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https://www.readbyqxmd.com/read/28645942/mutational-heterogeneity-in-apc-and-kras-arises-at-the-crypt-level-and%C3%A2-leads-to-polyclonality-in-early-colorectal-tumorigenesis
#1
Mireia Gausachs, Ester Borras, Kyle Chang, Sara González, Daniel Azuara, Axel Delgado Amador, Adriana Lopez-Doriga, F Anthony San Lucas, Xavier Sanjuan, Maria jOSE Paules, Melissa Taggart, Gareth Davies, Erik A Ehli, Jerry Fowler, Victor Moreno, Marta Pineda, Y Nancy You, Patrick M Lynch, Conxi Lazaro, Nicholas E Navin, Paul Scheet, Ernest T Hawk, Gabriel Capella, Eduardo Vilar
Purpose:  The majority of genomic alterations causing intratumoral heterogeneity (ITH) in colorectal cancer (CRC) are thought to arise during early stages of carcinogenesis as a burst but only after truncal mutations in APC have expanded a single founder clone. We have investigated if the initial source of ITH is consequent to multiple independent lineages derived from different crypts harboring distinct truncal APC and driver KRAS mutations, thus challenging the prevailing monoclonal monocryptal model. <p>Experimental design: High-depth next-generation sequencing and SNP arrays were performed in whole lesion extracts of 37 FAP colorectal adenomas...
June 23, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28644138/comparative-analysis-of-primary-versus-relapse-refractory-dlbcl-identifies-shifts-in-mutation-spectrum
#2
Danielle M Greenawalt, Winnie S Liang, Sakina Saif, Justin Johnson, Petar Todorov, Austin Dulak, Daniel Enriquez, Rebecca Halperin, Ambar Ahmed, Vladislav Saveliev, John Carpten, David Craig, J Carl Barrett, Brian Dougherty, Michael Zinda, Stephen Fawell, Jonathan R Dry, Kate Byth
Current understanding of the mutation spectrum of relapsed/refractory (RR) tumors is limited. We performed whole exome sequencing (WES) on 47 diffuse large B cell lymphoma (DLBCL) tumors that persisted after R-CHOP treatment, 8 matched to primary biopsies. We compared genomic alterations from the RR cohort against two treatment-naïve DLBCL cohorts (n=112). While the overall number and types of mutations did not differ significantly, we identified frequency changes in DLBCL driver genes. The overall frequency of MYD88 mutant samples increased (12% to 19%), but we noted a decrease in p...
June 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28643793/genomic-rearrangements-in-sporadic-lymphangioleiomyomatosis-an-evolving-genetic-story
#3
Stephen J Murphy, Simone B Terra, Faye R Harris, Aqsa Nasir, Jesse S Voss, James B Smadbeck, Sarah H Johnson, Vishnu Serla, Jay H Ryu, Eunhee S Yi, Benjamin R Kipp, George Vasmatzis, Eva M Carmona
Sporadic lymphangioleiomyomatosis is a progressive pulmonary cystic disease resulting from the infiltration of smooth muscle-like lymphangioleiomyomatosis cells into the lung. The migratory/metastasizing properties of the lymphangioleiomyomatosis cell together with the presence of somatic mutations, primarily in the tuberous sclerosis complex gene (TSC2), lead many to consider this a low-grade malignancy. As malignant tumors characteristically accumulate somatic structural variations, which have not been well studied in sporadic lymphangioleiomyomatosis, we utilized mate pair sequencing to define structural variations within laser capture microdissected enriched lymphangioleiomyomatosis cell populations from five sporadic lymphangioleiomyomatosis patients...
June 23, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28643781/recurrent-mutation-of-igf-signalling-genes-and-distinct-patterns-of-genomic-rearrangement-in-osteosarcoma
#4
Sam Behjati, Patrick S Tarpey, Kerstin Haase, Hongtao Ye, Matthew D Young, Ludmil B Alexandrov, Sarah J Farndon, Grace Collord, David C Wedge, Inigo Martincorena, Susanna L Cooke, Helen Davies, William Mifsud, Mathias Lidgren, Sancha Martin, Calli Latimer, Mark Maddison, Adam P Butler, Jon W Teague, Nischalan Pillay, Adam Shlien, Ultan McDermott, P Andrew Futreal, Daniel Baumhoer, Olga Zaikova, Bodil Bjerkehagen, Ola Myklebost, M Fernanda Amary, Roberto Tirabosco, Peter Van Loo, Michael R Stratton, Adrienne M Flanagan, Peter J Campbell
Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours encompassing all major histological subtypes. A key finding of our study is the identification of mutations in insulin-like growth factor (IGF) signalling genes in 8/112 (7%) of cases. We validate this observation using fluorescence in situ hybridization (FISH) in an additional 87 osteosarcomas, with IGF1 receptor (IGF1R) amplification observed in 14% of tumours...
