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https://www.readbyqxmd.com/read/29242895/comparison-of-laboratory-developed-tests-and-fda-approved-assays-for-braf-egfr-and-kras-testing
#1
Annette S Kim, Angela N Bartley, Julia A Bridge, Suzanne Kamel-Reid, Alexander J Lazar, Neal I Lindeman, Thomas A Long, Jason D Merker, Alex J Rai, David L Rimm, Paul G Rothberg, Patricia Vasalos, Joel T Moncur
Importance: The debate about the role of the Food and Drug Administration (FDA) in the regulation of laboratory-developed tests (LDTs) has focused attention on the analytical performance of all clinical laboratory testing. This study provides data comparing the performance of LDTs and FDA-approved companion diagnostics (FDA-CDs) in proficiency testing (PT) provided by the College of American Pathologists Molecular Oncology Committee. Objective: To compare the analytical performance of LDTs and FDA-CDs on well-characterized PT samples and to compare the practice characteristics of laboratories using these assays...
December 14, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/29241739/braf-and-kras-mutations-in-tubular-apocrine-adenoma-and-papillary-eccrine-adenoma-of-the-skin
#2
Jau-Yu Liau, Jia-Huei Tsai, Wen-Chang Huang, Jui Lan, Jin-Bon Hong, Chang-Tsu Yuan
Tubular apocrine adenoma (TAA) and papillary eccrine adenoma (PEA) are benign sweat gland tumors. Their names imply that they exhibit apocrine and eccrine differentiation, respectively. However, morphologically they are very similar and are often indistinguishable. The molecular pathogenesis of either tumor is poorly understood at present. On the basis of an index case of nipple adenoma that was morphologically reminiscent of cutaneous TAA/PEA and harbored a BRAFV600E mutation, we investigated whether a similar genetic change is also present in TAA/PEA...
December 11, 2017: Human Pathology
https://www.readbyqxmd.com/read/29241546/neutrophils-and-snail-orchestrate-the-establishment-of-a-pro-tumor-microenvironment-in-lung-cancer
#3
Julien Faget, Svenja Groeneveld, Gael Boivin, Martial Sankar, Nadine Zangger, Miguel Garcia, Nicolas Guex, Inti Zlobec, Loïc Steiner, Alessandra Piersigilli, Ioannis Xenarios, Etienne Meylan
Understanding the immune compartment of tumors facilitates the development of revolutionary new therapies. We used a Kras(G12D)-driven mouse model of lung cancer to establish an immune signature and identified a contribution of Gr1+ neutrophils to disease progression. Depletion experiments showed that Gr1+ cells (1) favor tumor growth, (2) reduce T cell homing and prevent successful anti-PD1 immunotherapy, and (3) alter angiogenesis, leading to hypoxia and sustained Snail expression in lung cancer cells. In turn, Snail accelerated disease progression and increased intratumoral Cxcl2 secretion and neutrophil infiltration...
December 12, 2017: Cell Reports
https://www.readbyqxmd.com/read/29241084/neoadjuvant-radiotherapy-combined-with-capecitabine-and-sorafenib-in-patients-with-advanced-kras-mutated-rectal-cancer-a-phase-i-ii-trial-sakk-41-08
#4
Roger von Moos, Dieter Koeberle, Sabina Schacher, Stefanie Hayoz, Ralph C Winterhalder, Arnaud Roth, György Bodoky, Panagiotis Samaras, Martin D Berger, Daniel Rauch, Piercarlo Saletti, Ludwig Plasswilm, Daniel Zwahlen, Urs R Meier, Pu Yan, Paola Izzo, Dirk Klingbiel, Daniela Bärtschi, Kathrin Zaugg
BACKGROUND: KRAS mutation occurs in ∼40% of locally advanced rectal cancers (LARCs). The multitarget tyrosine kinase inhibitor sorafenib has radiosensitising effects and might improve outcomes for standard preoperative chemoradiotherapy in patients with KRAS-mutated LARC. METHODS: Adult patients with KRAS-mutated T3/4 and/or N1/2M0 LARC were included in this phase I/II study. The phase I dose-escalation study of capecitabine plus sorafenib and radiotherapy was followed by a phase II study assessing efficacy and safety...
