Edelstein, Valérie Cheynet, Claire Bardel, Gaelle Vilchez, Zhenyu Xu, Pierre Paul Bringuier, Marc Barritault, Karen Brengle-Pesce, Marielle Guillet, Marion Chauvenet, Brigitte Manship, Marie Brevet, Claire Rodriguez-Lafrasse, Valérie Hervieu, Sébastien Couraud, Thomas Walter, Léa Payen
CfDNA samples from colon (mCRC) and non-small cell lung cancers (NSCLC) (CIRCAN cohort) were compared using three platforms: droplet digital PCR (ddPCR, Biorad); BEAMing/OncoBEAM™-RAS-CRC (Sysmex Inostics); next-generation sequencing (NGS, Illumina), utilizing the 56G oncology panel (Swift Biosciences). Tissue biopsy and time matched cfDNA samples were collected at diagnosis in the mCRC cohort and during 1st progression in the NSCLC cohort. Excellent matches between cfDNA/FFPE mutation profiles were observed...
April 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29760449/aurora-kinase-a-aurka-interaction-with-wnt-and-ras-mapk-signalling-pathways-in-colorectal-cancer
#3
Annika Jacobsen, Linda J W Bosch, Sanne R Martens-de Kemp, Beatriz Carvalho, Anke H Sillars-Hardebol, Richard J Dobson, Emanuele de Rinaldis, Gerrit A Meijer, Sanne Abeln, Jaap Heringa, Remond J A Fijneman, K Anton Feenstra
Hyperactivation of Wnt and Ras-MAPK signalling are common events in development of colorectal adenomas. Further progression from adenoma-to-carcinoma is frequently associated with 20q gain and overexpression of Aurora kinase A (AURKA). Interestingly, AURKA has been shown to further enhance Wnt and Ras-MAPK signalling. However, the molecular details of these interactions in driving colorectal carcinogenesis remain poorly understood. Here we first performed differential expression analysis (DEA) of AURKA knockdown in two colorectal cancer (CRC) cell lines with 20q gain and AURKA overexpression...
May 14, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29755687/clinical-application-of-targeted-next-generation-sequencing-for-colorectal-cancer-patients-a-multicentric-belgian-experience
#4
Nicky D'Haene, Quitterie Fontanges, Nancy De Nève, Oriane Blanchard, Barbara Melendez, Monique Delos, Marie-Françoise Dehou, Calliope Maris, Nathalie Nagy, Emmanuel Rousseau, Josse Vandenhove, André Gilles, Carine De Prez, Laurine Verset, Marie-Paule Van Craynest, Pieter Demetter, Jean-Luc Van Laethem, Isabelle Salmon, Marie Le Mercier
International guidelines made RAS (KRAS and NRAS) status a prerequisite for the use of anti-EGFR agents for metastatic colorectal cancer (CRC) patients. Daily, new data emerges on the theranostic and prognostic role of molecular biomarkers; this is a strong incentive for a validated, sensitive, and broadly available molecular screening test. Next-generation sequencing (NGS) has begun to supplant other technologies for genomic profiling. We report here our 2 years of clinical practice using NGS results to guide therapeutic decisions...
April 17, 2018: Oncotarget
https://www.readbyqxmd.com/read/29743592/a-novel-three-dimensional-high-throughput-screening-approach-identifies-inducers-of-a-mutant-kras-selective-lethal-phenotype
#5
Smitha Kota, Shurong Hou, William Guerrant, Franck Madoux, Scott Troutman, Virneliz Fernandez-Vega, Nina Alekseeva, Neeharika Madala, Louis Scampavia, Joseph Kissil, Timothy P Spicer
The RAS proteins are the most frequently mutated oncogenes in cancer, with highest frequency found in pancreatic, lung, and colon tumors. Moreover, the activity of RAS is required for the proliferation and/or survival of these tumor cells and thus represents a high-value target for therapeutic development. Direct targeting of RAS has proven challenging for multiple reasons stemming from the biology of the protein, the complexity of downstream effector pathways and upstream regulatory networks. Thus, significant efforts have been directed at identifying downstream targets on which RAS is dependent...
