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https://www.readbyqxmd.com/read/27899805/circulating-tumour-dna-analysis-demonstrates-spatial-mutational-heterogeneity-that-coincides-with-disease-relapse-in-myeloma
#1
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/27899776/-new-classification-for-advanced-colorectal-cancer-using-cancerplex%C3%A2-genomic-tests
#2
Hitoshi Kameyama, Yoshifumi Shimada, Hiroshi Ichikawa, Masayuki Nagahashi, Jun Sakata, Takashi Kobayashi, Hitoshi Nogami, Satoshi Maruyama, Yasumasa Takii, Shujiro Okuda, Yiwei Ling, Hiroshi Izutsu, Keisuke Kodama, Mitsutaka Nakada, Toshifumi Wakai
Recently, targeted drugs have been developed for the treatment of colorectal cancer(CRC). Among targets, it is well known that KRAS mutations are associated with resistance to epidermal growth factor receptor(EGFR)monoclonal antibodies. However, response rates using anti-EGFR monotherapy for CRC were less than 20-30% in previous clinical studies. Thus, because the RAS/MAP2K/MAPK and PI3K/AKT pathways are associated with CRC resistance to chemotherapy, we analyzed gene mutations in Stage IV CRC patients using a genomic test(CancerPlex®)...
November 2016: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/27898263/genetic-alterations-affecting-gtpases-and-t-cell-receptor-signaling-in-peripheral-t-cell-lymphomas
#3
Rebecca L Boddicker, Gina L Razidlo, Andrew L Feldman
Peripheral T-cell lymphomas (PTCLs) are rare, heterogeneous tumors with poor response to standard therapy and few targeted treatments available. The identification of mutations in the T-cell receptor (TCR) signaling pathway that either directly or indirectly affect Ras- and Rho-family GTPases is an emerging theme across PTCL subtypes. This review summarizes the role of GTPases in TCR signaling and highlights the constellation of mutations in this pathway among PTCLs. In particular, focus is given to the functional impact of the mutations and opportunities for targeted therapy...
November 29, 2016: Small GTPases
https://www.readbyqxmd.com/read/27894102/comparative-proteomics-of-a-model-mcf10a-krasg12v-cell-line-reveals-a-distinct-molecular-signature-of-the-krasg12v-cell-surface
#4
Xiaoying Ye, King C Chan, Andrew M Waters, Matthew Bess, Adam Harned, Bih-Rong Wei, Jadranka Loncarek, Brian T Luke, Benjamin C Orsburn, Bradley D Hollinger, Robert M Stephens, Rachel Bagni, Alex Martinko, James A Wells, Dwight V Nissley, Frank McCormick, Gordon Whiteley, Josip Blonder
Oncogenic Ras mutants play a major role in the etiology of most aggressive and deadly carcinomas in humans. In spite of continuous efforts, effective pharmacological treatments targeting oncogenic Ras isoforms have not been developed. Cell-surface proteins represent top therapeutic targets primarily due to their accessibility and susceptibility to different modes of cancer therapy. To expand the treatment options of cancers driven by oncogenic Ras, new targets need to be identified and characterized at the surface of cancer cells expressing oncogenic Ras mutants...
November 24, 2016: Oncotarget
https://www.readbyqxmd.com/read/27893191/young-investigator-challenge-molecular-testing-in-noninvasive-follicular-thyroid-neoplasm-with-papillary-like-nuclear-features
#5
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/27880995/frequency-of-k-ras-and-n-ras-gene-mutations-in-colorectal-cancers-in-southeastern-iran
#6
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
#7
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
https://www.readbyqxmd.com/read/27863786/preoperative-detection-of-ras-mutation-may-guide-extent-of-thyroidectomy
#8
Snehal G Patel, Sally E Carty, Kelly L McCoy, N Paul Ohori, Shane O LeBeau, Raja R Seethala, Marina N Nikiforova, Yuri E Nikiforov, Linwah Yip
BACKGROUND: Preoperative detection of RAS mutations can contribute to cancer risk assessment in indeterminate thyroid nodules, although RAS is not always associated with malignancy. METHODS: Fine-needle aspiration samples classified in 1 of 3 indeterminate cytology categories were prospectively tested for N-, H-, and K-RAS mutations using next-generation sequencing assay. RESULTS: In the study, 93 patients with 94 nodules had preoperative RAS detected, of whom 86 patients had an operation (69% total thyroidectomy, 29% lobectomy)...