December 11, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/29240583/site-specific-differences-in-colonic-adenocarcinoma-kras-mutations-and-high-tumor-budding-are-more-frequent-in-cecal-adenocarcinoma
#5
Michael A Landau, Benjamin Zhu, Frances N Akwuole, Reetesh K Pai
Recent literature indicates that adenocarcinomas of the cecum differ with respect to molecular alterations compared with noncecal proximal colon adenocarcinomas and that cecal tumor site may be a prognostically relevant variable. We compared molecular alterations, histopathologic features, and disease-specific survival in a series of 328 colonic adenocarcinomas identified over a 2-year period and stratified by tumor location (cecum, right colon, and left colon). Overall, cecal adenocarcinomas demonstrated the highest frequency of molecular abnormalities with 74% harboring either a KRAS exon 2 or 3 mutation, a BRAF mutation, or DNA mismatch repair protein deficiency...
December 7, 2017: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/29237428/nkx2-1-expression-as-a-prognostic-marker-in-early-stage-non-small-cell-lung-cancer
#6
Jorge Moisés, Alfons Navarro, Sandra Santasusagna, Nuria Viñolas, Laureano Molins, José Ramirez, Jeisson Osorio, Adela Saco, Joan Josep Castellano, Carmen Muñoz, Sara Morales, Mariano Monzó, Ramón María Marrades
BACKGROUND: NKX2-1, a key molecule in lung development, is highly expressed in non-small cell lung cancer (NSCLC), particularly in lung adenocarcinoma (ADK), where it is a diagnostic marker. Studies of the prognostic role of NKX2-1 in NSCLC have reported contradictory findings. Two microRNAs (miRNAs) have been associated with NKX2-1: miR-365, which targets NKX2-1; and miR-33a, which is downstream of NKX2-1. We have examined the effect of NKX2-1, miR-365 and miR-33a on survival in a cohort of early-stage NSCLC patients and in sub-groups of patients classified according to the mutational status of TP53, KRAS, and EGFR...
December 13, 2017: BMC Pulmonary Medicine
https://www.readbyqxmd.com/read/29237412/evaluation-of-epidermal-growth-factor-receptor-signaling-effects-in-gastric-cancer-cell-lines-by-detailed-motility-focused-phenotypic-characterization-linked-with-molecular-analysis
#7
Simone Keller, Julia Kneissl, Verena Grabher-Meier, Stefan Heindl, Jan Hasenauer, Dieter Maier, Julian Mattes, Peter Winter, Birgit Luber
BACKGROUND: Gastric cancers frequently overexpress the epidermal growth factor receptor (EGFR), which has been implicated in pathological processes including tumor cell motility, invasion and metastasis. Targeting EGFR with the inhibitory antibody cetuximab may affect the motile and invasive behavior of tumor cells. Here, we evaluated the effects of EGFR signaling in gastric cancer cell lines to link the phenotypic behavior of the cells with their molecular characteristics. METHODS: Phenotypic effects were analyzed in four gastric cancer cell lines (AGS, Hs746T, LMSU and MKN1) by time-lapse microscopy and transwell invasion assay...
December 13, 2017: BMC Cancer
https://www.readbyqxmd.com/read/29235861/kras-switch-mutants-d33e-and-a59g-crystallize-in-the-state-1-conformation
#8
Jia Lu, Asim Bera, Sudershan R Gondi, Kenneth Dale Westover
KRAS switch loop movements play a crucial role in regulating RAS signaling and alteration in these sensitive dynamics are a principal mechanism through which disease-associated RAS mutations lead to aberrant RAS activation. Prior studies suggest that despite high sequence similarity, the switches in KRAS are more dynamic than HRAS. We solved x-ray crystal structures of the rare tumorigenic KRAS mutants KRASD33E, in switch 1 (SW1), and KRASA59G, in switch 2 (SW2), bound to GDP and found these adopt nearly identical, open SW1 conformations as well as altered SW2 conformations...