May 10, 2018: Oncogene
https://www.readbyqxmd.com/read/29742286/study-of-promoter-hypomethylation-profiles-of-ras-oncogenes-in-hepatocellular-carcinoma-derived-from-hepatitis-c-virus-genotype-3a-in-pakistani-population
#6
Maria Maryam, Muhammad Idrees
Epigenetic modifications such as DNA methylation contribute to progression of Hepatitis C virus (HCV) infection to life-threatening hepatocellular carcinoma (HCC), by promoting the silencing of tumor suppressor genes due to DNA hypermethylation and by causing genomic instability due to global hypomethylation. However few studies addressed promoter region hypomethylation status of the oncogenes involved in HCV derived HCC. In this study, we analyzed the promoter region methylation pattern of RAS oncogenes (HRAS, KRAS, NRAS) using methylation-specific PCR (MSP) for 50 Chronic HCV patients infected with genotype 3a (27 HCC patients and 23 Control non-HCC patients)...
May 9, 2018: Journal of Medical Virology
https://www.readbyqxmd.com/read/29739790/phase-ib-ii-study-of-second-line-therapy-with-panitumumab-irinotecan-and-everolimus-pie-in-kras-wild-type-metastatic-colorectal-cancer
#7
Amanda Townsend, Niall C Tebbutt, Christos S Karapetis, Pamela Cooper, Nimit Singhal, Sue J Yeend, Louise Pirc, Rohit Joshi, Jennifer Elizabeth Hardingham, Timothy Price
PURPOSE: Inhibition of mTOR in addition to EGFR may overcome resistance to EGFR inhibitors in metastatic colorectal cancer (mCRC). This phase Ib/II study evaluated the safety and efficacy of the combination of irinotecan, panitumumab and everolimus. EXPERIMENTAL DESIGN: Patients with KRAS exon 2 WT mCRC following failure of fluoropyrimidine based therapy received IV irinotecan and panitumumab every 2 weeks, and everolimus orally throughout a 14 day cycle. The primary endpoint of the phase II study was response rate (RR)...
May 8, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29737864/panitumumab-in-the-treatment-of-metastatic-colorectal-cancer-including-wild-type-ras-kras-and-nras-mcrc
#8
Mark McGregor, Timothy J Price
The humanized monoclonal antibody panitumumab, targeted against EGFR, plays an important role in patients with metastatic colorectal cancer. This article reviews the body of evidence for panitumumab which demonstrates significant benefits across multiple lines of therapy in those without an extended RAS mutation. The use of panitumumab with RAS mutations is not beneficial and possibly harmful. Panitumumab is well tolerated with manageable toxicities. The role of panitumumab continues to evolve as understanding of sequencing of therapies grows...
May 8, 2018: Future Oncology
https://www.readbyqxmd.com/read/29736383/analysis-of-kras-gene-from-induced-pancreatic-cancer-rats-administered-with-momordica-charantia-and-ocimum-ba-s-ilicum-leaf-extracts
#9
J B Minari, C A Okelola, N C Ugochukwu
Objective: To analyze K-ras gene from induced pancreatic cancer rats administered with Momordica charantia and Ocimum basilicum leaf extracts. Methods: Twenty-five (25) adult rats weighing between 90-120 g were divided into 5 groups namely RA, RB, RC, NC and PC, each group had 5 rats. The PC which served as the control was fed with normal fish meal and water ad libitum; the NC which is the negative control received 20 mg/ml/week of Nitrosamines only while other groups received different concentrations of aqueous extract of both M ...