November 15, 2016: Surgery
https://www.readbyqxmd.com/read/27856123/prognostic-impact-of-primary-tumor-location-on-clinical-outcomes-of-metastatic-colorectal-cancer-treated-with-cetuximab-plus-oxaliplatin-based-chemotherapy-a-subgroup-analysis-of-the-jaccro-cc-05-06-trials
#9
Yu Sunakawa, Wataru Ichikawa, Akihito Tsuji, Tadamichi Denda, Yoshihiko Segawa, Yuji Negoro, Ken Shimada, Mitsugu Kochi, Masato Nakamura, Masahito Kotaka, Hiroaki Tanioka, Akinori Takagane, Satoshi Tani, Tatsuro Yamaguchi, Takanori Watanabe, Masahiro Takeuchi, Masashi Fujii, Toshifusa Nakajima
INTRODUCTION: Primary tumor location is a critical prognostic factor in metastatic colorectal cancer (mCRC); however, it remains unclear whether tumor location is a predictor of the response to cetuximab treatment. It is also uncertain if BRAF mutation contributes to the impact of tumor location on survival. We assessed the prognostic impact of tumor location on clinical outcomes in mCRC patients treated with first-line cetuximab chemotherapy. PATIENTS AND METHODS: The associations of tumor location with overall survival and progression-free survival were evaluated in mCRC patients with KRAS exon 2 wild-type tumors who were enrolled onto 2 clinical trials: JACCRO CC-05 of cetuximab plus FOLFOX (n = 57, UMIN000004197) and CC-06 of cetuximab plus SOX (n = 61, UMIN000007022)...
October 6, 2016: Clinical Colorectal Cancer
https://www.readbyqxmd.com/read/27852040/clinical-validation-of-prospective-liquid-biopsy-monitoring-in-patients-with-wild-type-ras-metastatic-colorectal-cancer-treated-with-folfiri-cetuximab
#10
Rodrigo A Toledo, Antonio Cubillo, Estela Vega, Elena Garralda, Rafael Alvarez, Lisardo U de la Varga, Jesús R Pascual, Gema Sánchez, Francesca Sarno, Susana H Prieto, Sofía Perea, Pedro P Lopéz-Casas, Fernando López-Ríos, Manuel Hidalgo
Cancer genomics and translational medicine rely on the molecular profiling of patient's tumor obtained during surgery or biopsy. Alternatively, blood is a less invasive source of tumor DNA shed, amongst other ways, as cell-free DNA (cfDNA). Highly-sensitive assays capable to detect cancer genetic events from patient's blood plasma became popularly known as liquid biopsy (LqB). Importantly, retrospective studies including small number of selected patients with metastatic colorectal cancer (mCRC) patients treated with anti-EGFR therapy have shown LqB capable to detect the acquired clonal mutations in RAS genes leading to therapy resistance...
November 11, 2016: Oncotarget
https://www.readbyqxmd.com/read/27846317/ras-mitogen-activated-protein-kinase-signal-is-required-for-enhanced-pd-l1-expression-in-human-lung-cancers
#11
Hidetoshi Sumimoto, Atsushi Takano, Koji Teramoto, Yataro Daigo
Ectopic programmed cell death ligand 1 (PD-L1) expression in non-small cell lung cancers (NSCLCs) is related to immune evasion by cancer, and it is a molecular target of immune checkpoint therapies. Although some altered signals in NSCLCs are responsible for ectopic PD-L1 expression, the precise mechanisms remain obscure. Because we found a higher frequency of EGFR/KRAS mutations in NSCLC cell lines with high PD-L1 expression (p < 0.001), we evaluated the relationships between downstream signals and PD-L1 expression, particularly in three KRAS-mutant adenocarcinoma cell lines...