December 13, 2017: Biochemistry
https://www.readbyqxmd.com/read/29233960/multiplexed-in-vivo-homology-directed-repair-and-tumor-barcoding-enables-parallel-quantification-of-kras-variant-oncogenicity
#9
Ian P Winters, Shin-Heng Chiou, Nicole K Paulk, Christopher D McFarland, Pranav V Lalgudi, Rosanna K Ma, Leszek Lisowski, Andrew J Connolly, Dmitri A Petrov, Mark A Kay, Monte M Winslow
Large-scale genomic analyses of human cancers have cataloged somatic point mutations thought to initiate tumor development and sustain cancer growth. However, determining the functional significance of specific alterations remains a major bottleneck in our understanding of the genetic determinants of cancer. Here, we present a platform that integrates multiplexed AAV/Cas9-mediated homology-directed repair (HDR) with DNA barcoding and high-throughput sequencing to simultaneously investigate multiple genomic alterations in de novo cancers in mice...
December 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/29233531/genomic-landscape-of-ovarian-clear-cell-carcinoma-via-whole-exome-sequencing
#10
Se Ik Kim, Ji Won Lee, Maria Lee, Hee Seung Kim, Hyun Hoon Chung, Jae-Weon Kim, Noh Hyun Park, Yong-Sang Song, Jeong-Sun Seo
OBJECTIVE: To analyze whole exome sequencing (WES) data on ovarian clear cell carcinoma (OCCC) in Korean patients via the technique of next generation sequencing (NGS). Genomic profiles were compared between endometriosis-associated OCCC (EMS-OCCC) and Non-EMS-OCCC. METHODS: We used serum samples and cancer tissues, stored at the Seoul National University Hospital Human Biobank, that were initially collected from women diagnosed with OCCC between 2012 and 2016. In total, 15 patients were enrolled: 5 with pathologically confirmed EMS-OCCC and 10 with Non-EMS-OCCC...
December 9, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/29233486/cetuximab-combined-with-induction-oxaliplatin-and-capecitabine-followed-by-neoadjuvant-chemoradiation-for-locally-advanced-rectal-cancer-swog-0713
#11
Cynthia Gail Leichman, Shannon L McDonough, Stephen R Smalley, Kevin G Billingsley, Heinz-Josef Lenz, Matthew A Beldner, Aram F Hezel, Mario R Velasco, Katherine A Guthrie, Charles D Blanke, Howard S Hochster
BACKGROUND: Neoadjuvant chemoradiation (NCRT) is standard treatment for locally advanced rectal cancer. Pathologic complete response (pCR) has associated with improved survival. In modern phase III trials of NCRT, pCR ranges from 10% to 20%. Cetuximab improves response in KRAS (KRAS proto-oncogene) wild type (wt) metastatic colorectal cancer. S0713 was designed to assess improvement in pCR with additional use of cetuximab with induction chemotherapy and NCRT for locally advanced, KRAS-wt rectal cancer...
October 24, 2017: Clinical Colorectal Cancer
https://www.readbyqxmd.com/read/29230882/molecular-profiling-and-genome-wide-analysis-based-on-somatic-copy-number-alterations-in-advanced-colorectal-cancers
#12
Tamotsu Sugai, Yayoi Takahashi, Makoto Eizuka, Ryo Sugimoto, Yasuko Fujita, Wataru Habano, Kouki Otsuka, Akira Sasaki, Eiichiro Yamamoto, Takayuki Matsumoto, Hiromu Suzuki
To characterize somatic alterations in colorectal cancer (CRC), we conducted a genome-scale analysis of 106 CRC specimens. We assessed comprehensive somatic copy number alterations (SCNAs) in these CRC specimens. In addition, we examined microsatellite instability (MSI; low and high), genetic mutations (KRAS, BRAF, TP53, and PIK3CA), and DNA methylation status (classified into low, intermediate, and high type). We stratified molecular alterations in the CRCs using a hierarchical cluster analysis. The examined CRCs could be categorized into 3 subgroups using hierarchical cluster analysis...