April 2018: Journal of Traditional and Complementary Medicine
https://www.readbyqxmd.com/read/29726952/comprehensive-genetic-analysis-of-follicular-thyroid-carcinoma-predicts-prognosis-independent-of-histology
#10
Norman G Nicolson, Timothy D Murtha, Weilai Dong, Johan O Paulsson, Jungmin Choi, Andrea L Barbieri, Taylor C Brown, John W Kunstman, Catharina Larsson, Manju L Prasad, Reju Korah, Richard P Lifton, C Christofer Juhlin, Tobias Carling
Context: Follicular thyroid cancer (FTC) is classified into minimally invasive (miFTC), encapsulated angioinvasive (eaFTC), and widely invasive (wiFTC) subtypes, according to the 2017 World Health Organization (WHO) guidelines. The genetic signatures of these subtypes may be crucial for diagnosis, prognosis, and treatment, but have not been described. Objective: Identify and describe the genetic underpinnings of subtypes of follicular thyroid cancer. Methods: Thirty-nine tumors, comprising 12 miFTCs, 17 eaFTCs, and 10 wiFTCs were whole-exome sequenced and analyzed...
May 2, 2018: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29725370/upregulation-of-c-mesenchymal-epithelial-transition-expression-and-ras-mutations-are-associated-with-late-lung-metastasis-and-poor-prognosis-in-colorectal-carcinoma
#11
Jianhua Liu, Weiqiang Zeng, Chengzhi Huang, Junjiang Wang, Lishu Xu, Dong Ma
The present study aimed to investigate whether c-mesenchymal epithelial transition factor (C-MET) overexpression combined with RAS (including KRAS, NRAS and HRAS ) or BRAF mutations were associated with late distant metastases and the prognosis of patients with colorectal cancer (CRC). A total of 374 patients with stage III CRC were classified into 4 groups based on RAS/BRAF and C-MET status for comprehensive analysis. Mutations in RAS / BRAF were determined using Sanger sequencing and C-MET expression was examined using immunohistochemistry...
May 2018: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29723601/clinical-utility-of-ezh1-mutations-in-the-diagnosis-of-follicular-patterned-thyroid-tumors
#12
Chan Kwon Jung, Yourha Kim, Sora Jeon, Kwanhoon Jo, Sohee Lee, Ja Seong Bae
Follicular-patterned tumors of the thyroid gland are characterized by a predominantly follicular growth pattern. They frequently harbor RAS mutations, not BRAF mutations. Technological advances in molecular testing have discovered novel RAS-type mutations. However, clinical significance of these mutations remains unknown. We investigated the prevalence and clinical impact of mutations of BRAF, NRAS, HRAS, KRAS, EZH1, EIF1AX, and TERT genes by Sanger sequencing in a series of 201 follicular-patterned thyroid tumors including follicular adenoma (n=40), Hürthle cell adenoma (n=54), noninvasive follicular thyroid neoplasms with papillary-like nuclear features (n=50), follicular thyroid carcinoma (n=40), Hürthle cell carcinoma (n=10), and poorly differentiated thyroid carcinoma arising in a well differentiated follicular neoplasm (n=7), and 120 classic papillary carcinoma...