2016: PloS One
https://www.readbyqxmd.com/read/27845624/targeting-mutant-ras-in-patient-derived-colorectal-cancer-organoids-by-combinatorial-drug-screening
#12
Carla S Verissimo, René M Overmeer, Bas Ponsioen, Jarno Drost, Sander Mertens, Ingrid Verlaan-Klink, Bastiaan van Gerwen, Marieke van der Ven, Marc van de Wetering, David A Egan, René Bernards, Hans Clevers, Johannes L Bos, Hugo J Snippert
Colorectal cancer (CRC) organoids can be derived from almost all CRC patients and therefore capture the genetic diversity of this disease. We assembled a panel of CRC organoids carrying either wild-type or mutant RAS, as well as normal organoids and tumor organoids with a CRISPR-introduced oncogenic KRAS mutation. Using this panel, we evaluated RAS pathway inhibitors and drug combinations that are currently in clinical trial for RAS mutant cancers. Presence of mutant RAS correlated strongly with resistance to these targeted therapies...
November 15, 2016: ELife
https://www.readbyqxmd.com/read/27835861/an-oncogenic-kras-transcription-program-activates-the-rhogef-arhgef2-to-mediate-transformed-phenotypes-in-pancreatic-cancer
#13
Oliver A Kent, María-José Sandí, Helen E Burston, Kevin R Brown, Robert Rottapel
Activating mutations of KRAS are nearly ubiquitous in pancreatic adenocarcinomas occurring in greater than 90% of cases. Cellular transformation by oncogenic RAS requires the RHO guanine exchange factor ARHGEF2 (also known as GEF-H1) for tumor growth and survival. Here, we find oncogenic KRAS activates ARHGEF2 through a minimal RAS responsive promoter. We have determined the endogenous ARHGEF2 promoter is positively regulated by the transcription factors ELK1, ETS1, SP1 and SP3 and negatively regulated by the RAS responsive element binding protein (RREB1)...
November 7, 2016: Oncotarget
https://www.readbyqxmd.com/read/27834083/molecular-diagnosis-using-residual-liquid-based-cytology-materials-for-patients-with-nondiagnostic-or-indeterminate-thyroid-nodules
#14
Hyemi Kwon, Won Gu Kim, Markus Eszlinger, Ralf Paschke, Dong Eun Song, Mijin Kim, Suyeon Park, Min Ji Jeon, Tae Yong Kim, Young Kee Shong, Won Bae Kim
BACKGROUND: Molecular analysis for common somatic mutations in thyroid cancer can improve diagnostic accuracy of fine-needle aspiration cytology (FNAC) in the nondiagnostic or indeterminate category of thyroid nodules. In this study, we evaluated the feasibility of molecular diagnosis from residual liquid-based cytology (LBC) material after cytological diagnosis. METHODS: This prospective study enrolled 53 patients with thyroid nodules diagnosed as nondiagnostic, atypia of undetermined significance (AUS), or follicular lesion of undetermined significance (FLUS) after FNAC...
November 4, 2016: Endocrinology and Metabolism
https://www.readbyqxmd.com/read/27823638/molecular-characteristics-of-biliary-tract-cancer
#15
REVIEW
Davendra P S Sohal, Shiva Shrotriya, Mohamed Abazeed, Michael Cruise, Alok Khorana
Biliary tract cancers (intrahepatic, perihilar and extrahepatic cholangiocarcinoma, and gallbladder and cystic duct cancers) are uncommon but highly lethal malignancies. Clinical presentation is often late, precluding curative surgical resection in most cases. For advanced disease, therapeutic options are limited to systemic chemotherapy, with suboptimal outcomes. An understanding of the molecular characteristics of biliary tract cancers may allow the clinical development of therapies targeting actionable alterations with the ultimate goal of improving clinical outcomes...
November 2016: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/27822414/differences-in-mek-inhibitor-efficacy-in-molecularly-characterized-low-grade-serous-ovarian-cancer-cell-lines
#16
Marta Llauradó Fernández, Gabriel E DiMattia, Amy Dawson, Sylvia Bamford, Shawn Anderson, Bryan T Hennessy, Michael S Anglesio, Trevor G Shepherd, Clara Salamanca, Josh Hoenisch, Anna Tinker, David G Huntsman, Mark S Carey
Advanced or recurrent low-grade serous ovarian cancers (LGSC) are resistant to conventional systemic treatments. LGSC carry mutations in RAS or RAF, leading to several clinical trials evaluating MEK inhibitors (MEKi). As LGSC cell lines and xenografts have been difficult to establish, little is known about the efficacy and on-target activity of MEKi treatment in this disease. We compared four different MEKi (trametinib, selumetinib, binimetinib and refametinib) in novel LGSC patient-derived cell lines. Molecular characterization of these cells included copy-number variation and hotspot mutational analysis...