December 12, 2017: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/29229670/kras-and-tumor-immunity-friend-or-foe
#13
Jane Cullis, Shipra Das, Dafna Bar-Sagi
With the recent breakthroughs in immunotherapy as curative treatments in certain tumor types, there has been renewed interest in the relationship between immunity and tumor growth. Although we are gaining a greater understanding of the complex interplay of immune modulating components in the tumor microenvironment, the specific role that tumor cells play in shaping the immune milieu is still not well characterized. In this review, we focus on how mutant Kras tumor cells contribute to tumor immunity, with a specific focus on processes induced directly or indirectly by the oncogene...
December 11, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/29229669/kras-the-critical-driver-and-therapeutic-target-for-pancreatic-cancer
#14
Andrew M Waters, Channing J Der
RAS genes (HRAS, KRAS, and NRAS) comprise the most frequently mutated oncogene family in human cancer. With the highest RAS mutation frequencies seen with the top three causes of cancer deaths in the United States (lung, colorectal, and pancreatic cancer), the development of anti-RAS therapies is a major priority for cancer research. Despite more than three decades of intense effort, no effective RAS inhibitors have yet to reach the cancer patient. With bitter lessons learned from past failures and with new ideas and strategies, there is renewed hope that undruggable RAS may finally be conquered...
December 11, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/29228650/ultrasensitive-plasma-ctdna-kras-assay-for-detection-prognosis-and-assessment-of-therapeutic-response-in-patients-with-unresectable-pancreatic-ductal-adenocarcinoma
#15
Inna Chen, Victoria M Raymond, Jennifer A Geis, Eric A Collisson, Benny V Jensen, Kirstine L Hermann, Mark G Erlander, Margaret Tempero, Julia S Johansen
Precision oncology requires sensitive and specific clinical biomarkers. Carbohydrate Antigen 19-9 (CA19-9) is widely used in pancreatic ductal adenocarcinoma (PDA) but lacks sensitivity and specificity. Nearly all PDAs harbor somatic KRAS mutations, nominating circulating tumor DNA (ctDNA) KRAS as an alternative disease biomarker, however, variable clinical performance has limited its clinical utility. We applied an ultrasensitive, PCR mutation enrichment, next generation sequencing ctDNA KRAS assay in a large cohort of patients with unresectable PDA (N = 189) recruited to the BIOPAC study between 2008-2015...
November 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29228562/clinical-mutational-profiling-of-1006-lung-cancers-by-next-generation-sequencing
#16
Peter B Illei, Deborah Belchis, Li-Hui Tseng, Doreen Nguyen, Federico De Marchi, Lisa Haley, Stacy Riel, Katie Beierl, Gang Zheng, Julie R Brahmer, Frederic B Askin, Christopher D Gocke, James R Eshleman, Patrick M Forde, Ming-Tseh Lin
Analysis of lung adenocarcinomas for actionable mutations has become standard of care. Here, we report our experience using next generation sequencing (NGS) to examine AKT1, BRAF, EGFR, ERBB2, KRAS, NRAS, and PIK3CA genes in 1006 non-small cell lung cancers in a clinical diagnostic setting. NGS demonstrated high sensitivity. Among 760 mutations detected, the variant allele frequency (VAF) was 2-5% in 33 (4.3%) mutations and 2-10% in 101 (13%) mutations. A single bioinformatics pipeline using Torrent Variant Caller, however, missed a variety of EGFR mutations...