April 30, 2018: Human Pathology
https://www.readbyqxmd.com/read/29721374/ppar%C3%AE-activation-increases-intestinal-m1-macrophages-and-mitigates-formation-of-serrated-adenomas-in-mutant-kras-mice
#13
Tobias Gutting, Christian A Weber, Philip Weidner, Frank Herweck, Sarah Henn, Teresa Friedrich, Shuiping Yin, Julia Kzhyshkowska, Timo Gaiser, Klaus-Peter Janssen, Wolfgang Reindl, Matthias P A Ebert, Elke Burgermeister
To identify novel hubs for cancer immunotherapy, we generated C57BL/6 J mice with concomitant deletion of the drugable transcription factor PPARγ and transgenic overexpression of the mutant KRASG12V oncogene in enterocytes. Animals developed epithelial hyperplasia, transmural inflammation and serrated adenomas in the small intestine with infiltration of CD3+ FOXP3+ T-cells and macrophages into the lamina propria of the non-malignant mucosa. Within serrated polyps, CD3+ CD8+ T-cells and phosphorylated ERK1/2 were reduced and the senescence marker P21 and macrophage counts up-regulated, indicative of an immunosuppressive tissue microenvironment...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29721157/bet-inhibition-is-an-effective-approach-against-kras-driven-pdac-and-nsclc
#14
Toni Jauset, Daniel Massó-Vallés, Sandra Martínez-Martín, Marie-Eve Beaulieu, Laia Foradada, Francesco Paolo Fiorentino, Jun Yokota, Bernard Haendler, Stephan Siegel, Jonathan R Whitfield, Laura Soucek
Effectively treating KRAS-driven tumors remains an unsolved challenge. The inhibition of downstream signaling effectors is a way of overcoming the issue of direct targeting of mutant KRAS, which has shown limited efficacy so far. Bromodomain and Extra-Terminal (BET) protein inhibition has displayed anti-tumor activity in a wide range of cancers, including KRAS-driven malignancies. Here, we preclinically evaluate the effect of BET inhibition making use of a new BET inhibitor, BAY 1238097, against Pancreatic Ductal Adenocarcinoma (PDAC) and Non-Small Cell Lung Cancer (NSCLC) models harboring RAS mutations both in vivo and in vitro ...
April 10, 2018: Oncotarget
https://www.readbyqxmd.com/read/29720900/update-on-sporadic-colorectal-cancer-genetics
#15
REVIEW
Karin M Hardiman
Our understanding of the genetics of colorectal cancer has changed dramatically over recent years. Colorectal cancer can be classified in multiple different ways. Along with the advent of whole-exome sequencing, we have gained an understanding of the scale of the genetic changes found in sporadic colorectal cancer. We now know that there are multiple pathways that are commonly involved in the evolution of colorectal cancer including Wnt/β-catenin, RAS, EGFR, and PIK3 kinase. Another recent leap in our understanding of colorectal cancer genetics is the recognition that many, if not all tumors, are actually genetically heterogeneous within individual tumors and also between tumors...
May 2018: Clinics in Colon and Rectal Surgery
https://www.readbyqxmd.com/read/29707525/ras-braf-circulating-tumor-dna-mutations-as-a-predictor-of-response-to-first-line-chemotherapy-in-metastatic-colorectal-cancer-patients
#16
Jiannan Yao, Wanchun Zang, Yang Ge, Nathaniel Weygant, Pan Yu, Lei Li, Guanhua Rao, Zhi Jiang, Rui Yan, Linjia He, Yang Yu, Mulan Jin, Gang Cheng, Guangyu An
Background: Since circulating tumor DNA (ctDNA) offers clear advantages as a minimally invasive method for tumor monitoring compared with tumor tissue, we aimed to evaluate genotyping ctDNA using a next-generation sequencing- (NGS-) based panel to identify the prognostic value of mutation status in metastatic colorectal cancer (mCRC) patients with primary tumor resected and with subsequent lines of treatment in this study. Methods: 76 mCRC patients treated in Beijing Chao-Yang Hospital from 2011 to 2017 were enrolled...
2018: Canadian Journal of Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/29704308/a-sibling-pair-with-cardiofaciocutaneous-syndrome-cfc-secondary-to-braf-mutation-with-unaffected-parents-the-first-cases-of-gonadal-mosaicism-in-cfc
#17
Sarah Geoghegan, Graham King, Jennifer Henchliffe, Simon C Ramsden, Raymond J Barry, Andrew J Green, Susan M O'Connell
Cardiofaciocutaneous (CFC) syndrome is a RASopathy characterized by intellectual disability, congenital heart defects, a characteristic facial appearance, gastro-intestinal complications, ectodermal abnormalities and growth failure. The RASopathies result from germline mutations in the Ras/Mitogen-activated-protein-kinase (MAPK) pathway. CFC is associated with mutations in BRAF, KRAS, MEK1 and MEK2. CFC has been considered a "sporadic" disorder, with minimal recurrence risk to siblings. In recent years, vertical transmission of CFC has been seen in mutations involving the MEK2 and KRAS genes, but has not previously been reported with BRAF mutations...