June 23, 2017: Nature Communications
https://www.readbyqxmd.com/read/28642787/mutational-signatures-are-critical-for-proper-estimation-of-purifying-selection-pressures-in-cancer-somatic-mutation-data-when-using-the-dn-ds-metric
#5
Jimmy Van den Eynden, Erik Larsson
Large cancer genome sequencing initiatives have led to the identification of cancer driver genes based on signals of positive selection in somatic mutation data. Additionally, the identification of purifying (negative) selection has the potential to identify essential genes that may be of therapeutic interest. The most widely used way of quantifying selection pressures in protein-coding genes is the dN/dS metric, which compares non-synonymous to synonymous substitution rates. In this study, we examine whether and how this metric is influenced by the mutational processes that have been active during tumor evolution...
2017: Frontiers in Genetics
https://www.readbyqxmd.com/read/28642281/utility-of-genomic-analysis-in-circulating-tumor-dna-from-patients-with-carcinoma-of-unknown-primary
#6
Shumei Kato, Nithya Krishnamurthy, Kimberly C Banks, Pradip De, Kirstin Williams, Casey Williams, Brian Leyland-Jones, Scott M Lippman, Richard B Lanman, Razelle Kurzrock
Carcinoma of unknown primary (CUP) is a rare and difficult-to-treat malignancy, the management of which might be improved by the identification of actionable driver mutations. We interrogated interrogated 54-70 genes in 442 patients with CUP using targeted clinical-grade, next-generation sequencing (NGS) of circulating tumor DNA (ctDNA). Overall, 80% of patients exhibited ctDNA alterations; 66%, ≥ 1 characterized alteration(s) excluding variants of unknown significance. TP53-associated genes were most commonly altered (37...
June 22, 2017: Cancer Research
https://www.readbyqxmd.com/read/28640953/overview-of-transgenic-mouse-models-of-myeloproliferative-neoplasms-mpns
#7
Andrew Dunbar, Abbas Nazir, Ross Levine
Myeloproliferative neoplasms (MPNs) are a class of hematologic diseases characterized by aberrant proliferation of one or more myeloid lineages and progressive bone marrow fibrosis. In 2005, seminal work by multiple groups identified the JAK2V617F mutation in a significant fraction of MPN patients. Since that time, murine models of JAK2V617F have greatly enhanced the understanding of the role of aberrant JAK-STAT signaling in MPN pathogenesis and have provided an in vivo pre-clinical platform that can be used to develop novel therapies...
June 22, 2017: Current Protocols in Pharmacology
https://www.readbyqxmd.com/read/28638489/harnessing-integrative-omics-to-facilitate-molecular-imaging-of-the-human-epidermal-growth-factor-receptor-family-for-precision-medicine
#8
REVIEW
Martin Pool, H Rudolf de Boer, Marjolijn N Lub-de Hooge, Marcel A T M van Vugt, Elisabeth G E de Vries
Cancer is a growing problem worldwide. The cause of death in cancer patients is often due to treatment-resistant metastatic disease. Many molecularly targeted anticancer drugs have been developed against 'oncogenic driver' pathways. However, these treatments are usually only effective in properly selected patients. Resistance to molecularly targeted drugs through selective pressure on acquired mutations or molecular rewiring can hinder their effectiveness. This review summarizes how molecular imaging techniques can potentially facilitate the optimal implementation of targeted agents...
2017: Theranostics
https://www.readbyqxmd.com/read/28637623/ddx41-related-myeloid-neoplasia
#9
REVIEW
Jaroslaw P Maciejewski, Richard A Padgett, Anna L Brown, Carsten Müller-Tidow
While early presentation of familial leukemia syndromes is typical, long disease anticipation may mask cases of familial traits in seemingly spontaneous disease. Germline mutations in DDX41 gene have been discovered in several leukemia families, as well as in mostly adult patients with seemingly spontaneous disease but having strong family histories of myeloid neoplasia. As with other familial genes, DDX41 mutation carriers can develop neoplasia through acquisition of another somatic mutation, thereby affecting both DDX41 alleles...
April 2017: Seminars in Hematology
https://www.readbyqxmd.com/read/28637487/the-nf1-somatic-mutational-landscape-in-sporadic-human-cancers
#10
REVIEW
Charlotte Philpott, Hannah Tovell, Ian M Frayling, David N Cooper, Meena Upadhyaya
BACKGROUND: Neurofibromatosis type 1 (NF1: Online Mendelian Inheritance in Man (OMIM) #162200) is an autosomal dominantly inherited tumour predisposition syndrome. Heritable constitutional mutations in the NF1 gene result in dysregulation of the RAS/MAPK pathway and are causative of NF1. The major known function of the NF1 gene product neurofibromin is to downregulate RAS. NF1 exhibits variable clinical expression and is characterized by benign cutaneous lesions including neurofibromas and café-au-lait macules, as well as a predisposition to various types of malignancy, such as breast cancer and leukaemia...