November 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/29227476/the-molecular-landscape-of-pediatric-acute-myeloid-leukemia-reveals-recurrent-structural-alterations-and-age-specific-mutational-interactions
#17
Hamid Bolouri, Jason E Farrar, Timothy Triche, Rhonda E Ries, Emilia L Lim, Todd A Alonzo, Yussanne Ma, Richard Moore, Andrew J Mungall, Marco A Marra, Jinghui Zhang, Xiaotu Ma, Yu Liu, Yanling Liu, Jaime M Guidry Auvil, Tanja M Davidsen, Patee Gesuwan, Leandro C Hermida, Bodour Salhia, Stephen Capone, Giridharan Ramsingh, Christian Michel Zwaan, Sanne Noort, Stephen R Piccolo, E Anders Kolb, Alan S Gamis, Malcolm A Smith, Daniela S Gerhard, Soheil Meshinchi
We present the molecular landscape of pediatric acute myeloid leukemia (AML) and characterize nearly 1,000 participants in Children's Oncology Group (COG) AML trials. The COG-National Cancer Institute (NCI) TARGET AML initiative assessed cases by whole-genome, targeted DNA, mRNA and microRNA sequencing and CpG methylation profiling. Validated DNA variants corresponded to diverse, infrequent mutations, with fewer than 40 genes mutated in >2% of cases. In contrast, somatic structural variants, including new gene fusions and focal deletions of MBNL1, ZEB2 and ELF1, were disproportionately prevalent in young individuals as compared to adults...
December 11, 2017: Nature Medicine
https://www.readbyqxmd.com/read/29227120/-molecular-mechanisms-of-primary-and-secondary-resistance-molecular-genetic-features-and-characteristics-of-kit-pdgfra-non-mutated-gists
#18
Alena Kalfusová, Roman Kodet
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Most of them arise due to activating mutations in KIT (75 - 85 %) or PDGFRA (less than 10 %) genes. Identification of the activating mutations in KIT and PDGFRA genes, which code for receptor tyrosine kinases (RTKs), has improved the outcome of targeted therapy of metastatic, unresectable or recurrent GISTs. Primary and/or secondary resistance represents a significant problem in the targeted therapy by Imatinib mesylate (IM) in patients with GIST...
2017: Ceskoslovenská Patologie
https://www.readbyqxmd.com/read/29223986/kras-testing-tumor-location-and-survival-in-patients-with-stage-iv-colorectal-cancer-seer-2010-2013
#19
Mary E Charlton, Amanda R Kahl, Alissa A Greenbaum, Jordan J Karlitz, Chi Lin, Charles F Lynch, Vivien W Chen
Purpose:KRAS mutations and tumor location have been associated with response to targeted therapy among patients with stage IV colorectal cancer (CRC) in various trials. This study performed the first population-based examination of associations between KRAS mutations, tumor location, and survival, and assessed factors associated with documented KRAS testing. Methods: Patients with stage IV adenocarcinoma of the colon/rectum diagnosed from 2010 to 2013 were extracted from SEER data. Analyses of patient characteristics, KRAS testing, and tumor location were conducted using logistic regression...
December 2017: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/29223537/rankl-signaling-sustains-primary-tumor-growth-in-genetically-engineered-mouse-models-of-lung-adenocarcinoma
#20
Julien Faget, Caroline Contat, Nadine Zangger, Solange Peters, Etienne Meylan
HYPOTHESIS: Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality. Recent retrospective clinical analyses suggest that blocking the receptor activator of NF-κB (RANK) signaling pathway inhibits the growth of NSCLC and might represent a new treatment strategy. METHODS: RANK and RANKL expression in human lung adenocarcinoma was interrogated from publicly available gene expression datasets. Several genetically engineered mouse models were used to evaluate treatment efficacy of RANK-Fc to block RANKL, with primary tumor growth measured longitudinally using micro-computed tomography...
December 6, 2017: Journal of Thoracic Oncology
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