April 28, 2018: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29703606/final-analysis-of-outcomes-and-ras-braf-status-in-a-randomized-phase-3-study-of-panitumumab-and-best-supportive-care-in-chemorefractory-wild-type-kras-metastatic-colorectal-cancer
#18
Tae Won Kim, Anneli Elme, Joon Oh Park, Anghel Adrian Udrea, Sun Young Kim, Joong Bae Ahn, Ricardo Villalobos Valencia, Srinivasan Krishnan, Nebojsa Manojlovic, Xuesong Guan, Catherine Lofton-Day, A Scott Jung, Eduard Vrdoljak
INTRODUCTION: Tumor rat sarcoma gene (RAS) status is a negative predictive biomarker for anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer (mCRC). We analyzed outcomes according to RAS and v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutational status, and evaluated early tumor shrinkage (ETS) and depth of response (DpR) for patients with wild type RAS. PATIENTS AND METHODS: Patients with confirmed metastatic colon or rectum adenocarcinoma, wild type Kristen rat sarcoma gene tumor exon 2 status, clinical/radiologic disease progression or toxicity during irinotecan or oxaliplatin treatment, and no previous anti-EGFR therapy were randomized 1:1 to receive best supportive care (BSC) with or without panitumumab (6...
March 21, 2018: Clinical Colorectal Cancer
https://www.readbyqxmd.com/read/29703472/single-cell-coagulomes-as-constituents-of-the-oncogene-driven-coagulant-phenotype-in-brain-tumours
#19
Nadim Tawil, Shilpa Chennakrishnaiah, Rayhaan Bassawon, Radia Johnson, Esterina D'Asti, Janusz Rak
Molecular profiling of human cancers revealed a startling diversity in disease-causing mechanisms superseding histological and anatomical commonalities. The emerging molecular subtypes and disease entities are often driven by distinct oncogenic pathways and their effectors, including those acting extracellularly on the vascular and coagulation systems. Indeed, several oncogenic mutations such as those affecting protein-coding genes (RAS, EGFR, PTEN, TP53) and non-coding RNA (microRNA) regulate multiple effectors of the coagulation system (coagulome), including tissue factor, protease activated receptors, clotting factors, mediators of platelet function and fibrinolysis...
April 2018: Thrombosis Research
https://www.readbyqxmd.com/read/29692343/clonal-interference-of-signaling-mutations-holds-prognostic-relevance-in-core-binding-factor-acute-myeloid-leukemia
#20
Raphael Itzykson, Nicolas Duployez, Annette Fasan, Gauthier Decool, Alice Marceau-Renaut, Manja Meggendorfer, Eric Jourdan, Arnaud Petit, Hélène Lapillonne, Jean-Baptiste Micol, Pascale Cornillet-Lefebvre, Norbert Ifrah, Guy Leverger, Hervé Dombret, Nicolas Boissel, Torsten Haferlach, Claude Preudhomme
Mutations in receptor tyrosine kinase/RAS signaling pathway genes are frequent in Core Binding Factor Acute Myeloid Leukemias (CBF AML), but their prognostic relevance is debated. A subset of CBF AML patients harbors several signaling gene mutations. Genotyping of colonies and of relapse samples indicates that these arise in independent clones, thus defining a process of clonal interference (or parallel evolution). Clonal interference is pervasive in cancers but the mechanisms underlying this process remain unclear, and its prognostic impact unknown...
April 24, 2018: Blood
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