June 21, 2017: Human Genomics
https://www.readbyqxmd.com/read/28637000/precision-medicine-for-hepatocellular-carcinoma-driver-mutations-and-targeted-therapy
#11
REVIEW
Xiao-Xiao Ding, Qing-Ge Zhu, Shi-Ming Zhang, Lei Guan, Ting Li, Lei Zhang, Shi-Yang Wang, Wan-Li Ren, Xue-Mei Chen, Jing Zhao, Song Lin, Zhi-Zhen Liu, Yan-Xia Bai, Bing He, Hu-Qin Zhang
Hepatocellular carcinoma (HCC) is the third most frequent cause of tumor-related mortality and there are an estimated approximately 850,000 new cases annually. Most HCC patients are diagnosed at middle or advanced stage, losing the opportunity of surgery. The development of HCC is promoted by accumulated diverse genetic mutations, which confer selective growth advantages to tumor cells and are called "driver mutations". The discovery of driver mutations provides a novel precision medicine strategy for late stage HCC, called targeted therapy...
June 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28636652/integrative-analysis-of-genomic-alterations-in-triple-negative-breast-cancer-in-association-with-homologous-recombination-deficiency
#12
Masahito Kawazu, Shinya Kojima, Toshihide Ueno, Yasushi Totoki, Hiromi Nakamura, Akiko Kunita, Wei Qu, Jun Yoshimura, Manabu Soda, Takahiko Yasuda, Natsuko Hama, Mihoko Saito-Adachi, Kazuhito Sato, Shinji Kohsaka, Eirin Sai, Masako Ikemura, Shigeru Yamamoto, Tomoko Ogawa, Masashi Fukayama, Keiichiro Tada, Yasuyuki Seto, Shinichi Morishita, Shoichi Hazama, Tatsuhiro Shibata, Yoshihiro Yamashita, Hiroyuki Mano
Triple-negative breast cancer (TNBC) cells do not express estrogen receptors, progesterone receptors, or human epidermal growth factor receptor 2. Currently, apart from poly ADP-ribose polymerase inhibitors, there are few effective therapeutic options for this type of cancer. Here, we present comprehensive characterization of the genetic alterations in TNBC performed by high coverage whole genome sequencing together with transcriptome and whole exome sequencing. Silencing of the BRCA1 gene impaired the homologous recombination pathway in a subset of TNBCs, which exhibited similar phenotypes to tumors with BRCA1 mutations; they harbored many structural variations (SVs) with relative enrichment for tandem duplication...
June 21, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28636540/implementation-and-utilization-of-the-molecular-tumor-board-to-guide-precision-medicine
#13
REVIEW
Shuko Harada, Rebecca Arend, Qian Dai, Jessica A Levesque, Thomas S Winokur, Rongjun Guo, Martin J Heslin, Lisle Nabell, L Burt Nabors, Nita A Limdi, Kevin A Roth, Edward E Partridge, Gene P Siegal, Eddy S Yang
BACKGROUND: With rapid advances in genomic medicine, the complexity of delivering precision medicine to oncology patients across a university health system demanded the creation of a Molecular Tumor Board (MTB) for patient selection and assessment of treatment options. The objective of this report is to analyze our progress to date and discuss the importance of the MTB in the implementation of personalized medicine. MATERIALS AND METHODS: Patients were reviewed in the MTB for appropriateness for comprehensive next generation sequencing (NGS) cancer gene set testing based on set criteria that were in place...
June 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28633480/a-prospective-examination-of-circulating-tumor-cell-profiles-in-non-small-cell-lung-cancer-molecular-subgroups
#14
C R Lindsay, V Faugeroux, S Michiels, E Pailler, F Facchinetti, D Ou, M V Bluthgen, C Pannet, M Ngo-Camus, G Bescher, C Caramella, F Billiot, J Remon, D Planchard, J-C Soria, B Besse, F Farace
Background: We report the first study examining the clinical, numerical and biological properties of circulating tumor cells (CTCs) according to molecular subtypes of non-small cell lung cancer (NSCLC). Patients and Methods: 125 patients with treatment-naïve stage IIIb-IV NSCLC were prospectively recruited for CellSearch analysis. Anti-vimentin antibody was included for examination of CTCs to assess their mesenchymal character. Associations of total CTCs and vimentin-positive (vim +) CTCs with clinical characteristics, tumor genotype and survival were assessed...