2016: American Journal of Cancer Research
https://www.readbyqxmd.com/read/27821733/a-diaphanous-related-formin-links-ras-signaling-directly-to-actin-assembly-in-macropinocytosis-and-phagocytosis
#17
Alexander Junemann, Vedrana Filić, Moritz Winterhoff, Benjamin Nordholz, Christof Litschko, Helena Schwellenbach, Till Stephan, Igor Weber, Jan Faix
Phagocytosis and macropinocytosis are Ras-regulated and actin-driven processes that depend on the dynamic rearrangements of the plasma membrane that protrudes and internalizes extracellular material by cup-shaped structures. However, the regulatory mechanisms underlying actin assembly in large-scale endocytosis remain elusive. Here, we show that the Diaphanous-related formin G (ForG) from the professional phagocyte Dictyostelium discoideum localizes to endocytic cups. Biochemical analyses revealed that ForG is a rather weak nucleator but efficiently elongates actin filaments in the presence of profilin...
November 7, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27815357/braf-and-nras-locus-specific-variants-have-different-outcomes-on-survival-to-colorectal-cancer
#18
Matthew Summers, Christopher G Smith, Timothy S Maughan, Rick Kaplan, Valentina Escott-Price, Jeremy P Cheadle
PURPOSE: Somatic mutation status at KRAS, BRAF and NRAS is associated with prognosis in patients with advanced colorectal cancer (aCRC); however, it remains unclear whether there are intra-locus, variant-specific differences in survival and other clinicopathological parameters. EXPERIMENTAL DESIGN: We profiled 2,157 aCRCs for somatic mutations in KRAS, BRAF and NRAS and determined microsatellite instability status. We sought inter- and intra-locus correlations between mutations, and variant-specific associations with survival and clinicopathology...
November 4, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27805251/in-silico-rna-seq-and-experimental-analyses-reveal-the-differential-expression-and-splicing-of-epdr1-and-znf518b-genes-in-relation-to-kras-mutations-in-colorectal-cancer-cells
#19
Ángela L Riffo-Campos, Josefa Castillo, Azahara Vallet-Sánchez, Guillermo Ayala, Andrés Cervantes, Gerardo López-Rodas, Luis Franco
Several drugs used for the treatment of colorectal cancer (CRC) are targeted at the epidermal growth factor receptor, but mutations in genes of the RAS family cause resistance to these drugs. Thus, extensive research is being carried out to counterbalance this resistance. The G13D mutation of KRAS is common in humans, and we previously reported that this mutation results in the epigenetic modification of hnRNP proteins, involved in RNA splicing. As aberrant splicing often results in oncogenicity, the present study aimed to identify the genes which show altered splicing patterns in connection with the G13D KRAS mutation...
October 27, 2016: Oncology Reports
https://www.readbyqxmd.com/read/27784278/ras-testing-practices-and-ras-mutation-prevalence-among-patients-with-metastatic-colorectal-cancer-results-from-a-europe-wide-survey-of-pathology-centres
#20
Annemarie Boleij, Véronique Tack, Aliki Taylor, George Kafatos, Sophie Jenkins-Anderson, Lien Tembuyser, Els Dequeker, J Han van Krieken
BACKGROUND: Treatment options for patients with metastatic colorectal cancer (mCRC) include anti-epithelial growth factor therapies, which, in Europe, are indicated in patients with RAS wild-type tumours only and require prior mutation testing of "hot-spot" codons in exons 2, 3 and 4 of KRAS and NRAS. The aim of this study was to evaluate the implementation of RAS testing methods and estimate the RAS mutation prevalence in mCRC patients. METHODS: Overall, 194 pathology laboratories were invited to complete an online survey...
October 26, 2016: BMC Cancer
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