June 19, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28630336/the-red-queen-and-king-in-finite-populations
#15
Carl Veller, Laura K Hayward, Christian Hilbe, Martin A Nowak
In antagonistic symbioses, such as host-parasite interactions, one population's success is the other's loss. In mutualistic symbioses, such as division of labor, both parties can gain, but they might have different preferences over the possible mutualistic arrangements. The rates of evolution of the two populations in a symbiosis are important determinants of which population will be more successful: Faster evolution is thought to be favored in antagonistic symbioses (the "Red Queen effect"), but disfavored in certain mutualistic symbioses (the "Red King effect")...
June 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28630229/observing-clonal-dynamics-across-spatiotemporal-axes-a-prelude-to-quantitative-fitness-models-for-cancer
#16
Andrew W McPherson, Fong Chun Chan, Sohrab P Shah
The ability to accurately model evolutionary dynamics in cancer would allow for prediction of progression and response to therapy. As a prelude to quantitative understanding of evolutionary dynamics, researchers must gather observations of in vivo tumor evolution. High-throughput genome sequencing now provides the means to profile the mutational content of evolving tumor clones from patient biopsies. Together with the development of models of tumor evolution, reconstructing evolutionary histories of individual tumors generates hypotheses about the dynamics of evolution that produced the observed clones...
June 19, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28625643/sequential-liquid-biopsies-reveal-dynamic-alterations-of-egfr-driver-mutations-and-indicate-egfr-amplification-as-a-new-mechanism-of-resistance-to-osimertinib-in-nsclc
#17
Franciele H Knebel, Fabiana Bettoni, Andrea K Shimada, Manoel Cruz, João Victor Alessi, Marcelo V Negrão, Luiz Fernando L Reis, Artur Katz, Anamaria A Camargo
Osimertinib is an EGFR-T790M-specific TKI, which has demonstrated impressive response rates in NSCLC, after failure to first-line anti-EGFR TKIs. However, acquired resistance to osimertinib is also observed and the molecular mechanisms of resistance are not yet fully understood. Monitoring and managing NSCLC patients who progressed on osimertinib is, therefore, emerging as an important clinical challenge. Sequential liquid biopsies were used to monitor a patient with EGFR-exon19del positive NSCLC, who received erlotinib and progressed through the acquisition of the EGFR-T790M mutation...
June 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28623377/collision-and-composite-tumors-radiologic-and-pathologic-correlation
#18
Calvin T Sung, Anup Shetty, Christine O Menias, Roozbeh Houshyar, Shreya Chatterjee, Thomas K Lee, Paul Tung, Mohammed Helmy, Chandana Lall
The terms composite and collision tumors have been used interchangeably throughout radiological literature. Both composite and collision tumors involve two morphologically and immunohistochemically distinct neoplasms coexisting within a single organ. However, collision tumors lack the histological cellular intermingling seen in composite tumors. Composite tumors often arise from a common driver mutation that induces a divergent histology from a common neoplastic source while collision tumors may arise from coincidental neoplastic change...
June 16, 2017: Abdominal Radiology
https://www.readbyqxmd.com/read/28622624/primary-myelofibrosis-older-age-and-high-jak2v617f-allele-burden-are-associated-with-elevated-plasma-high-sensitivity-c-reactive-protein-levels-and-a-phenotype-of-progressive-disease
#19
Giovanni Barosi, Margherita Massa, Rita Campanelli, Gabriela Fois, Paolo Catarsi, Gianluca Viarengo, Laura Villani, Valentina Poletto, Tiziana Bosoni, Umberto Magrini, Robert P Gale, Vittorio Rosti
We measured plasma levels of high-sensitivity C-reactive protein (hs-CRP) in 526 subjects with primary myelofibrosis (PMF). Thirty-eight percent had an elevated hs-CRP level (≥0.3mg/dL). Elevated hs-CRP levels were associated with a progressive disease phenotype, including anemia, high white blood cell count, low platelet count, increased splenomegaly, increased risk of blast transformation, and worse survival. Age≥52years, but no other demographic characteristics, was associated with an elevated hs-CRP level in multivariable logistic regression (odds ratio [OR], 4...
June 7, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28619758/co-targeting-of-mek-and-pdgfr-stat3-pathways-to-treat-pancreaticductal-adenocarcinoma
#20
Nisebita Sahu, Emily Chan, Felix Chu, Thinh Pham, Hartmut Koeppen, William Forrest, Mark Merchant, Jeff Settleman
Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal human diseases and remains largely refractory to available drug treatments.  Insufficient targeting of the known oncogenic drivers and activation of compensatory feedback loops and inability to prevent metastatic spread contribute to poor prognosis for this disease. The KRAS-driven MEK pathway is mutationally activated in most pancreatic cancers and is an important target for therapeutics. Using a 2-dimensional monolayer culture system as well as 3-dimensional spheroid culture system, we conducted a screen of a large panel of anti-cancer agents, and found that MEK inhibitors were most effective in targeting PDAC spheroids in comparison to monolayer cultures...
June 15, 2017: Molecular Cancer Therapeutics
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